app.R

library(shiny)
library(shinythemes)
library(fontawesome)
library(DT)
library(highcharter)
library(ggplot2)
library(limma)
library(ggrepel)
library(shinycssloaders)
library(fgsea)
library(msigdbr)
library(dplyr)
library(tidyr)
library(qs2)
library(ggpubr)
library(png)
library(grid)
library(base64enc)
logo_b64 <- base64enc::dataURI(file = "www/Charm_logo.png", mime = "image/png")
# Embedded like the logo (not served from www/), so it cannot fail to load as a static file
schematic_b64 <- base64enc::dataURI(file = "www/charm_schematic.svg", mime = "image/svg+xml")

source("plot_theme.R")       # one font/size/style for every plot
source("correlation_reference.R")   # percentile / permutation-null context for correlations
source("helper_functions.R")

# --- Data directory -----------------------------------------------------
# Points at the qs2-serialized, dtype-optimized data store produced by
# optimize_data.R. Falls back to the legacy QS_Files/ store (old `qs`
# format) if the optimized store hasn't been generated yet, so the app
# never fails to start -- NOTE: that fallback path requires the archived
# `qs` package to still be installed, since qs2 cannot read old .qs files.
# Once data/QS2_Files/ has been validated in production, delete
# data/QS_Files/ and this fallback can be removed.
DATA_DIR <- if (dir.exists("data/QS2_Files")) {
  "data/QS2_Files"
} else {
  "data/QS_Files"
}
DATA_EXT <- if (DATA_DIR == "data/QS2_Files") ".qs2" else ".qs"

qload <- function(name) {
  path <- file.path(DATA_DIR, paste0(name, DATA_EXT))
  if (DATA_EXT == ".qs2") qs2::qs_read(path) else qs::qread(path)
}

# Reference distributions for "how unusual is this correlation?" (built offline by
# build_correlation_reference.R). Optional: if the file is missing the app simply
# shows the plain correlation bar plots, as before.
CORR_REF <- tryCatch(qload("Correlation_Reference"), error = function(e) NULL)
# Same idea for binding profiles (built by build_binding_reference.R)
BIND_REF <- tryCatch(qload("Binding_Correlation_Reference"), error = function(e) NULL)
# Taller plot box when the density panel is stacked under the bar plot
corr_plot_height <- function(key) if (corr_has_ref(key)) "800px" else "500px"

# --- Lazy, single-instance dataset-family caches ---------------------------
# Charm.object (3 cell-line variants: Both/K562/HEPG2) and the Binding tables
# (6 variants: event type x cell line) are the two largest pieces of the data
# store. Eagerly loading every variant at startup (the old behavior) pulled
# everything into memory regardless of which single variant a given session
# was actually looking at -- ~6.7GB compressed on disk was ballooning to
# ~35GB in R's memory. Since every session runs in its own dedicated
# container (confirmed: no pooled/shared R process across users), it's safe
# to keep this cache at app/global scope -- there is exactly one session per
# process, so evicting the previous variant on a dataset switch can never
# pull data out from under a different concurrent user.
#
# Trade-off: switching cell lines/event types now costs a real (if brief)
# qs2 decompression instead of being instant. And a handful of features that
# genuinely compare *across* cell lines in one view (the "Similar RBPs"
# comparison-with-uploaded-file panels, and the RBP similarity network
# builder) will still materialize more than one variant at once for the
# duration of that specific action -- that's inherent to what those features
# do, not a gap in this cache.
charm_cache <- new.env(parent = emptyenv())

get_charm_object <- function(dataset) {
  key <- switch(dataset %||% "Both", "K562" = "K562", "HEPG2" = "HEPG2", "Both")
  if (is.null(charm_cache$key) || !identical(charm_cache$key, key)) {
    file <- switch(key, "K562" = "Charm.object_K562", "HEPG2" = "Charm.object_HEPG2", "Charm.object")
    charm_cache$obj <- qload(file)
    charm_cache$key <- key
    gc(FALSE)  # release the evicted variant's memory right away, not at the next scheduled GC
  }
  charm_cache$obj
}

# A few features (the splicing "compare all 3 cell lines" panels, and the
# RBP similarity network builder) genuinely need Both/K562/HEPG2 all loaded
# at the same time. Routing that through get_charm_object() one call at a
# time is actively counterproductive: get_charm_object() is a single-slot
# cache, so calling it 3x in a row for "Both" -> "K562" -> "HEPG2" evicts
# and re-decompresses from disk on every single call (no variant is ever
# still in the cache by the time the next call asks for a different one),
# which showed up as the "Both Cells" panel of these multi-way comparisons
# being the slowest/most likely to look hung -- it's always loaded (and
# evicted) first. This loads all 3 directly, independent of charm_cache, so
# each variant is read from disk exactly once per call regardless of order,
# and doesn't disturb whatever single variant get_charm_object() has cached
# for the rest of the session.
load_all_charm_variants <- function() {
  list(
    "Both Cells" = qload("Charm.object"),
    "K562"       = qload("Charm.object_K562"),
    "HEPG2"      = qload("Charm.object_HEPG2")
  )
}

binding_cache <- new.env(parent = emptyenv())

get_binding_object <- function(eventtype, dataset) {
  is_ir <- grepl("Intron Retention", eventtype %||% "", ignore.case = TRUE)
  cell  <- switch(dataset %||% "Both Cells", "K562" = "K562", "HEPG2" = "HEPG2", "Both Cells")
  key   <- paste(if (is_ir) "IR" else "ES", cell)
  if (is.null(binding_cache$key) || !identical(binding_cache$key, key)) {
    file <- if (is_ir) {
      switch(cell, "K562" = "Binding_IR_K562", "HEPG2" = "Binding_IR_HEPG2", "Binding_IR_both")
    } else {
      switch(cell, "K562" = "Binding_K562", "HEPG2" = "Binding_HEPG2", "Binding_both")
    }
    binding_cache$obj <- qload(file)
    binding_cache$key <- key
    gc(FALSE)
  }
  binding_cache$obj
}

`%||%` <- function(a, b) if (is.null(a) || (length(a) == 1 && is.na(a))) b else a

# Flexible reader for the three Discovery-mode file uploads (Expression,
# Splicing, Binding). Previously each upload handler called
# read.table(path, sep = "\t") directly, which is unforgiving in two ways
# that real user files hit in practice:
#   1. Delimiter: users frequently export from Excel with commas or
#      semicolons rather than tabs.
#   2. Line endings: a file using old Mac-style bare "\r" line terminators
#      (no "\n" at all) reads back as a single giant "line" under a plain
#      read.table() call -- confirmed via the user-supplied example file
#      example_data/AllwSG.txt, which is exactly what broke the Binding
#      Discovery upload.
# This normalizes line endings up front and auto-detects the delimiter from
# the header row (tab > comma > semicolon > whitespace, by whichever splits
# the header into the most fields) before handing off to read.table().
read_user_table <- function(path) {
  raw_bytes <- readBin(path, what = "raw", n = file.info(path)$size)
  txt <- rawToChar(raw_bytes)
  txt <- gsub("\r\n", "\n", txt, fixed = TRUE)
  txt <- gsub("\r",   "\n", txt, fixed = TRUE)

  lines <- strsplit(txt, "\n", fixed = TRUE)[[1]]
  lines <- lines[nzchar(trimws(lines))]
  if (length(lines) < 2) stop("File has no data rows.")
  header <- lines[1]

  candidates <- list(tab = "\t", comma = ",", semicolon = ";")
  field_counts <- vapply(candidates, function(d) {
    length(strsplit(header, d, fixed = TRUE)[[1]])
  }, integer(1))
  best_delim <- names(which.max(field_counts))

  if (field_counts[[best_delim]] > 1) {
    read.table(text = txt, header = TRUE, sep = candidates[[best_delim]],
               stringsAsFactors = FALSE, strip.white = TRUE, check.names = FALSE)
  } else {
    # No delimiter produced more than one field -- fall back to
    # whitespace-separated parsing (read.table's default sep = "").
    read.table(text = txt, header = TRUE, sep = "",
               stringsAsFactors = FALSE, check.names = FALSE)
  }
}

# Load small, always-needed objects once when the app starts (all under
# ~90MB combined -- not worth swapping).
sh_effect_vector       <- qload("shRNA_Efficiency")
sh_effect_vector_K562  <- qload("shRNA_Efficiency_K562")
sh_effect_vector_HEPG2 <- qload("shRNA_Efficiency_HEPG2")

# Warm the default ("Both Cells", Exon Skipping) variants so the app's
# default view loads with no extra delay, and capture the RBP/pathway name
# lists that several static UI dropdowns need regardless of which dataset
# variant ends up active later. Name sets are identical across all
# Charm.object / Binding_* variants (confirmed via direct inspection during
# the qs2 migration), so these lists stay valid even after the cache above
# evicts the object they were read from.
.default_charm <- get_charm_object("Both")
ALL_RBP_NAMES <- names(.default_charm)
HALLMARK_CHOICES <- sort(unique(.default_charm[["RBFOX2"]]$GSEA$pathway))

.default_binding_es <- get_binding_object("Exon Skipping", "Both Cells")
ALL_BINDING_RBP_NAMES_ES <- names(.default_binding_es)
# Intron Retention isn't the default event type, so this read gets evicted
# again the moment a session actually requests ES data -- that's fine, it's
# a one-time startup cost just to capture the name list.
ALL_BINDING_RBP_NAMES_IR <- names(qload("Binding_IR_both"))
rm(.default_charm, .default_binding_es)

#Similarity stuff
similar_expression_all    <- qload("RBPs.t_All")
similar_expression_K562   <- qload("RBPs.t_K562")
similar_expression_HEPG2  <- qload("RBPs.t_HEPG2")
similar_gsea_all          <- qload("RBPs.gsea_All")
similar_gsea_K562         <- qload("RBPs.gsea_K562")
similar_gsea_HEPG2        <- qload("RBPs.gsea_HEPG2")

#For eCLIPSE
eCLIPSE_Intron_full  <- qload("eCLIPSE_INTRONRET")
eCLIPSE_BigExon_full <- qload("eCLIPSE_BIGEXON")

#SearchBarPopulation
GenesBoth   <- qload("AvailableGenes_both")
GenesK562   <- qload("AvailableGenes_K562")
GenesHEPG2  <- qload("AvailableGenes_HEPG2")
EventsBoth  <- qload("AvailableEvents_Both")
EventsK562  <- qload("AvailableEvents_K562")
EventsHEPG2 <- qload("AvailableEvents_HEPG2")

#Binding similarity stuff — loaded lazily on first Network tab use (see server)
# similar_binding_* objects are loaded via the binding_sim_cache reactive below


ui <- fluidPage(
  theme = shinytheme("flatly"),
  
  # Custom CSS for bold tabs
  tags$head(
    tags$style(HTML("
      .search-box {
        border-radius: 20px;
        padding: 6px 12px;
        border: 1px solid #ccc;
        box-shadow: inset 0 1px 3px rgba(0,0,0,0.1);
        font-size: 14px;
      }
      .search-box:focus {
        border-color: #2c3e50;
        outline: none;
        box-shadow: 0 0 5px rgba(44,62,80,0.4);
      }
      .charm-home { max-width: 1180px; margin: 0 auto; padding: 0 20px 60px; }
      .charm-hero { display: flex; align-items: center; justify-content: center; gap: 22px;
                    margin: 22px 0 6px; flex-wrap: wrap; }
      .charm-hero-logo img { height: 90px; }
      .charm-hero-text h1 { margin: 0; font-weight: bold; }
      .charm-hero-text h4 { margin: 2px 0 0; font-weight: bold; }
      .charm-section { margin: 30px 0; }
      .charm-section h2 { text-align: center; font-weight: bold; font-size: 26px; margin: 0 0 14px; }
      .charm-lead { max-width: 900px; margin: 0 auto 10px; font-size: 15.5px; line-height: 1.55;
                    color: #333; text-align: center; }
      .charm-schematic { display: block; width: 100%; max-width: 1100px; height: auto; margin: 18px auto 6px; }
      .charm-coverage { text-align: center; font-size: 12.5px; color: #666; margin: 4px 0 0; }
      .charm-layers { display: grid; grid-template-columns: repeat(auto-fit, minmax(280px, 1fr));
                      gap: 18px; margin: 8px 0 0; }
      .charm-layer { background: #f6f7f7; border-top: 3px solid #2c3e50; border-radius: 6px; padding: 14px 18px; }
      .charm-layer h4 { display: inline-block; margin: 0 0 6px 8px; font-weight: bold; }
      .charm-layer-num { display: inline-flex; width: 26px; height: 26px; border-radius: 50%;
                         background: #2c3e50; color: #fff; font-weight: bold; align-items: center;
                         justify-content: center; font-size: 14px; }
      .charm-layer p { margin: 0; font-size: 14px; color: #333; }
      .charm-layer { cursor: pointer; transition: transform .15s, box-shadow .15s; }
      .charm-layer:hover { transform: translateY(-3px); box-shadow: 0 6px 16px rgba(0,0,0,.15); }
      .charm-layer-go { display: block; margin-top: 8px; font-size: 13px; font-weight: bold; color: #2c3e50; }
      .charm-questions { display: grid; grid-template-columns: repeat(auto-fit, minmax(340px, 1fr)); gap: 12px 22px; }
      .charm-q { border-left: 4px solid #BA3B46; padding: 6px 0 6px 14px; }
      .charm-q b { display: block; font-size: 15px; margin-bottom: 2px; }
      .charm-q span { font-size: 13.5px; color: #444; }
      .charm-cards { display: flex; gap: 24px; justify-content: center; flex-wrap: wrap; }
      .charm-card { flex: 1 1 420px; max-width: 560px; cursor: pointer; background: #EAEBEB; color: black;
                    border: 2px solid #2c3e50; border-radius: 20px; overflow: hidden; text-align: center;
                    transition: transform .12s ease, box-shadow .12s ease; }
      .charm-card:hover { transform: translateY(-3px); box-shadow: 0 6px 16px rgba(0,0,0,.18); }
      .charm-card-body { padding: 22px 24px 24px; }
      .charm-card-body h3 { margin: 4px 0 8px; font-weight: bold; }
      .charm-card-body p { margin: 0; }
      .charm-tutorial { text-align: center; margin: 16px 0 0; font-size: 14px; }
      .charm-footer { text-align: center; font-size: 12px; color: #666; max-width: 900px;
                      margin: 0 auto; padding-top: 14px; border-top: 1px solid #e0e0e0; }
      #charm-info { position: fixed; bottom: 20px; right: 20px; z-index: 1000; text-align: right; }
      #charm-info-btn { background: #EAEBEB; border: 1px solid #2c3e50; border-radius: 999px;
                        padding: 5px 13px; font-size: 12px; color: #2c3e50; cursor: pointer; }
      #charm-info-btn:hover { background: #dfe1e1; }
      #charm-info-panel { display: none; position: absolute; bottom: 100%; right: 0; margin-bottom: 8px;
                          min-width: 130px; background: #EAEBEB; padding: 8px 12px; border-radius: 10px;
                          border: 1px solid #2c3e50; text-align: center; box-shadow: 0 4px 12px rgba(0,0,0,.2); }
      #charm-info.open #charm-info-panel { display: block; }
    ")),
    tags$script(HTML("
      Shiny.addCustomMessageHandler('toggleCursor', function(state) {
        document.body.style.cursor = state ? 'wait' : 'default';
      });
      Shiny.addCustomMessageHandler('clickButton', function(msg) {
        setTimeout(function() {
          var btn = document.getElementById(msg.id);
          if (btn) btn.click();
        }, msg.delay || 300);
      });
      document.addEventListener('click', function(e) {
        var w = document.getElementById('charm-info');
        if (!w) return;
        var btn = document.getElementById('charm-info-btn');
        if (e.target.closest('#charm-info-btn')) {
          var open = w.classList.toggle('open');
          btn.setAttribute('aria-expanded', open ? 'true' : 'false');
        } else if (!e.target.closest('#charm-info-panel') || e.target.closest('#charm-info-panel a')) {
          w.classList.remove('open');
          btn.setAttribute('aria-expanded', 'false');
        }
      });
      document.addEventListener('keydown', function(e) {
        if (e.key === 'Escape') {
          var w = document.getElementById('charm-info');
          if (w) { w.classList.remove('open'); document.getElementById('charm-info-btn').setAttribute('aria-expanded', 'false'); }
        }
      });
      Shiny.addCustomMessageHandler('showStatus', function(msg) {
        var bar = document.getElementById('charm-status-bar');
        if (!bar) return;
        if (msg.show) {
          bar.innerText = msg.text || 'Loading\u2026';
          bar.style.display = 'block';
        } else {
          bar.style.display = 'none';
        }
      });
    ")),
    
    # Persistent status bar — shown during long computations
    tags$div(
      id = "charm-status-bar",
      style = "display:none; position:fixed; top:0; left:0; right:0; z-index:9999;
               background:#2c3e50; color:white; font-weight:bold; font-size:14px;
               padding:10px 20px; text-align:center;
               box-shadow:0 2px 8px rgba(0,0,0,0.3);"
    )
  ),
  
  # Tabset with 5 tabs
  tabsetPanel(
    type = "tabs",
    id = "main_tabs",
    
    # Home tab
    tabPanel(
      tagList(fa("home", fill = "black", height = "1em"), " Home"),
      value = "Home",
      div(
        class = "charm-home",

        # ── Hero (compact) ──────────────────────────────────────────────────
        div(
          class = "charm-hero",
          div(class = "charm-hero-logo", tags$img(src = logo_b64, alt = "CHARM logo")),
          div(
            class = "charm-hero-text",
            tags$h1("CHARM"),
            tags$h4("Comprehensive Hub of Alternative Regulatory Mapping")
          )
        ),

        # ── Why CHARM: the biological motivation ────────────────────────────
        div(
          class = "charm-section",
          tags$h2("Why CHARM?"),
          tags$p(
            class = "charm-lead",
            "RNA-binding proteins (RBPs) govern nearly every stage of RNA metabolism, and their dysfunction is linked to ",
            "neurodegeneration, viral infection, ageing and cancer. Among their roles, alternative splicing is particularly ",
            "consequential, and it depends on where an RBP binds."
          ),
          tags$p(
            class = "charm-lead",
            "ENCODE provides eCLIP binding and knockdown RNA-seq for over a hundred RBPs, but turning them into ",
            "splicing maps takes custom, code-heavy pipelines. CHARM removes that barrier, putting RBP ",
            tags$b("expression, splicing and binding"), " side by side in a single no-code app."
          ),
          tags$img(class = "charm-schematic", src = schematic_b64,
                   alt = "Schematic: an RBP binds pre-mRNA near an alternatively spliced region (binding), changes splicing outcome (splicing) and alters gene expression. CHARM covers all three layers."),
          tags$p(
            class = "charm-coverage",
            sprintf("Currently covering %d RBPs with expression and splicing data and %d with eCLIP binding maps, ",
                    length(ALL_RBP_NAMES), length(ALL_BINDING_RBP_NAMES_ES)),
            "from ENCODE knockdown and eCLIP experiments in HepG2 and K562 cells."
          )
        ),

        # ── What each layer adds ────────────────────────────────────────────
        div(
          class = "charm-layers",
          div(class = "charm-layer",
              onclick = "Shiny.setInputValue('home_go_layer', 'Binding', {priority: 'event'});",
              div(class = "charm-layer-num", "1"),
              tags$h4("Binding"),
              tags$p("Where does an RBP bind, and what are its consequences? RNA splicing maps from eCLIP show where it binds around affected events, helping to separate direct targets from indirect ones."),
              tags$span(class = "charm-layer-go", "Open Binding \u2192")),
          div(class = "charm-layer",
              onclick = "Shiny.setInputValue('home_go_layer', 'Splicing', {priority: 'event'});",
              div(class = "charm-layer-num", "2"),
              tags$h4("Splicing"),
              tags$p("Which splicing events depend on the RBP? Changes in exon skipping and intron retention (dPSI) after knockdown, across VastDB-annotated events."),
              tags$span(class = "charm-layer-go", "Open Splicing \u2192")),
          div(class = "charm-layer",
              onclick = "Shiny.setInputValue('home_go_layer', 'Expression', {priority: 'event'});",
              div(class = "charm-layer-num", "3"),
              tags$h4("Expression"),
              tags$p("Which genes and cellular programs change? Differential expression after knockdown, with Hallmark gene-set enrichment."),
              tags$span(class = "charm-layer-go", "Open Expression \u2192"))
        ),

        # ── Questions CHARM can answer ──────────────────────────────────────
        div(
          class = "charm-section",
          tags$h2("Questions CHARM helps you answer"),
          div(
            class = "charm-questions",
            div(class = "charm-q", tags$b("How does an RBP regulate splicing?"),
                tags$span("Generate RNA splicing maps for many RBPs, and see how their knockdown affects these maps.")),
            div(class = "charm-q", tags$b("Is an RBP active even though its expression has not changed?"),
                tags$span("Detect changes in RBP function, such as relocalisation or a lost partner, through its binding rather than its expression.")),
            div(class = "charm-q", tags$b("Do two RBPs act together?"),
                tags$span("See whether knocking down one perturbs the binding of another, hinting at their interaction.")),
            div(class = "charm-q", tags$b("Which RBP could explain my data?"),
                tags$span("Upload an expression or splicing signature and rank the RBPs whose knockdown looks most like it.")),
            div(class = "charm-q", tags$b("What controls my gene, event or pathway?"),
                tags$span("Search by gene, splicing event or Hallmark gene set to find the RBPs that move it.")),
            div(class = "charm-q", tags$b("Is the effect cell-type specific?"),
                tags$span("Compare HepG2 and K562, or look at both together."))
          )
        ),

        # ── Entry points ────────────────────────────────────────────────────
        div(
          class = "charm-section",
          tags$h2("Start here"),
          div(
            class = "charm-cards",
            div(
              class = "charm-card",
              onclick = "Shiny.setInputValue('home_go_explore', Math.random());",
              div(class = "charm-card-body",
                  div(class = "charm-card-icon", fa("globe", fill = "black", height = "2em")),
                  tags$h3("Explore"),
                  tags$p("Investigate how a known RBP affects expression, splicing, and binding, based on ENCODE's gene silencing series and eCLIP data."))
            ),
            div(
              class = "charm-card",
              onclick = "Shiny.setInputValue('home_go_discover', Math.random());",
              div(class = "charm-card-body",
                  div(class = "charm-card-icon", fa("map", fill = "black", height = "2em")),
                  tags$h3("Discovery"),
                  tags$p("Upload your own expression, splicing, or binding data to discover which RBPs are most likely altered in your biological system."))
            )
            # DISABLED: Network module intentionally commented out. Code kept intact for a future redesign; to restore, uncomment this block, the Home card, and the home_go_network observer. [Home card]
            # ,div(
            # class = "charm-card",
            # onclick = "Shiny.setInputValue('home_go_network', Math.random());",
            # div(class = "charm-card-body",
            # div(class = "charm-card-icon", fa("project-diagram", fill = "black", height = "2em")),
            # tags$h3("Network"),
            # tags$p("Explore multi-omic RBP similarity via an integrated network combining expression, splicing, and binding layers."))
            # )
          ),
          tags$p(class = "charm-tutorial",
                 "New to CHARM? ",
                 tags$a(href = "https://diseasetranscriptomicslab.github.io/CHARM/", target = "_blank",
                        "Read the step-by-step tutorial."))
        ),

        # ── Footer: data sources and citation ───────────────────────────────
        div(
          class = "charm-footer",
          "CHARM is developed by the Disease Transcriptomics Lab. Data: ENCODE (Luo et al., 2020); ",
          "splicing quantified with betAS (Ferreira et al., 2024) using VastDB event IDs (Tapial et al., 2017). ",
          "Archived at ", tags$a(href = "https://doi.org/10.5281/zenodo.21724194", target = "_blank",
                                 "doi:10.5281/zenodo.21724194"), "."
        )
      )
    ),
    
    # Expression tab
    tabPanel(
      tagList(fa("dna", fill = "black", height = "1em"), " Expression"),
      value = "Expression",
      fluidPage(
        fluidRow(
          # Left sidebar
          # Left sidebar (width = 3)
          column(
            width = 3,
            wellPanel(
              
              # --- Mode selection ---
              radioButtons(
                inputId = "expr_mode",
                label = "Select mode:",
                choices = c("Explore", "Discovery"),
                selected = "Explore"
              ),
              
              # --- Explore Mode ---
              conditionalPanel(
                condition = "input.expr_mode == 'Explore'",
                
                # Dataset selection
                selectInput(
                  inputId = "expr_dataset",
                  label = "Select option:",
                  choices = c("Both Cells", "K562", "HEPG2", "Similar RBPs")
                ),
                
                # ---- Search by RBP ----
                div(
                  style = "margin-top: 15px;",
                  tags$h5("Search by RBP"),
                  tags$p("Find out how RBPs influence expression and gene set enrichment",
                         style = "font-size: 12px; color: #666; margin-top: -5px;"),
                  div(
                    style = "display: flex; align-items: center;",
                    selectizeInput(
                      inputId = "expr_search_rbp",
                      label = NULL,
                      choices = NULL,   # dynamically populated in server
                      multiple = FALSE,
                      options = list(placeholder = "RBP"),
                      width = "400px"
                    ),
                    conditionalPanel(
                      condition = "input.expr_dataset != 'Similar RBPs'",
                      div(
                        style = "display: flex; align-items: center; margin-left: 10px;",
                        actionButton("search_btn_rbp", tagList(fa("search"), " Search"),
                                     class = "btn btn-primary", style = "margin-right: 10px; border-radius: 20px;"),
                        actionButton("reset_btn_rbp", tagList(fa("redo"), " Reset"),
                                     class = "btn btn-secondary", style = "border-radius: 20px;")
                      )
                    )
                  )
                ),
                
                # ---- Search by Gene (hidden for Similar RBPs) ----
                conditionalPanel(
                  condition = "input.expr_dataset != 'Similar RBPs'",
                  div(
                    style = "margin-top: 25px;",
                    tags$h5("Search by Gene"),
                    selectizeInput(
                      inputId = "expr_search_gene",
                      label = NULL,
                      choices = NULL,   # dynamically populated in server
                      multiple = FALSE,
                      options = list(placeholder = "Gene"),
                      width = "400px"
                    ),
                    div(
                      style = "margin-top: 5px;",
                      actionButton("search_btn_gene", tagList(fa("search"), " Search"),
                                   class = "btn btn-primary", style = "margin-right: 10px; border-radius: 20px;"),
                      actionButton("reset_btn_gene", tagList(fa("redo"), " Reset"),
                                   class = "btn btn-secondary", style = "border-radius: 20px;")
                    )
                  )
                ),
                
                # ---- Search by Hallmark Gene Set (hidden for Similar RBPs) ----
                conditionalPanel(
                  condition = "input.expr_dataset != 'Similar RBPs'",
                  div(
                    style = "margin-top: 25px;",
                    tags$h5("Search by Hallmark Gene Set"),
                    selectizeInput(
                      inputId = "expr_search_hallmark",
                      label = NULL,
                      choices = NULL,   # dynamically populated in server
                      multiple = FALSE,
                      options = list(placeholder = "Hallmark Gene Set"),
                      width = "400px"
                    ),
                    div(
                      style = "margin-top: 5px;",
                      actionButton("search_btn_hallmark", tagList(fa("search"), " Search"),
                                   class = "btn btn-primary", style = "margin-right: 10px; border-radius: 20px;"),
                      actionButton("reset_btn_hallmark", tagList(fa("redo"), " Reset"),
                                   class = "btn btn-secondary", style = "border-radius: 20px;")
                    )
                  )
                ),
                
                # ---- Similar RBPs options (single, no duplication) ----
                
                conditionalPanel(
                  condition = "input.expr_dataset == 'Similar RBPs'",
                  
                  # Correlation type
                  radioButtons(
                    inputId = "similar_mode",
                    label = "Select correlation type:",
                    choices = c("By Gene Expression" = "expr", "By Gene Set Enrichment" = "gsea"),
                    selected = "expr",
                    inline = TRUE
                  ),
                  
                  # Expression correlation inputs - ONLY show when expr mode is selected
                  conditionalPanel(
                    condition = "input.similar_mode == 'expr'",
                    selectizeInput(
                      inputId = "similar_rbps_select_expr",
                      label = "Compare with specific RBPs (optional)",
                      choices = NULL,
                      multiple = TRUE,
                      options = list(placeholder = "Select one or more RBPs")
                    ),
                    numericInput("correl_num_expr", "Show top N correlated RBPs (optional):", value = NA, min = 1),
                    numericInput("n_pos_expr", "Show top N positive correlations (optional):", value = NA, min = 1),
                    numericInput("n_neg_expr", "Show top N negative correlations (optional):", value = NA, min = 1)
                  ),
                  
                  # GSEA correlation inputs - ONLY show when gsea mode is selected
                  conditionalPanel(
                    condition = "input.similar_mode == 'gsea'",
                    selectizeInput(
                      inputId = "similar_rbps_select_gsea",
                      label = "Compare with specific RBPs (optional)",
                      choices = NULL,
                      multiple = TRUE,
                      options = list(placeholder = "Select one or more RBPs")
                    ),
                    numericInput("correl_num_gsea", "Show top N correlated RBPs (optional):", value = NA, min = 1),
                    numericInput("n_pos_gsea", "Show top N positive correlations (optional):", value = NA, min = 1),
                    numericInput("n_neg_gsea", "Show top N negative correlations (optional):", value = NA, min = 1)
                  ),
                  
                  # Plot / Reset buttons
                  div(
                    style = "display: flex; align-items: center; margin-top: 15px;",
                    actionButton("similar_plot_btn", tagList(fa("chart-line"), " Plot"),
                                 class = "btn btn-primary", style = "margin-right: 10px; border-radius: 20px;"),
                    actionButton("similar_reset_btn", tagList(fa("redo"), " Reset"),
                                 class = "btn btn-secondary", style = "border-radius: 20px;")
                  )
                )
              ),
              
              # --- Discovery Mode: User File Upload ---
              conditionalPanel(
                condition = "input.expr_mode == 'Discovery'",
                hr(),
                tags$p("Alternatively, upload your own table with differential expression values. Data must have a header, and the first column must be the HGNC gene symbol, and the second column the t-stats."),
                fileInput("user_file_expr", "Upload your file:", accept = c(".txt", ".csv", ".tsv")),
                uiOutput("file_warning_expr"),
                uiOutput("user_file_options")
              )
            )
          )
          ,
          # Right content area
          column(
            width = 9,
            tags$h3("Expression Results"),
            conditionalPanel(
              condition = "input.expr_mode == 'Explore'",
              uiOutput("expr_nav_bar")
            ),
            
            # --- Explore Mode (default mode) ---
            conditionalPanel(
              condition = "input.expr_mode == 'Explore' && input.expr_dataset != 'Similar RBPs'",
              
              # --- Top panel: shows gene OR hallmark plot, whichever was searched most recently ---
              # (server-controlled visibility, see expr_top_panel_ui in server)
              uiOutput("expr_top_panel_ui"),
              
              # --- Default RBP plots ---
              fluidRow(
                column(width = 6,
                  plotOutput("expr_violin", height = "400px"),
                  uiOutput("dl_ui_expr_violin")
                ),
                column(
                  width = 6,
                  plotOutput("shrna_plot"),
                  uiOutput("dl_ui_shrna"),
                  uiOutput("shrna_warning")
                )
              ),
              fluidRow(
                column(width = 6,
                  highchartOutput("volcano_plot", height = "450px"),
                  uiOutput("dl_ui_volcano")
                ),
                column(width = 6,
                  DTOutput("volcano_table"),
                  uiOutput("dl_ui_volcano_table")
                )
              ),
              fluidRow(
                column(width = 6,
                  plotOutput("gsea_plot", height = "600px"),
                  uiOutput("dl_ui_gsea")
                ),
                column(width = 6,
                  DTOutput("geneset_table"),
                  uiOutput("dl_ui_geneset_table")
                )
              )
            ),
            
            # --- Similar RBPs (Explore Mode, special layout) ---
            conditionalPanel(
              condition = "input.expr_mode == 'Explore' && input.expr_dataset == 'Similar RBPs'",
              uiOutput("similar_expr_plots")
            ),
            
            # --- Discovery Mode ---
            conditionalPanel(
              condition = "input.expr_mode == 'Discovery'",
              uiOutput("userfilesimilar_expr"),
              uiOutput("userfilesimilar_gsea")
            )
          )
        )
      )
    ),
    
    # Splicing tab
    tabPanel(
      tagList(fa("scissors", fill = "black", height = "1em"), " Splicing"),
      value = "Splicing",
      fluidPage(
        fluidRow(
          column(
            width = 3,
            wellPanel(
              radioButtons("splice_mode", "Select mode:", choices = c("Explore", "Discovery"), selected = "Explore"),
              
              conditionalPanel(
                condition = "input.splice_mode == 'Explore'",
                selectInput(
                  "splice_dataset", "Select option:",
                  choices = c("Both Cells", "K562", "HEPG2", "Similar RBPs")
                ),
                
                # ---- Search by RBP (always visible) ----
                div(
                  style = "margin-top: 15px;",
                  tags$h5("Search by RBP"),
                  tags$p(
                    "Visualize how splicing of an RBP impacts alternative splicing across datasets.",
                    style = "font-size: 12px; color: #666; margin-top: -5px;"
                  ),
                  div(
                    style = "display: flex; align-items: center;",
                    selectizeInput(
                      inputId = "splice_search",
                      label = NULL,
                      choices = NULL,
                      multiple = FALSE,
                      options = list(placeholder = "RBP"),
                      width = "400px"
                    ),
                    conditionalPanel(
                      condition = "input.splice_dataset != 'Similar RBPs'",
                      div(
                        style = "display: flex; align-items: center; margin-left: 10px;",
                        actionButton(
                          "splice_search_btn",
                          tagList(fa("search"), " Search"),
                          class = "btn btn-primary",
                          style = "margin-right: 10px; border-radius: 20px;"
                        ),
                        actionButton(
                          "splice_reset_btn",
                          tagList(fa("redo"), " Reset"),
                          class = "btn btn-secondary",
                          style = "border-radius: 20px;"
                        )
                      )
                    )
                  )
                ),
                
                # ---- Search by Event ID (hidden when Similar RBPs is selected) ----
                conditionalPanel(
                  condition = "input.splice_dataset != 'Similar RBPs'",
                  div(
                    style = "margin-top: 25px;",
                    tags$h5("Search by Event ID"),
                    tags$p(
                      list(
                        "Find out which RBPs most strongly regulate a specific splicing event. Event IDs are obtained from ",
                        tags$a(
                          href = "https://vastdb.crg.eu/",
                          "VastDB",
                          target = "_blank",
                          style = "color: #007bff; text-decoration: none;"
                        ),
                        "."
                      ),
                      style = "font-size: 12px; color: #666; margin-top: -5px;"
                    ),
                    div(
                      style = "display: flex; align-items: center;",
                      selectizeInput(
                        inputId = "splice_search_event",   # <-- consistent ID
                        label = NULL,
                        choices = NULL,
                        multiple = FALSE,
                        options = list(placeholder = "Event ID"),
                        width = "400px"
                      ),
                      div(
                        style = "display: flex; align-items: center; margin-left: 10px;",
                        actionButton(
                          "search_btn_event",
                          tagList(fa("search"), " Search"),
                          class = "btn btn-primary",
                          style = "margin-right: 10px; border-radius: 20px;"
                        ),
                        actionButton(
                          "splice_event_reset_btn",
                          tagList(fa("redo"), " Reset"),
                          class = "btn btn-secondary",
                          style = "border-radius: 20px;"
                        )
                      )
                    )
                  )
                ),
                conditionalPanel(
                  condition = "input.splice_dataset == 'Similar RBPs'",
                  selectizeInput("similar_rbps_select_splice", "Compare with specific RBPs (optional)", choices = NULL, multiple = TRUE, options = list(placeholder = "Select one or more RBPs")),
                  numericInput("correl_num_splice", "Show top N correlated RBPs (optional):", value = NA, min = 1),
                  numericInput("n_pos_splice", "Show top N positive correlations (optional):", value = NA, min = 1),
                  numericInput("n_neg_splice", "Show top N negative correlations (optional):", value = NA, min = 1),
                  div(
                    style = "display: flex; align-items: center; margin-top: 15px;",
                    actionButton("similar_plot_btn_splice", tagList(fa("chart-line"), " Plot"), class = "btn btn-primary", style = "margin-right: 10px; border-radius: 20px;"),
                    actionButton("similar_reset_btn_splice", tagList(fa("redo"), " Reset"), class = "btn btn-secondary", style = "border-radius: 20px;")
                  )
                )
              ),
              conditionalPanel(
                condition = "input.splice_mode == 'Discovery'",
                hr(),
                tags$p(
                  list(
                    "Alternatively, upload your own table with differential splicing values. Table must be directly obtained from ",
                    tags$a(
                      href   = "https://compbio.imm.medicina.ulisboa.pt/app/betAS",
                      "betAS",
                      target = "_blank",
                      style  = "color: #007bff; text-decoration: none;"
                    ),
                    "."
                  )
                ),
                fileInput("user_file_splice", "Upload your file:", accept = c(".txt", ".csv", ".tsv")),
                uiOutput("file_warning_splice"),
                uiOutput("user_file_options_splice")
              )
            )
          ),
          #Right Side, where plots will appear
          # Right Side, where plots will appear
          column(
            width = 9,
            tags$h3("Splicing Data Results"),
            conditionalPanel(
              condition = "input.splice_mode == 'Explore'",
              uiOutput("splice_nav_bar")
            ),
            
            # --- Explore Mode (default mode, NOT Similar RBPs) ---
            conditionalPanel(
              condition = "input.splice_mode == 'Explore' && input.splice_dataset != 'Similar RBPs'",
              
              # --- Top panel: Event ID plot, shown when searched (server-controlled) ---
              uiOutput("splice_top_panel_ui"),
              
              # --- Default Explore-Mode Plots ---
              fluidRow(
                column(width = 6,
                  plotOutput("violin_splice_plot", height = "400px"),
                  uiOutput("dl_ui_splice_violin")
                ),
                column(width = 6,
                  plotOutput("plot_shrna_effect", height = "400px"),
                  uiOutput("dl_ui_shrna_splice")
                )
              ),
              fluidRow(
                column(width = 6,
                  highchartOutput("plot_splice_volcano", height = "450px"),
                  uiOutput("dl_ui_splice_volcano")
                ),
                column(width = 6,
                  DTOutput("splice_volcano_table"),
                  uiOutput("dl_ui_splice_volcano_table")
                )
              )
            ),
            
            # --- Explore Mode: Similar RBPs ---
            conditionalPanel(
              condition = "input.splice_mode == 'Explore' && input.splice_dataset == 'Similar RBPs'",
              uiOutput("similar_splice_plots")
            ),
            
            # --- Discovery Mode ---
            conditionalPanel(
              condition = "input.splice_mode == 'Discovery'",
              shinycssloaders::withSpinner(
                plotOutput("user_file_initial_plot_splice", height = "420px"),
                type = 6
              ),
              uiOutput("dl_ui_splice_initial"),
              br(),
              uiOutput("similar_splice_plots_file")
            )
          )
        )
      )
    ),
    
    # Binding tab
    tabPanel(
      tagList(fa("link", fill = "black", height = "1em"), " Binding"),
      value = "Binding",
      fluidPage(
        fluidRow(
          column(
            width = 3,
            wellPanel(
              radioButtons("binding_eventtype", "Event Type:",
                           choices = c("Exon Skipping", "Intron Retention"),
                           selected = "Exon Skipping"),
              
              radioButtons("binding_mode", "Select mode:",
                           choices = c("Explore", "Discovery"),
                           selected = "Explore"),
              
              # -------------------------
              # EXPLORE MODE
              # -------------------------
              conditionalPanel(
                condition = "input.binding_mode == 'Explore'",
                
                selectInput("binding_dataset", "Select option:",
                            choices = c("Both Cells", "K562", "HEPG2", "Similar Profiles")),
                
                div(
                  style = "display: flex; align-items: center; margin-top: 15px;",
                  selectizeInput("binding_search", NULL,
                                 choices = NULL, multiple = FALSE,
                                 options = list(placeholder = "RBP"),
                                 width = "400px"),
                  actionButton("search_btn",
                               tagList(fa("search"), " Search"),
                               class = "btn btn-primary",
                               style = "margin-left: 10px; border-radius: 20px;"),
                  actionButton("reset_btn",
                               tagList(fa("redo"), " Reset"),
                               class = "btn btn-secondary",
                               style = "margin-left: 10px; border-radius: 20px;")
                ),
                
                # Show only when not "Similar RBPs"
                conditionalPanel(
                  condition = "input.binding_dataset != 'Similar Profiles'",
                  
                  
                  hr(),
                  tags$h5("eCLIPSE Binding Map"),
                  tags$p("Investigate where a chosen RBP binds relative to splicing events regulated by the shRNA knockdown above. Select one target for a full binding map, or multiple targets for a heatmap overview.",
                         style = "font-size: 12px; color: #666; margin-top: -5px;"),
                  
                  uiOutput("binding_target_ui"),
                  uiOutput("binding_target_warning"),
                  uiOutput("binding_dpsi_ui"),
                  
                  selectInput("binding_metric", "Metric:",
                              choices = c("FDR", "EffectSize"),
                              selected = "FDR")
                ),
                
                # Show only when "Similar Profiles" is selected.
                # NOTE: the query-profile UI (free-text "RBP__Target" query
                # selector, "compare with specific profiles" list, and the
                # 6-panel Both Cells/K562/HEPG2 x inc/dec results) used to
                # live under Discovery mode (behind the file-upload gate),
                # even though it needs no uploaded file at all -- it only
                # reads the same precomputed binding-similarity objects this
                # Explore-mode panel already uses. It belongs here instead;
                # see output$binding_similar_profiles_options below.
                conditionalPanel(
                  condition = "input.binding_dataset == 'Similar Profiles'",
                  uiOutput("binding_similar_profiles_options")
                )
              ),
              
              # -------------------------
              # DISCOVERY MODE
              # -------------------------
              conditionalPanel(
                condition = "input.binding_mode == 'Discovery'",
                hr(),
                tags$p(
                  list(
                    "Alternatively, upload your own table with differential splicing values. Table must be directly obtained from ",
                    tags$a(
                      href   = "https://compbio.imm.medicina.ulisboa.pt/app/betAS",
                      "betAS",
                      target = "_blank",
                      style  = "color: #007bff; text-decoration: none;"
                    ),
                    "."
                  )
                ),
                fileInput("user_file_binding", "Upload your file:", accept = c(".txt", ".csv", ".tsv")),
                uiOutput("file_warning_binding"),
                uiOutput("binding_discovery_options")
              )
            )
          ),
          
          # =========================================================
          # RIGHT SIDE: RESULTS + PLOT AREA
          # =========================================================
          column(
            width = 9,
            
            tags$h3("Binding Data Results"),
            conditionalPanel(
              condition = "input.binding_mode == 'Explore'",
              uiOutput("binding_nav_bar")
            ),
            
            div(
              tagList(
                fa("clock", fill = "#555", height = "0.9em"),
                " Selecting many targets (or \"All\") may take a moment — larger selections require computing binding profiles for each target."
              ),
              style = "border: 1px solid #c8cbcf;
        background-color: #f8f9fa;
        padding: 7px 10px;
        border-radius: 6px;
        font-size: 12px;
        color: #555;
        margin-bottom: 12px;"
            ),
            
            # Explore Mode plot
            conditionalPanel(
              condition = "input.binding_mode == 'Explore' && input.binding_dataset != 'Similar Profiles'",
              uiOutput("binding_plot_ui")
            ),
            
            # Explore Mode — Similar Profiles plot
            conditionalPanel(
              condition = "input.binding_mode == 'Explore' && input.binding_dataset == 'Similar Profiles'",
              uiOutput("binding_similar_profiles_plot_ui")
            ),

            # Discovery Mode plot
            conditionalPanel(
              condition = "input.binding_mode == 'Discovery'",
              uiOutput("binding_discovery_plot_ui")
            )
            
          )
        )
      )
    )
    
    # DISABLED: Network module intentionally commented out. Code kept intact for a future redesign; to restore, uncomment this block, the Home card, and the home_go_network observer.
    # tabPanel(
    #   tagList(fa("project-diagram", fill = "black", height = "1em"), " Network"),
    #   value = "Network",
    #   fluidPage(
    #     fluidRow(
    #       # ── Left sidebar ──────────────────────────────────────────────────
    #       column(
    #         width = 3,
    #         wellPanel(
    #           # Cell line
    #           radioButtons(
    #             "network_cellline",
    #             "Cell line:",
    #             choices  = c("Both", "K562", "HEPG2"),
    #             selected = "Both"
    #           ),
    # 
    #           hr(),
    # 
    #           # ── Plot type ──
    #           tags$h5("Plot type:", style = "font-weight: bold;"),
    #           radioButtons(
    #             "network_plot_type",
    #             label    = NULL,
    #             choices  = c("MDS", "PCA", "t-SNE", "Dendrogram"),
    #             selected = "MDS"
    #           ),
    # 
    #           hr(),
    # 
    #           # Data layers
    #           tags$h5("Data layers:", style = "font-weight: bold;"),
    #           checkboxGroupInput(
    #             "network_layers",
    #             label    = NULL,
    #             choices  = c("Expression", "Splicing", "Binding"),
    #             selected = "Binding"
    #           ),
    # 
    #           # Slow-layer warning
    #           conditionalPanel(
    #             condition = "input.network_layers.indexOf('Expression') !== -1 ||
    #                          input.network_layers.indexOf('Splicing') !== -1",
    #             tags$div(
    #               style = "background:#fff3cd; border:1px solid #ffc107;
    #                        border-radius:6px; padding:8px 10px; margin-top:6px;
    #                        font-size:11px; color:#856404;",
    #               tags$b("\u26a0 Note:"),
    #               " Expression and Splicing layers build large feature matrices
    #                 and may take a few minutes to compute depending on the
    #                 number of RBPs. Please be patient after clicking Plot."
    #             )
    #           ),
    # 
    #           # ── Binding sub-options ──
    #           conditionalPanel(
    #             condition = "input.network_layers.indexOf('Binding') !== -1",
    #             tags$h6("Event type:", style = "margin-top: 10px; font-weight: bold;"),
    #             checkboxGroupInput(
    #               "network_binding_type",
    #               label    = NULL,
    #               choices  = c("Intron Retention", "Exon Skipping"),
    #               selected = c("Intron Retention", "Exon Skipping")
    #             ),
    #             tags$h6("Direction:", style = "margin-top: 8px; font-weight: bold;"),
    #             checkboxGroupInput(
    #               "network_binding_dir",
    #               label    = NULL,
    #               choices  = c("Increased", "Decreased"),
    #               selected = c("Increased", "Decreased")
    #             )
    #           ),
    # 
    #           hr(),
    # 
    #           # ── Layer weights ──
    #           tags$h5("Layer weights:", style = "font-weight: bold;"),
    #           tags$p(
    #             "Weights are automatically normalised to sum to 1.",
    #             style = "font-size: 11px; color: #888; margin-top: -5px;"
    #           ),
    # 
    #           conditionalPanel(
    #             condition = "input.network_layers.indexOf('Expression') !== -1",
    #             sliderInput("network_weight_expr",   "Expression weight:",
    #                         min = 0, max = 1, value = 0.33, step = 0.05)
    #           ),
    #           conditionalPanel(
    #             condition = "input.network_layers.indexOf('Splicing') !== -1",
    #             sliderInput("network_weight_splice", "Splicing weight:",
    #                         min = 0, max = 1, value = 0.33, step = 0.05)
    #           ),
    #           conditionalPanel(
    #             condition = "input.network_layers.indexOf('Binding') !== -1",
    #             sliderInput("network_weight_binding","Binding weight:",
    #                         min = 0, max = 1, value = 0.34, step = 0.05)
    #           ),
    # 
    #           hr(),
    # 
    #           # ── RBP highlight search ──
    #           tags$h5("Highlight RBPs:", style = "font-weight: bold;"),
    #           tags$p("Selected RBPs will be highlighted in red on the plot.",
    #                  style = "font-size: 11px; color: #888; margin-top: -5px;"),
    #           selectizeInput(
    #             "network_highlight_rbps",
    #             label   = NULL,
    #             choices = sort(ALL_RBP_NAMES),
    #             multiple = TRUE,
    #             options  = list(placeholder = "Type to search RBPs...")
    #           ),
    # 
    #           hr(),
    # 
    #           actionButton(
    #             "network_plot_btn",
    #             tagList(fa("chart-line"), " Plot"),
    #             class = "btn btn-primary",
    #             style = "border-radius: 20px; width: 100%;"
    #           )
    #         )
    #       ),
    # 
    #       # ── Right plot area ───────────────────────────────────────────────
    #       column(
    #         width = 9,
    #         tags$h3("RBP Similarity Network"),
    #         tags$p(
    #           "Multi-omic ordination of RBP similarity. Each point is an RBP;
    #            proximity reflects similarity across the selected data layers
    #            (Expression: t-statistics across shared genes; Splicing: dPSI
    #            across shared events; Binding: profile shape across regulated
    #            splice sites). Layer weights are normalised to sum to 1.",
    #           style = "color: #555; font-size: 13px; margin-bottom: 15px;"
    #         ),
    #         shinycssloaders::withSpinner(
    #           plotOutput("network_mds_plot", height = "600px"),
    #           type = 6
    #         ),
    #         uiOutput("dl_ui_network")
    #       )
    #     )
    #   )
    # )
  ),
  
  # Info button floating across ALL tabs: collapsed to a small "Info" pill,
  # click to open the panel (version, packages, tutorial, Zenodo, GitHub).
  tags$div(
    id = "charm-info",
    tags$button(
      id = "charm-info-btn", type = "button", "aria-expanded" = "false",
      fa("circle-info", fill = "#2c3e50", height = "1em"), " Info"
    ),
    tags$div(
      id = "charm-info-panel",
    tags$div(
      style = "font-size: 11px; color: #2c3e50; margin-bottom: 4px;",
      "Version: 0.9.3"
    ),
    tags$div(
      style = "margin-bottom: 4px;",
      actionLink(
        "show_packages_modal",
        label = tagList(fa("r-project", fill = "black", height = "1.1em"), " Packages"),
        style = "color: black; text-decoration: none; font-size: 12px;"
      )
    ),
    tags$div(
      style = "margin-bottom: 4px;",
      tags$a(
        href = "https://diseasetranscriptomicslab.github.io/CHARM/",
        target = "_blank",
        style = "color: black; text-decoration: none; font-size: 12px;",
        fa("book", fill = "black", height = "1.1em"),
        " Tutorial"
      )
    ),
    tags$div(
      style = "margin-bottom: 4px;",
      tags$a(
        href = "https://doi.org/10.5281/zenodo.21724194",
        target = "_blank",
        style = "color: black; text-decoration: none; font-size: 12px;",
        fa("database", fill = "black", height = "1.1em"),
        " Zenodo"
      )
    ),
    tags$a(
      href = "https://github.com/DiseaseTranscriptomicsLab/CHARM",
      target = "_blank",
      style = "color: black; text-decoration: none;",
      fa("github", fill = "black", height = "1.5em"),
      " GitHub"
    )
    )
  )
)

# ---- Server ----

server <- function(input, output, session) {
  
  # ── Downloadable plot stores ──────────────────────────────────────────────
  # Each reactiveVal holds the last ggplot rendered for that output,
  # so downloadHandler can call ggsave() on it at any time.
  dl_store <- list(
    expr_violin    = reactiveVal(NULL),
    shrna          = reactiveVal(NULL),
    volcano        = reactiveVal(NULL),
    gsea           = reactiveVal(NULL),
    expr_gene      = reactiveVal(NULL),
    expr_hallmark  = reactiveVal(NULL),
    splice_violin  = reactiveVal(NULL),
    shrna_splice   = reactiveVal(NULL),
    splice_volcano = reactiveVal(NULL),
    binding        = reactiveVal(NULL),
    network        = reactiveVal(NULL),
    event_dpsi     = reactiveVal(NULL),
    # Discovery-mode plots (user-uploaded-file tabs) -- these previously had
    # no save option at all.
    splice_initial = reactiveVal(NULL),
    binding_disc   = reactiveVal(NULL)
  )

  # Generic download-button counter for Discovery-mode plots that are
  # rendered dynamically (one per dataset variant, e.g. "Both Cells" /
  # "K562" / "HEPG2"), so each gets its own reactiveVal + downloadHandler +
  # downloadButton with a unique id built from the plot's own output name.
  dyn_dl_store <- reactiveValues()
  make_dyn_dl_handler <- function(plotname, filename_prefix,
                                  width = 10, height = 7, dpi = 300) {
    downloadHandler(
      filename = function() paste0(filename_prefix, "_", Sys.Date(), ".png"),
      content  = function(file) {
        p <- dyn_dl_store[[plotname]]
        req(p)
        ggplot2::ggsave(file, plot = p, device = "png",
                        width = width, height = height, dpi = dpi, bg = "white")
      }
    )
  }
  
  # ── Status bar helpers ────────────────────────────────────────────────────
  show_status <- function(msg = "Loading\u2026") {
    session$sendCustomMessage("showStatus", list(show = TRUE, text = msg))
    session$sendCustomMessage("toggleCursor", TRUE)
  }
  hide_status <- function() {
    session$sendCustomMessage("showStatus", list(show = FALSE))
    session$sendCustomMessage("toggleCursor", FALSE)
  }
  
  # ── Download handlers ─────────────────────────────────────────────────────
  # Helper: build a plot downloadHandler from a dl_store key
  make_dl_handler <- function(store_key, filename_prefix,
                              width = 10, height = 7, dpi = 300) {
    downloadHandler(
      filename = function() {
        rbp <- if (!is.null(input$expr_search_rbp) && nchar(input$expr_search_rbp) > 0)
                 input$expr_search_rbp
               else if (!is.null(input$splice_search) && nchar(input$splice_search) > 0)
                 input$splice_search
               else if (!is.null(input$binding_search) && nchar(input$binding_search) > 0)
                 input$binding_search
               else if (!is.null(input$splice_search_event) && nchar(input$splice_search_event) > 0)
                 input$splice_search_event
               else "plot"
        paste0(filename_prefix, "_", rbp, "_", Sys.Date(), ".png")
      },
      content = function(file) {
        p <- dl_store[[store_key]]()
        req(p)
        ggplot2::ggsave(file, plot = p, device = "png",
                        width = width, height = height, dpi = dpi, bg = "white")
      }
    )
  }
  
  # Helper: build a table downloadHandler from a reactiveVal holding a data.frame
  make_table_dl_handler <- function(data_fn, filename_prefix) {
    downloadHandler(
      filename = function() paste0(filename_prefix, "_", Sys.Date(), ".csv"),
      content  = function(file) {
        df <- data_fn()
        req(!is.null(df) && nrow(df) > 0)
        # Some tables (e.g. fgsea's geneset_table) carry list-columns
        # (leadingEdge is a vector-per-row). write.csv() doesn't error on
        # these, but it writes each cell as an R-syntax dump like
        # 'c("GENE1", "GENE2")', which reads as garbage/HTML-looking noise
        # in the CSV. Flatten any list-column to a clean "; "-joined string.
        list_cols <- vapply(df, is.list, logical(1))
        if (any(list_cols)) {
          df[list_cols] <- lapply(df[list_cols], function(col) {
            vapply(col, function(x) paste(x, collapse = "; "), character(1))
          })
        }
        write.csv(df, file, row.names = FALSE)
      }
    )
  }
  
  # Helper: render a download button only once the corresponding store is non-NULL
  make_dl_ui <- function(store_key, dl_id, label = "\u2193 Download plot") {
    output[[paste0("dl_ui_", store_key)]] <- renderUI({
      req(!is.null(dl_store[[store_key]]()))
      downloadButton(dl_id, label,
                     class = "btn btn-sm btn-default",
                     style = "margin-top:5px;")
    })
  }

  # Helper: which RBPs in a *loaded* charm-object variant actually have
  # usable expression data. An RBP can be present as a *name* in a given
  # dataset variant (e.g. CPEB4 shows up in the "Both Cells"/"HEPG2"
  # Charm.object) while its per-RBP entry is missing/degenerate there --
  # CPEB4 only has real corcounts/SampleType data in the K562 variant, for
  # instance. Rather than let users pick a name that's guaranteed to hit
  # the "no data" fallback, filter the search choices down to RBPs that
  # will actually work for violinplotter()/plot_rbp_volcano()/plot_gsea()
  # on the currently selected dataset: a corcounts matrix plus a SampleType
  # vector that includes both "Control" and the RBP's own label.
  valid_expr_rbp_names <- function(charm_obj) {
    if (is.null(charm_obj)) return(character(0))
    keep <- vapply(names(charm_obj), function(rbp) {
      entry <- charm_obj[[rbp]]
      if (is.null(entry)) return(FALSE)
      grp <- entry$SampleType
      !is.null(entry$corcounts) && !is.null(grp) && length(grp) > 0 &&
        "Control" %in% grp && rbp %in% grp
    }, logical(1), USE.NAMES = FALSE)
    names(charm_obj)[keep]
  }

  # Same idea for the Splicing tab: violin_splice_plot()/plot_splice_volcano()
  # need a non-empty VulcanTable for the RBP.
  valid_splice_rbp_names <- function(charm_obj) {
    if (is.null(charm_obj)) return(character(0))
    keep <- vapply(names(charm_obj), function(rbp) {
      entry <- charm_obj[[rbp]]
      !is.null(entry) && !is.null(entry$VulcanTable) && nrow(entry$VulcanTable) > 0
    }, logical(1), USE.NAMES = FALSE)
    names(charm_obj)[keep]
  }

  # Helper: turn plot_rbp_volcano()'s top_table into the display-ready table
  # with "gene"/"highlight" columns. plot_rbp_volcano() deliberately returns
  # an empty data.frame() (0 rows, 0 cols) when an RBP has no usable DE
  # results (missing/degenerate design, no Control level, etc. -- e.g. this
  # is what happens for some RBPs' data, such as CPEB4). Building tbl$gene
  # on that produces a 1-column data.frame, and `tbl[, "gene"]` then
  # collapses (drop = TRUE) to a bare character vector -- so the *next* line
  # (`tbl$highlight <- ...`) crashed with "$ operator is invalid for atomic
  # vectors". Detect the empty case up front and hand callers back a
  # zero-row table with the right column names instead of ever reaching
  # that collapse.
  build_volcano_table <- function(result, rbp_sel) {
    tbl <- as.data.frame(result$top_table)
    if (nrow(tbl) == 0) {
      return(data.frame(gene = character(0), highlight = character(0)))
    }
    if (!"gene" %in% colnames(tbl)) tbl$gene <- rownames(tbl)
    tbl <- tbl[, c("gene", setdiff(colnames(tbl), "gene")), drop = FALSE]
    tbl$highlight <- ifelse(tbl$gene == rbp_sel, "RBP", "None")
    tbl
  }

  # ── Plot download handlers ─────────────────────────────────────────────────
  output$dl_expr_violin   <- make_dl_handler("expr_violin",   "expression_violin",   width = 8,  height = 6)
  output$dl_shrna         <- make_dl_handler("shrna",         "shrna_efficiency",    width = 8,  height = 6)
  output$dl_volcano       <- make_dl_handler("volcano",       "expression_volcano",  width = 8,  height = 7)
  output$dl_gsea          <- make_dl_handler("gsea",          "expression_gsea",     width = 10, height = 8)
  output$dl_expr_gene     <- make_dl_handler("expr_gene",     "expression_gene",     width = 8,  height = 7)
  output$dl_expr_hallmark <- make_dl_handler("expr_hallmark", "expression_hallmark", width = 8,  height = 7)
  output$dl_splice_violin <- make_dl_handler("splice_violin", "splicing_violin",     width = 8,  height = 6)
  output$dl_shrna_splice  <- make_dl_handler("shrna_splice",  "shrna_efficiency_splice", width = 8, height = 6)
  output$dl_splice_volcano<- make_dl_handler("splice_volcano","splicing_volcano",    width = 8,  height = 7)
  # dl_binding is NOT built via make_dl_handler(): the Binding "All targets"
  # heatmap can have 100+ rows, and a fixed 12x9in export crammed every row
  # label on top of the next -- unreadable, even though the same heatmap
  # looks fine on screen because binding_plot_ui() scales the plotOutput's
  # pixel height with the row count.
  #
  # Shared by dl_binding (Explore mode) and dl_binding_disc (Discovery
  # mode) below -- both heatmaps have the exact same "readable on screen,
  # crowded once saved" problem, so both call this one function.
  #
  # height_px tracks the SAME on-screen plotOutput scaling formula used
  # for the live plot (900 + (n-1)*10 px per row), but the on-screen-to-
  # inches conversion is height_px/72, not /96: shiny::renderPlot()
  # rasterizes at its documented default res = 72, so the on-screen plot's
  # TRUE physical canvas size is height_px/72 inches. Using /96 (the CSS
  # "96px = 1in" convention) undersized every saved PNG relative to what
  # was actually on screen, which is why row labels came out cramped in
  # the download even when height_px numerically matched the live plot.
  #
  # An earlier revision over-corrected this by ALSO inflating the per-row
  # pixel budget (14px instead of 10px) and adding a 25% margin on top,
  # which produced downloads with much more row spacing than the on-screen
  # version actually has -- rows looked too large/spread out. This version
  # just fixes the /72-vs-/96 conversion and otherwise matches the
  # on-screen formula exactly (10px/row, same 900px base), so a download
  # looks like a 1:1 copy of what's on screen rather than larger OR
  # smaller. The only deliberate difference is a taller cap (4000px vs.
  # the on-screen view's 2000px): a saved file has no viewport to fit
  # into, so very large "All" selections (beyond ~111 targets, where the
  # on-screen plot itself stops growing) can keep getting a bit more room
  # in the download than the live view ever shows.
  binding_heatmap_dl_height_in <- function(n_targets) {
    height_px <- min(900 + (n_targets - 1) * 10, 4000)
    height_px / 72
  }

  output$dl_binding <- downloadHandler(
    filename = function() {
      rbp <- if (!is.null(input$binding_search) && nchar(input$binding_search) > 0)
               input$binding_search else "plot"
      paste0("binding_map_", rbp, "_", Sys.Date(), ".png")
    },
    content = function(file) {
      p <- dl_store$binding()
      req(p)
      targets <- input$binding_target
      n_targets <- tryCatch({
        if (!is.null(targets) && "All" %in% targets) {
          data <- binding_data()
          rbp  <- input$binding_search
          if (!is.null(data) && !is.null(rbp) && rbp %in% names(data)) {
            length(names(data[[rbp]]))
          } else 1
        } else {
          length(targets)
        }
      }, error = function(e) 1)
      if (is.null(n_targets) || length(n_targets) == 0 || is.na(n_targets) || n_targets < 1) n_targets <- 1
      height_in <- binding_heatmap_dl_height_in(n_targets)
      ggplot2::ggsave(file, plot = p, device = "png",
                      width = 12, height = height_in, dpi = 300, bg = "white",
                      limitsize = FALSE)
    }
  )
  output$dl_network       <- make_dl_handler("network",       "network",             width = 12, height = 9)
  output$dl_event_dpsi    <- make_dl_handler("event_dpsi",    "splicing_event_dpsi", width = 10, height = 8)

  # Discovery-mode (user-uploaded-file) plots -- previously not saveable.
  output$dl_splice_initial <- make_dl_handler("splice_initial", "splicing_discovery_overview", width = 8,  height = 6)
  output$dl_binding_disc   <- downloadHandler(
    filename = function() paste0("binding_discovery_", Sys.Date(), ".png"),
    content  = function(file) {
      p <- dl_store$binding_disc()
      req(p)
      # Mirror the same on-screen scaling logic used for the Binding tab's
      # Explore-mode heatmap (see dl_binding above) -- Discovery mode's
      # multi-target heatmap has the exact same "readable on screen, garbled
      # once saved at a fixed size" problem as more targets are selected,
      # including "All" needing to be expanded to its real count first.
      targets <- input$binding_disc_target
      n_targets <- tryCatch({
        if (!is.null(targets) && "All" %in% targets) {
          if (grepl("Intron Retention", input$binding_eventtype, ignore.case = TRUE)) {
            length(ALL_BINDING_RBP_NAMES_IR)
          } else {
            length(ALL_BINDING_RBP_NAMES_ES)
          }
        } else {
          length(targets)
        }
      }, error = function(e) 1)
      if (is.null(n_targets) || length(n_targets) == 0 || is.na(n_targets) || n_targets < 1) n_targets <- 1
      # Same shared helper as dl_binding above (see its definition for why
      # this is height_px/72, not /96, plus the taller ceiling for downloads).
      height_in <- binding_heatmap_dl_height_in(n_targets)
      ggplot2::ggsave(file, plot = p, device = "png",
                      width = 12, height = height_in, dpi = 300, bg = "white",
                      limitsize = FALSE)
    }
  )

  # ── Conditional download button UIs (appear only after plot is rendered) ──
  make_dl_ui("expr_violin",   "dl_expr_violin")
  make_dl_ui("shrna",         "dl_shrna")
  make_dl_ui("volcano",       "dl_volcano")
  make_dl_ui("gsea",          "dl_gsea")
  make_dl_ui("expr_gene",     "dl_expr_gene")
  make_dl_ui("expr_hallmark", "dl_expr_hallmark")
  make_dl_ui("splice_violin", "dl_splice_violin")
  make_dl_ui("shrna_splice",  "dl_shrna_splice")
  make_dl_ui("splice_volcano","dl_splice_volcano")
  make_dl_ui("binding",       "dl_binding")
  make_dl_ui("network",       "dl_network")
  make_dl_ui("event_dpsi",    "dl_event_dpsi")
  make_dl_ui("splice_initial","dl_splice_initial")
  make_dl_ui("binding_disc",  "dl_binding_disc")

  # ── "Packages" modal (floating corner box) ─────────────────────────────────
  # Reads installed.packages() live from the running container instead of a
  # hand-typed list, so this always reflects exactly what the Docker image
  # actually has installed -- no separate list to keep in sync with the
  # Dockerfile by hand every time a package version changes there.
  build_package_version_table <- function() {
    ip <- as.data.frame(installed.packages()[, c("Package", "Version", "Priority")],
                        stringsAsFactors = FALSE)
    # Priority is "base" or "recommended" for packages that ship with R
    # itself (grid, stats, methods, MASS, ...), NA for everything actually
    # installed via install.packages()/BiocManager::install() -- i.e.
    # exactly the packages the Dockerfile is responsible for.
    ip <- ip[is.na(ip$Priority), c("Package", "Version")]
    ip <- ip[order(ip$Package), ]
    rownames(ip) <- NULL
    ip
  }

  output$packages_table <- renderDT({
    datatable(build_package_version_table(), filter = "none", rownames = FALSE,
              options = list(pageLength = 15, scrollX = TRUE, searching = TRUE))
  })

  observeEvent(input$show_packages_modal, {
    showModal(modalDialog(
      title = tagList(fa("r-project", fill = "black", height = "1em"), " R Packages"),
      size = "l",
      easyClose = TRUE,
      footer = modalButton("Close"),
      tags$p(
        style = "font-size: 12px; color: #666; margin-top: -5px;",
        paste0("R ", getRversion(),
               " — package versions as installed in this running container ",
               "(i.e. exactly what the Docker image was built with).")
      ),
      DTOutput("packages_table")
    ))
  })

  # ── Table download handlers ────────────────────────────────────────────────
  output$dl_volcano_table        <- make_table_dl_handler(display_table,  "expression_volcano_table")
  output$dl_geneset_table        <- make_table_dl_handler(gsea_table_rv,  "expression_gsea_table")
  output$dl_splice_volcano_table <- make_table_dl_handler(
    reactive({
      res <- result_splice()
      if (is.null(res)) return(NULL)
      # Drop the internal "text" column: it holds an HTML-formatted tooltip
      # string (e.g. "Gene: ...<br>Event: ...<br>") used only for the volcano
      # plot's hover text. Leaving it in wrote raw <br> tags into the CSV --
      # the on-screen table already excludes it the same way (see splice_volcano_table
      # renderDT above), so the download should match what the user sees.
      res$top_table %>% dplyr::select(-dplyr::any_of("text"))
    }),
    "splicing_volcano_table"
  )
  
  # Table download button UIs
  output$dl_ui_volcano_table <- renderUI({
    req(!is.null(display_table()) && nrow(display_table()) > 0)
    downloadButton("dl_volcano_table", "\u2193 Download table",
                   class = "btn btn-sm btn-default", style = "margin-top:5px;")
  })
  output$dl_ui_geneset_table <- renderUI({
    req(!is.null(gsea_table_rv()) && nrow(gsea_table_rv()) > 0)
    downloadButton("dl_geneset_table", "\u2193 Download table",
                   class = "btn btn-sm btn-default", style = "margin-top:5px;")
  })
  output$dl_ui_splice_volcano_table <- renderUI({
    res <- result_splice()
    req(!is.null(res) && !is.null(res$top_table) && nrow(res$top_table) > 0)
    downloadButton("dl_splice_volcano_table", "\u2193 Download table",
                   class = "btn btn-sm btn-default", style = "margin-top:5px;")
  })
  
  # ── Lazy-load all 12 similar_binding_* objects on first Network/Binding use ──
  # Using a reactive means the 12 qs::qread() calls only happen the first time
  # this reactive is evaluated, and the result is cached for all subsequent calls.
  # This shaves the 12 file reads off app startup time.
  binding_sim_cache <- reactive({
    keys <- c(
      "ES_both_inc",  "ES_both_dec",
      "ES_K562_inc",  "ES_K562_dec",
      "ES_HEPG2_inc", "ES_HEPG2_dec",
      "IR_both_inc",  "IR_both_dec",
      "IR_K562_inc",  "IR_K562_dec",
      "IR_HEPG2_inc", "IR_HEPG2_dec"
    )
    objs <- lapply(keys, function(k) {
      qload(paste0("similar_binding_", k))
    })
    names(objs) <- paste0("similar_binding_", keys)
    objs
  })
  # Home: the three layer boxes ("Binding" / "Splicing" / "Expression") open their tab
  observeEvent(input$home_go_layer, {
    req(input$home_go_layer %in% c("Binding", "Splicing", "Expression"))
    updateTabsetPanel(session, "main_tabs", selected = input$home_go_layer)
  })
  observeEvent(input$home_go_explore, {
    updateTabsetPanel(session, "main_tabs", selected = "Expression")
  })
  observeEvent(input$home_go_discover, {
    updateTabsetPanel(session, "main_tabs", selected = "Expression")
    updateRadioButtons(session, "expr_mode", selected = "Discovery")
  })
  # observeEvent(input$home_go_network, {
  # updateTabsetPanel(session, "main_tabs", selected = "Network")
  # })
  
  
  image_to_ggplot <- function(path) {
    img <- png::readPNG(path)
    g <- grid::rasterGrob(img, interpolate = TRUE)
    ggplot() + annotation_custom(g, xmin = -Inf, xmax = Inf, ymin = -Inf, ymax = Inf) +
      theme_charm_void()
  }
  
  
  
  result_splice <- reactiveVal(NULL)
  
  # ---- Helper functions to pick correct dataset ----
  # Expression tab
  current_charm_expr <- reactive({
    req(input$expr_dataset)
    get_charm_object(input$expr_dataset)
  })

  # Splicing tab
  current_charm_splice <- reactive({
    req(input$splice_dataset)
    get_charm_object(input$splice_dataset)
  })
  
  current_shrna_expr <- reactive({
    req(input$expr_dataset)
    switch(input$expr_dataset,
           "K562"  = sh_effect_vector_K562,
           "HEPG2" = sh_effect_vector_HEPG2,
           sh_effect_vector)
  })
  
  current_shrna_splice <- reactive({
    req(input$splice_dataset)
    switch(input$splice_dataset,
           "K562"  = sh_effect_vector_K562,
           "HEPG2" = sh_effect_vector_HEPG2,
           sh_effect_vector)
  })
  
  
  # Reactive storage
  display_table <- reactiveVal(NULL)
  rbp_current   <- reactiveVal(NULL)
  gsea_table_rv <- reactiveVal(NULL)
  
  # ── Cross-tab RBP navigation ──────────────────────────────────────────────
  # nav_rbp holds the RBP to jump to, plus the source tab so we don't
  # fire the observer back on the originating tab.
  nav_rbp <- reactiveVal(list(rbp = NULL, from = NULL))
  binding_nav_trigger <- reactiveVal(NULL)
  binding_nav_target  <- reactiveVal(NULL)   # stores the pre-chosen target for nav
  
  # When binding_nav_trigger is set, watch for binding_search to update
  # (which happens synchronously when updateSelectizeInput fires), then
  # select the target and click Search. We watch binding_search rather than
  # binding_target because binding_target is NULL until the user interacts
  # with it, so its change never fires when navigating programmatically.
  #
  # This is a plain observe(), not observeEvent(input$binding_search, ...):
  # binding_data() itself needs input$binding_eventtype/input$binding_dataset,
  # which live in the Binding sidebar and only exist once the tab switch +
  # binding_mode update have round-tripped to the client and back. If
  # binding_data() wasn't ready yet at the exact moment binding_search
  # changed, an observeEvent keyed on binding_search's change would abort via
  # req() and then simply never run again (nothing about binding_search
  # itself changes afterwards) -- silently killing the whole navigation
  # with the "Loading binding data..." status stuck up forever. A plain
  # observe() re-evaluates whenever ANY reactive it reads changes, so it
  # naturally retries once binding_data() becomes available.
  observe({
    trigger_rbp <- binding_nav_trigger()
    req(!is.null(trigger_rbp))
    req(!is.null(input$binding_search), input$binding_search == trigger_rbp)

    data <- binding_data()
    req(!is.null(data))
    available_targets <- names(data[[trigger_rbp]])

    target_to_use <- if (trigger_rbp %in% available_targets) {
      trigger_rbp
    } else if (length(available_targets) > 0) {
      available_targets[1]
    } else {
      NULL
    }

    if (is.null(target_to_use)) {
      # No usable target for this RBP -- without this, req() below would
      # silently abort and, since nothing else about this RBP ever changes,
      # this observer would just never run again: binding_nav_trigger stays
      # set and the "Loading binding data..." status banner (shown right
      # before this was triggered) would stay up forever.
      hide_status()
      binding_nav_trigger(NULL)
      return(invisible(NULL))
    }
    binding_nav_trigger(NULL)          # clear so this doesn't re-fire
    binding_nav_target(target_to_use)  # binding_target_ui reads this to pre-select
                                        # itself at creation time (see renderUI below);
                                        # results() also reads it as a fallback.

    # Click Search after a delay so results() fires with binding_nav_target set
    session$sendCustomMessage("clickButton", list(id = "search_btn", delay = 500))
  })
  
  # Helper: render the navigation bar for a given tab
  make_nav_bar <- function(rbp, current_tab) {
    other_tabs <- setdiff(c("Expression", "Splicing", "Binding"), current_tab)
    links <- lapply(other_tabs, function(tab) {
      btn_id <- paste0("nav_to_", tab, "_from_", current_tab)
      icon_name <- switch(tab,
        "Expression" = "dna",
        "Splicing"   = "scissors",
        "Binding"    = "link"
      )
      actionButton(
        btn_id,
        tagList(fa(icon_name, height = "0.9em"), paste0(" View in ", tab, " \u2192")),
        class = "btn btn-sm btn-outline-secondary",
        style = "margin-right:8px; border-radius:20px;"
      )
    })
    div(
      style = "background:#f0f4f8; border:1px solid #d0d8e4; border-radius:8px;
               padding:8px 14px; margin-bottom:12px; display:flex; align-items:center;",
      tags$span(
        style = "font-weight:bold; margin-right:12px; color:#2c3e50;",
        paste0("Viewing: ", rbp)
      ),
      tagList(links)
    )
  }
  
  # Expression nav bar — shown when an RBP is active
  output$expr_nav_bar <- renderUI({
    rbp <- rbp_current()
    req(!is.null(rbp))
    make_nav_bar(rbp, "Expression")
  })
  
  # Splicing nav bar
  output$splice_nav_bar <- renderUI({
    rbp <- rbp_current()
    req(!is.null(rbp))
    make_nav_bar(rbp, "Splicing")
  })
  
  # Binding nav bar — shown when binding_search is set and a plot has been made
  output$binding_nav_bar <- renderUI({
    rbp <- input$binding_search
    req(!is.null(rbp) && nchar(rbp) > 0 && show_plot())
    make_nav_bar(rbp, "Binding")
  })
  
  # ── Navigation button handlers ─────────────────────────────────────────────
  # Expression → Splicing
  observeEvent(input$nav_to_Splicing_from_Expression, {
    rbp <- rbp_current(); req(!is.null(rbp))
    updateTabsetPanel(session, "main_tabs", selected = "Splicing")
    updateRadioButtons(session, "splice_mode", selected = "Explore")
    updateSelectizeInput(session, "splice_search", selected = rbp)
    nav_rbp(list(rbp = rbp, from = "Expression", to = "Splicing"))
  })
  
  # Expression → Binding
  observeEvent(input$nav_to_Binding_from_Expression, {
    rbp <- rbp_current(); req(!is.null(rbp))
    updateTabsetPanel(session, "main_tabs", selected = "Binding")
    updateRadioButtons(session, "binding_mode", selected = "Explore")
    # binding_search is a server-side selectize (server = TRUE elsewhere) --
    # updateSelectizeInput(selected = rbp) alone is unreliable once the
    # widget has already been interacted with, because the client only
    # knows about options its last search actually fetched from the server.
    # If rbp was never searched for, the client can't select it and just
    # clears the field instead (silently -- this is what caused "See in
    # Binding" to hang forever on any navigation after Binding had already
    # been used once). Passing it as an explicit choice guarantees the
    # client has it available to select.
    updateSelectizeInput(session, "binding_search", choices = setNames(rbp, rbp), selected = rbp, server = TRUE)
    nav_rbp(list(rbp = rbp, from = "Expression", to = "Binding"))
  })
  
  # Splicing → Expression
  observeEvent(input$nav_to_Expression_from_Splicing, {
    rbp <- rbp_current(); req(!is.null(rbp))
    updateTabsetPanel(session, "main_tabs", selected = "Expression")
    updateRadioButtons(session, "expr_mode", selected = "Explore")
    updateSelectizeInput(session, "expr_search_rbp", selected = rbp)
    nav_rbp(list(rbp = rbp, from = "Splicing", to = "Expression"))
  })
  
  # Splicing → Binding
  observeEvent(input$nav_to_Binding_from_Splicing, {
    rbp <- rbp_current(); req(!is.null(rbp))
    updateTabsetPanel(session, "main_tabs", selected = "Binding")
    updateRadioButtons(session, "binding_mode", selected = "Explore")
    # See the Expression -> Binding observer above for why choices is passed
    # here instead of just selected.
    updateSelectizeInput(session, "binding_search", choices = setNames(rbp, rbp), selected = rbp, server = TRUE)
    nav_rbp(list(rbp = rbp, from = "Splicing", to = "Binding"))
  })
  
  # Binding → Expression
  observeEvent(input$nav_to_Expression_from_Binding, {
    rbp <- input$binding_search; req(!is.null(rbp) && nchar(rbp) > 0)
    updateTabsetPanel(session, "main_tabs", selected = "Expression")
    updateRadioButtons(session, "expr_mode", selected = "Explore")
    updateSelectizeInput(session, "expr_search_rbp", selected = rbp)
    nav_rbp(list(rbp = rbp, from = "Binding", to = "Expression"))
  })
  
  # Binding → Splicing
  observeEvent(input$nav_to_Splicing_from_Binding, {
    rbp <- input$binding_search; req(!is.null(rbp) && nchar(rbp) > 0)
    updateTabsetPanel(session, "main_tabs", selected = "Splicing")
    updateRadioButtons(session, "splice_mode", selected = "Explore")
    updateSelectizeInput(session, "splice_search", selected = rbp)
    nav_rbp(list(rbp = rbp, from = "Binding", to = "Splicing"))
  })
  
  # ── Auto-fire search when landing via navigation ───────────────────────────
  # Each observer fires only when nav_rbp targets *its* tab, so the originating
  # tab's search is never re-triggered.
  observeEvent(nav_rbp(), {
    nav <- nav_rbp()
    req(!is.null(nav$rbp), !is.null(nav$to))
    
    if (nav$to == "Expression") {
      rbp_sel   <- nav$rbp
      charm_obj <- current_charm_expr()
      shrna_obj <- current_shrna_expr()
      req(rbp_sel %in% valid_expr_rbp_names(charm_obj))
      rbp_current(rbp_sel)
      expr_top_panel(NULL)
      output$expr_violin    <- renderPlot(NULL)
      output$shrna_plot     <- renderPlot(NULL)
      output$volcano_plot   <- renderHighchart(NULL)
      output$volcano_table  <- renderDT(NULL)
      output$gsea_plot      <- renderPlot(NULL)
      output$geneset_table  <- renderDT(NULL)
      display_table(NULL)
      output$expr_violin <- renderPlot({
        p <- violinplotter(charm_obj, rbp_sel)
        dl_store$expr_violin(p); p
      })
      output$shrna_plot <- renderPlot({
        p <- plot_shRNA_effect(shrna_obj, rbp_sel)
        dl_store$shrna(p); p
      })
      result <- plot_rbp_volcano(charm_obj, rbp_sel)
      tbl <- build_volcano_table(result, rbp_sel)
      if (nrow(tbl) == 0) {
        showModal(modalDialog(
          title = "No data",
          paste("No differential expression results are available for", rbp_sel,
                "in this cell line — its data may be incomplete."),
          easyClose = TRUE, footer = NULL
        ))
        return(NULL)
      }
      display_table(tbl)
      output$volcano_plot <- renderHighchart({
        p <- make_volcano_plot(display_table(), rbp_sel)
        dl_store$volcano(p)
        make_volcano_plot_hc(display_table(), rbp_sel)
      })
      output$volcano_table <- renderDT({
        datatable(display_table(), filter = "none", selection = "single",
                  rownames = FALSE, options = list(pageLength = 10, scrollX = TRUE, searching = TRUE))
      })
      gsea_result <- plot_gsea(charm_obj, rbp_sel, thresh = 0.05)
      gsea_table_rv(gsea_result$geneset_table)
      output$gsea_plot <- renderPlot({
        p <- gsea_result$gsea_plot; dl_store$gsea(p); p
      })
      output$geneset_table <- renderDT({
        datatable(gsea_result$geneset_table, filter = "none", rownames = FALSE,
                  options = list(pageLength = 10, scrollX = TRUE))
      })
    }
    
    if (nav$to == "Splicing") {
      rbp_sel   <- nav$rbp
      charm_obj <- current_charm_splice()
      shrna_obj <- current_shrna_splice()
      req(rbp_sel %in% valid_splice_rbp_names(charm_obj))
      rbp_current(rbp_sel)
      splice_top_panel(NULL)
      output$violin_splice_plot  <- renderPlot(NULL)
      output$plot_shrna_effect   <- renderPlot(NULL)
      output$plot_splice_volcano <- renderHighchart(NULL)
      output$splice_volcano_table <- renderDT(NULL)
      output$violin_splice_plot <- renderPlot({
        p <- violin_splice_plot(charm_obj, rbp_sel)
        dl_store$splice_violin(p); p
      })
      output$plot_shrna_effect <- renderPlot({
        p <- plot_shRNA_effect(shrna_obj, rbp_sel)
        dl_store$shrna_splice(p); p
      })
      splice_res <- plot_splice_volcano(charm_obj, rbp_sel)
      req(!is.null(splice_res))
      result_splice(splice_res)
      output$plot_splice_volcano <- renderHighchart({
        req(result_splice())
        tbl <- result_splice()$top_table
        p <- ggplot(tbl, aes(x = dPSI, y = Pdiff, key = Event.ID, color = highlight)) +
          geom_point(alpha = 0.7) +
          scale_color_manual(values = c("None" = "#CCCCCC", "RBP" = "#A10702", "Selected" = "#008057")) +
          theme_charm() + theme(legend.position = "none") +
          labs(title = paste0("Volcano Plot: ", rbp_sel, " KD"), x = "dPSI (shRNA - CTRL)", y = "PDiff")
        dl_store$splice_volcano(p)
        make_splice_volcano_plot_hc(tbl, rbp_sel)
      })
      output$splice_volcano_table <- DT::renderDataTable({
        req(result_splice())
        result_splice()$top_table %>% select(-text)
      }, rownames = FALSE, selection = "single", options = list(pageLength = 10))
    }
    
    if (nav$to == "Binding") {
      rbp <- nav$rbp
      show_status(paste0("Loading binding data for ", rbp, " \u2014 please wait\u2026"))
      binding_nav_trigger(rbp)
    }
    
    nav_rbp(list(rbp = NULL, from = NULL, to = NULL))  # reset to avoid re-firing
  }, ignoreNULL = TRUE, ignoreInit = TRUE)
  
  # Tracks which panel (if any) should appear pinned at the top of the
  # Expression Explore page: "gene", "hallmark", or NULL (none).
  expr_top_panel <- reactiveVal(NULL)
  
  output$expr_top_panel_ui <- renderUI({
    panel <- expr_top_panel()
    if (is.null(panel)) return(NULL)
    if (panel == "gene") {
      tagList(
        fluidRow(column(width = 12, plotOutput("expr_gene_plot", height = "600px"))),
        uiOutput("dl_ui_expr_gene")
      )
    } else if (panel == "hallmark") {
      tagList(
        fluidRow(column(width = 12, plotOutput("expr_hallmark_plot", height = "600px"))),
        uiOutput("dl_ui_expr_hallmark")
      )
    } else {
      NULL
    }
  })
  
  # ---- Search bar population (Expression tab) ----
  observe({
    req(current_charm_expr(), input$expr_dataset)
    
    # 1️⃣ RBP search bar (depends on selected dataset) -- only offer RBPs
    # that actually have usable data in *this* dataset variant (see
    # valid_expr_rbp_names()), so users can't pick one guaranteed to hit
    # the "no data" fallback (e.g. CPEB4 outside the K562 variant).
    rbp_choices <- valid_expr_rbp_names(current_charm_expr())
    updateSelectizeInput(
      session,
      "expr_search_rbp",
      choices = rbp_choices,
      server = TRUE
    )
    
    # 2️⃣ Gene search bar (depends on selected dataset)
    gene_choices <- switch(
      input$expr_dataset,
      "K562"  = GenesK562,
      "HEPG2" = GenesHEPG2,
      GenesBoth # default for "Both Cells" or anything else
    )
    updateSelectizeInput(
      session,
      "expr_search_gene",
      choices = sort(unique(gene_choices)),
      server = TRUE
    )
    
    # 3️⃣ Hallmark Gene Set search bar (always from RBFOX2; precomputed at
    # startup as HALLMARK_CHOICES so this doesn't force-reload the "Both"
    # Charm.object variant every time the dataset selector changes)
    updateSelectizeInput(
      session,
      "expr_search_hallmark",
      # displayed without underscores; the value sent to the server stays the raw ID
      choices = stats::setNames(HALLMARK_CHOICES, gsub("_", " ", HALLMARK_CHOICES)),
      server = TRUE
    )
  })
  
  
  # ---- Search bar population (Splicing tab) ----
  observe({
    req(current_charm_splice())
    
    # Only offer RBPs with a usable (non-empty) VulcanTable in this dataset
    # variant -- see valid_splice_rbp_names() / valid_expr_rbp_names().
    rbp_choices_splice <- valid_splice_rbp_names(current_charm_splice())
    updateSelectizeInput(
      session,
      "splice_search",
      choices = rbp_choices_splice,
      server = TRUE
    )

    updateSelectizeInput(session, "similar_rbps_select_splice", choices = rbp_choices_splice)
  })
  
  # ---- Populate Event ID choices based on dataset ----
  observe({
    req(current_charm_splice())
    req(input$splice_dataset)
    
    event_choices <- switch(
      input$splice_dataset,
      "Both Cells" = EventsBoth,
      "K562"       = EventsK562,
      "HEPG2"      = EventsHEPG2,
      NULL
    )
    
    updateSelectizeInput(
      session,
      "splice_search_event",  # must match UI
      choices = event_choices,
      server = TRUE
    )
  })
  
  # Tracks whether the Event ID panel should appear pinned at the top of the
  # Splicing Explore page: "event" or NULL (none).
  splice_top_panel <- reactiveVal(NULL)
  
  output$splice_top_panel_ui <- renderUI({
    panel <- splice_top_panel()
    if (is.null(panel)) return(NULL)
    if (panel == "event") {
      fluidRow(column(width = 12,
        plotOutput("heatmap_splicing_dpsi", height = "600px"),
        uiOutput("dl_ui_event_dpsi")
      ))
    } else {
      NULL
    }
  })
  
  # ---- Event ID Search button ----
  observeEvent(input$search_btn_event, {
    req(input$splice_search_event)
    event_id <- input$splice_search_event
    
    charm_obj <- current_charm_splice()
    
    splice_top_panel("event")
    
    output$heatmap_splicing_dpsi <- renderPlot({
      p <- plot_event_dpsi_barplot(charm_obj, event_id)
      dl_store$event_dpsi(p)
      p
    })
  })

  ###EXPRESSION (user File)
  upload_ok <- reactiveVal(FALSE)
  user_expr_df <- reactiveVal(NULL)
  
  observeEvent(input$user_file_expr, {
    req(input$user_file_expr)
    file_path <- input$user_file_expr$datapath
    
    df <- tryCatch(
      read_user_table(file_path),
      error = function(e) NULL
    )
    
    if (is.null(df)) {
      upload_ok(FALSE)
      user_expr_df(NULL)
      error_msg <- "Could not read the file. Please check that it is a plain text table (tab, comma, or semicolon separated)."
    } else if (ncol(df) != 2) {
      upload_ok(FALSE)
      user_expr_df(NULL)
      error_msg <- "File must have exactly 2 columns."
    } else if (!is.character(df[[1]])) {
      upload_ok(FALSE)
      user_expr_df(NULL)
      error_msg <- "First column must be character (gene names)."
    } else if (!is.numeric(df[[2]])) {
      upload_ok(FALSE)
      user_expr_df(NULL)
      error_msg <- "Second column must be numeric (t-statistics)."
    } else {
      colnames(df) <- c("Gene", "t")
      upload_ok(TRUE)
      user_expr_df(df)   # save dataframe globally
      error_msg <- NULL
    }
    
    output$file_warning_expr <- renderUI({
      if (upload_ok()) {
        df_prev <- user_expr_df()
        tagList(
          div(style = "color:green; font-weight:bold; margin-top:10px;",
              sprintf("\u2713 Upload successful — %d genes detected.", nrow(df_prev))),
          tags$small(style = "color:#666;",
                     paste("Columns:", paste(colnames(df_prev), collapse = ", "))),
          br(),
          DT::renderDataTable(
            head(df_prev, 6),
            options = list(dom = "t", ordering = FALSE, pageLength = 6),
            rownames = FALSE,
            class    = "compact"
          )
        )
      } else {
        div(style = "color:red; font-weight:bold; margin-top:10px;",
            paste("Upload failed:", error_msg))
      }
    })
  })
  
  # Only show extra options if upload is successful
  output$user_file_options <- renderUI({
    if (!upload_ok()) return(NULL)
    
    tagList(
      radioButtons(
        inputId = "user_file_mode_expr",
        label = "Select correlation type:",
        choices = c("By Gene Expression" = "expr",
                    "By Gene Set Enrichment" = "gsea"),
        selected = "expr",
        inline = TRUE
      ),
      
      # Gene Expression options
      conditionalPanel(
        condition = "input.user_file_mode_expr == 'expr'",
        selectizeInput(
          inputId = "user_file_compare_expr",
          label = "Compare with specific RBPs (optional)",
          choices = ALL_RBP_NAMES,
          multiple = TRUE,
          options = list(placeholder = "Select one or more RBPs")
        ),
        numericInput(
          "user_file_topN_expr",
          "Show top N correlated RBPs (optional):",
          value = NA, min = 1
        ),
        helpText("Tip: By selecting a number here, this will take precedence over the two inputs below."),
        numericInput(
          "user_file_n_pos_expr",
          "Show top N positive correlations (optional):",
          value = NA, min = 1
        ),
        numericInput(
          "user_file_n_neg_expr",
          "Show top N negative correlations (optional):",
          value = NA, min = 1
        ),
        helpText("Tip: You may use one or both of the numeric inputs above."),
        # Plot / Reset buttons
        div(
          style = "display: flex; align-items: center; margin-top: 15px;",
          actionButton(
            "user_file_plot_btn",
            tagList(fa("chart-line"), " Plot"),
            class = "btn btn-primary",
            style = "margin-right: 10px; border-radius: 20px;"
          ),
          actionButton(
            "user_file_reset_btn",
            tagList(fa("redo"), " Reset"),
            class = "btn btn-secondary",
            style = "border-radius: 20px;"
          )
        )
      ),
      
      # GSEA options
      conditionalPanel(
        condition = "input.user_file_mode_expr == 'gsea'",
        selectizeInput(
          inputId = "user_file_compare_gsea",
          label = "Compare with specific RBPs (optional)",
          choices = ALL_RBP_NAMES,
          multiple = TRUE,
          options = list(placeholder = "Select one or more RBPs")
        ),
        numericInput(
          "user_file_topN_gsea",
          "Show top N correlated RBPs (optional):",
          value = NA, min = 1
        ),
        helpText("Tip: By selecting a number here, this will take precedence over the two inputs below."),
        numericInput(
          "user_file_n_pos_gsea",
          "Show top N positive correlations (optional):",
          value = NA, min = 1
        ),
        numericInput(
          "user_file_n_neg_gsea",
          "Show top N negative correlations (optional):",
          value = NA, min = 1
        ),
        helpText("Tip: You may use one or both of the numeric inputs above."),
        # Plot / Reset buttons
        div(
          style = "display: flex; align-items: center; margin-top: 15px;",
          actionButton(
            "user_file_plot_btn",
            tagList(fa("chart-line"), " Plot"),
            class = "btn btn-primary",
            style = "margin-right: 10px; border-radius: 20px;"
          ),
          actionButton(
            "user_file_reset_btn",
            tagList(fa("redo"), " Reset"),
            class = "btn btn-secondary",
            style = "border-radius: 20px;"
          )
        )
      )
    )
  })
  
  # ---- User File Similarity Plots ----
  observeEvent(input$user_file_plot_btn, {
    req(user_expr_df())
    show_status("Generating comparison plots — please wait…")
    on.exit(hide_status(), add = TRUE)
    mode <- input$user_file_mode_expr

    # Choose datasets and plotting functions
    if (mode == "expr") {
      datasets <- list(
        "Both Cells" = similar_expression_all,
        "K562"       = similar_expression_K562,
        "HEPG2"      = similar_expression_HEPG2
      )
      selected_rbps <- input$user_file_compare_expr
      scatter_fun <- correl_exp_rbp_hc
      heatmap_fun <- exp_correl
      target_ui <- "userfilesimilar_expr"
    } else {  # mode == "gsea"
      datasets <- list(
        "Both Cells" = similar_gsea_all,
        "K562"       = similar_gsea_K562,
        "HEPG2"      = similar_gsea_HEPG2
      )
      selected_rbps <- input$user_file_compare_gsea
      scatter_fun <- correl_scatter_gsea_hc
      heatmap_fun <- gsea_correl
      target_ui <- "userfilesimilar_gsea"
    }
    
    if (length(selected_rbps) == 0) selected_rbps <- NULL
    
    output[[target_ui]] <- renderUI({
      tagList(
        # Generate all dataset plots dynamically
        lapply(names(datasets), function(ds_name) {
          # Sanitize: ds_name can be "Both Cells" (contains a space), which
          # is an invalid Shiny output ID. plotOutput/renderPlot tolerated
          # it, but highchartOutput/renderHighchart's widget binding does
          # not -- the plot silently never appears, no error anywhere.
          plotname <- paste0("userfile_plot_", gsub("[^A-Za-z0-9_]+", "_", ds_name))
          dl_ui <- NULL

          # Dynamic output creation
          if (!is.null(selected_rbps) && length(selected_rbps) == 1) {
            output[[plotname]] <- renderHighchart({
              scatter_fun(
                datasets[[ds_name]],
                user_expr_df(),
                selected_rbps[1],
                plot_title = ds_name
              )
            })
            plot_ui <- highchartOutput(plotname, height = "500px")
          } else {
            output[[plotname]] <- renderPlot({
              heat_res <- heatmap_fun(
                datasets[[ds_name]],
                user_expr_df(),
                correl_num = if (mode == "expr") input$user_file_topN_expr else input$user_file_topN_gsea,
                n_pos      = if (mode == "expr") input$user_file_n_pos_expr else input$user_file_n_pos_gsea,
                n_neg      = if (mode == "expr") input$user_file_n_neg_expr else input$user_file_n_neg_gsea,
                other_rbps = if (!is.null(selected_rbps) && length(selected_rbps) > 1) selected_rbps else NULL,
                ref_key    = corr_key(if (mode == "expr") "expr" else "gsea", ds_name)
              )
              dyn_dl_store[[plotname]] <- heat_res$heatmap
              heat_res$heatmap   # ✅ FIXED
            })
            plot_ui <- plotOutput(plotname, height = corr_plot_height(corr_key(if (mode == "expr") "expr" else "gsea", ds_name)))
            dl_id <- paste0("dl_", plotname)
            output[[dl_id]] <- make_dyn_dl_handler(plotname, paste0("expression_discovery_", plotname))
            dl_ui <- downloadButton(dl_id, "↓ Download plot",
                                    class = "btn btn-sm btn-default", style = "margin-top:5px;")
          }

          # Return UI element for each dataset
          column(
            width = 12,
            tags$h4(ds_name, style = "text-align:center;"),
            shinycssloaders::withSpinner(plot_ui),
            dl_ui
          )
        }) %>% tagList()  # flatten
      )
    })
  })
  # ---- Reset button ----
  observeEvent(input$user_file_reset_btn, {
    output$userfilesimilar_expr <- renderUI(NULL)
    output$userfilesimilar_gsea <- renderUI(NULL)
    updateSelectizeInput(session, "user_file_compare_expr", selected = "")
    updateSelectizeInput(session, "user_file_compare_gsea", selected = "")
  })
  
  ### SPICING (user File)
  upload_ok_splice <- reactiveVal(FALSE)
  user_splice_df <- reactiveVal(NULL)
  
  # ---- File upload ----
  observeEvent(input$user_file_splice, {
    req(input$user_file_splice)
    file_path <- input$user_file_splice$datapath
    
    df <- tryCatch(
      read_user_table(file_path),
      error = function(e) NULL
    )
    
    if (is.null(df)) {
      upload_ok_splice(FALSE)
      user_splice_df(NULL)
      error_msg <- "Could not read the file. Please check that it is a plain text table (tab, comma, or semicolon separated)."
    } else if (ncol(df) != 4) {
      upload_ok_splice(FALSE)
      user_splice_df(NULL)
      error_msg <- "File must have exactly 4 columns."
    } else if (!is.character(df[[1]])) {
      upload_ok_splice(FALSE)
      user_splice_df(NULL)
      error_msg <- "First column must be character (Event IDs)."
    } else if (!is.numeric(df[[3]])) {
      upload_ok_splice(FALSE)
      user_splice_df(NULL)
      error_msg <- "Third column must be numeric (dPSI values)."
    } else {
      colnames(df) <- c("Event.ID", "Gene", "dPSI", "PDiff")
      upload_ok_splice(TRUE)
      user_splice_df(df)
      error_msg <- NULL
      
    }
    
    output$file_warning_splice <- renderUI({
      if (upload_ok_splice()) {
        df_prev <- user_splice_df()
        tagList(
          div(style = "color:green; font-weight:bold; margin-top:10px;",
              sprintf("\u2713 Upload successful — %d events detected.", nrow(df_prev))),
          tags$small(style = "color:#666;",
                     paste("Columns:", paste(colnames(df_prev), collapse = ", "))),
          br(),
          DT::renderDataTable(
            head(df_prev, 6),
            options = list(dom = "t", ordering = FALSE, pageLength = 6),
            rownames = FALSE,
            class    = "compact"
          )
        )
      } else {
        div(style = "color:red; font-weight:bold; margin-top:10px;",
            paste("Upload failed:", error_msg))
      }
    })
  })
  # ---- Only show extra options if upload is successful ----
  output$user_file_options_splice <- renderUI({
    if (!upload_ok_splice()) return(NULL)
    
    tagList(
      selectizeInput(
        inputId = "user_file_compare_splice",
        label = "Compare with specific RBPs (optional)",
        choices = ALL_RBP_NAMES,
        multiple = TRUE,
        options = list(placeholder = "Select one or more RBPs")
      ),
      numericInput(
        "user_file_topN_splice",
        "Show top N correlated RBPs (optional):",
        value = NA, min = 1
      ),
      helpText("Tip: You may use one or both of the numeric inputs below."),
      numericInput(
        "user_file_n_pos_splice",
        "Show top N positive correlations (optional):",
        value = NA, min = 1
      ),
      numericInput(
        "user_file_n_neg_splice",
        "Show top N negative correlations (optional):",
        value = NA, min = 1
      ),
      div(
        style = "display: flex; align-items: center; margin-top: 15px;",
        actionButton(
          "user_file_plot_btn_splice",
          tagList(fa("chart-line"), " Plot"),
          class = "btn btn-primary",
          style = "margin-right: 10px; border-radius: 20px;"
        ),
        actionButton(
          "user_file_reset_btn_splice",
          tagList(fa("redo"), " Reset"),
          class = "btn btn-secondary",
          style = "border-radius: 20px;"
        )
      )
    )
  })
  
  # Auto-preview violin plot for uploaded file
  output$user_file_initial_plot_splice <- renderPlot({
    req(upload_ok_splice())          # only plot after successful upload
    df <- user_splice_df()
    req(df)
    
    # derive Type from Event.ID (same logic as your function)
    dpsi_table <- df %>%
      mutate(Type = case_when(
        startsWith(Event.ID, "HsaEX")  ~ "EX",
        startsWith(Event.ID, "HsaINT") ~ "IR",
        TRUE                           ~ NA_character_
      )) %>%
      filter(!is.na(Type))
    
    # If no EX/IR events present, show a message plot
    if (nrow(dpsi_table) == 0) {
      dl_store$splice_initial(NULL)
      plot.new()
      title(main = "No EX or IR events detected in uploaded file")
      return(invisible(NULL))
    }
    
    # Calculate average dPSI by type (safe)
    avg_vals <- dpsi_table %>%
      group_by(Type) %>%
      summarise(mean_dPSI = mean(dPSI, na.rm = TRUE)) %>%
      pivot_wider(names_from = Type, values_from = mean_dPSI)
    
    # Build subtitle text safely (handle missing types)
    mean_EX <- ifelse("EX" %in% names(avg_vals), sprintf("%.3f", avg_vals$EX), "NA")
    mean_IR <- ifelse("IR" %in% names(avg_vals), sprintf("%.3f", avg_vals$IR), "NA")
    subtitle_text <- paste0("Mean dPSI — EX: ", mean_EX, " | IR: ", mean_IR)
    
    # Violin + jitter plot similar to your function
    p <- ggplot(dpsi_table, aes(x = Type, y = dPSI)) +
      geom_jitter(width = 0.2, alpha = 0.6, size = 1.5) +
      geom_violin(alpha = .7) +
      theme_charm() +
      ylab("dPSI (shRNA - CTRL)") +
      xlab("Event Type") +
      ggtitle("Uploaded data", subtitle = subtitle_text) +
      coord_flip() +
      geom_hline(yintercept = 0, linetype = "dashed")
    dl_store$splice_initial(p)
    p
  })
  
  # ---- Render similarity plots ----
  observeEvent(input$user_file_plot_btn_splice, {
    req(user_splice_df())
    # This feature loads all 3 Charm.object variants from disk before it can
    # build any of the comparison plots below, which is the actual slow part
    # (the plots themselves render quickly once the placeholders exist) --
    # show the global status banner for that load instead of leaving the
    # user staring at nothing until everything pops in at once.
    show_status("Loading comparison datasets — please wait…")
    on.exit(hide_status(), add = TRUE)
    selected_rbps <- input$user_file_compare_splice

    # NOTE: this feature compares all 3 cell lines side by side, so it
    # necessarily materializes all 3 Charm.object variants at once for the
    # duration of this action -- that's inherent to what it does. Loaded via
    # load_all_charm_variants() (direct qload(), bypassing the single-slot
    # get_charm_object() cache) so requesting all 3 back-to-back doesn't
    # evict-and-reload each one out from under the next.
    datasets <- load_all_charm_variants()

    output$similar_splice_plots_file <- renderUI({
      tagList(
        lapply(names(datasets), function(ds_name) {
          # See the "userfile_plot_" block above for why this is sanitized.
          # Include the plot TYPE in the output id. The same id must never be
          # reused across renderHighchart (scatter, 1 RBP) and renderPlot (bar,
          # 0/>1 RBPs): Shiny keeps the previous type's client-side binding and
          # the new plot won't appear until the UI is torn down -- that was the
          # "have to click Reset after a scatter" symptom. Distinct ids fix it.
          is_scatter <- !is.null(selected_rbps) && length(selected_rbps) == 1
          plotname <- paste0("userfile_plot_splice_",
                             if (is_scatter) "scatter_" else "bar_",
                             gsub("[^A-Za-z0-9_]+", "_", ds_name))
          dl_ui <- NULL

          if (is_scatter) {
            output[[plotname]] <- renderHighchart({
              correl_splicing_rbp_hc(datasets[[ds_name]], user_splice_df(), selected_rbps)
            })
            plot_ui <- highchartOutput(plotname, height = "500px")
          } else {
            output[[plotname]] <- renderPlot({
              heat_res <- splicing_correl(
                datasets[[ds_name]],
                user_splice_df(),
                correl_num = input$user_file_topN_splice,
                n_pos = input$user_file_n_pos_splice,
                n_neg = input$user_file_n_neg_splice,
                other_rbps = if (!is.null(selected_rbps) && length(selected_rbps) > 1) selected_rbps else NULL,
                ref_key = corr_key("splice", ds_name)
              )
              dyn_dl_store[[plotname]] <- heat_res$heatmap
              heat_res$heatmap  # <-- make sure to return $heatmap, not $plot
            })
            plot_ui <- plotOutput(plotname, height = corr_plot_height(corr_key("splice", ds_name)))
            dl_id <- paste0("dl_", plotname)
            output[[dl_id]] <- make_dyn_dl_handler(plotname, paste0("splicing_discovery_", plotname))
            dl_ui <- downloadButton(dl_id, "↓ Download plot",
                                    class = "btn btn-sm btn-default", style = "margin-top:5px;")
          }

          column(
            width = 12,
            tags$h4(ds_name, style = "text-align:center;"),
            shinycssloaders::withSpinner(plot_ui),
            dl_ui
          )
        }) %>% tagList()
      )
    })
  })
  # ---- Reset button ----
  observeEvent(input$user_file_reset_btn_splice, {
    # Clear the UI for user_file plots
    output$similar_splice_plots_file <- renderUI(NULL)
    
    # Reset the selectize input
    updateSelectizeInput(session, "user_file_compare_splice", selected = "")
    
    # Reset numeric inputs if any
    updateNumericInput(session, "user_file_topN_splice", value = NA)
    updateNumericInput(session, "user_file_n_pos_splice", value = NA)
    updateNumericInput(session, "user_file_n_neg_splice", value = NA)
  })
  
  #BINDING (Discovery Mode)
  upload_ok_binding <- reactiveVal(FALSE)
  user_binding_df   <- reactiveVal(NULL)

  observeEvent(input$user_file_binding, {
    req(input$user_file_binding)
    # Unlike the Expression/Splicing upload handlers, this one had no status
    # feedback at all -- the user just sees nothing happen until the file
    # preview AND the Discovery options panel both pop in together, which
    # reads as "this takes forever" even when the actual parsing is quick.
    show_status("Reading uploaded file — please wait…")
    on.exit(hide_status(), add = TRUE)
    file_path <- input$user_file_binding$datapath

    df <- tryCatch(
      read_user_table(file_path),
      error = function(e) NULL
    )

    error_msg <- NULL

    if (is.null(df)) {
      error_msg <- "Could not read the file. Please check that it is a plain text table (tab, comma, or semicolon separated)."
    } else if (ncol(df) != 4) {
      error_msg <- "File must have exactly 4 columns (Event.ID, Gene, dPSI, PDiff)."
    } else if (!is.character(df[[1]])) {
      error_msg <- "First column must be character (Event IDs)."
    } else if (!is.numeric(df[[3]])) {
      error_msg <- "Third column must be numeric (dPSI values)."
    } else {
      colnames(df) <- c("Event.ID", "Gene", "dPSI", "PDiff")
    }

    if (is.null(error_msg)) {
      upload_ok_binding(TRUE)
      user_binding_df(df)
    } else {
      upload_ok_binding(FALSE)
      user_binding_df(NULL)
    }

    output$file_warning_binding <- renderUI({
      if (upload_ok_binding()) {
        df_prev <- user_binding_df()
        tagList(
          div(style = "color:green; font-weight:bold; margin-top:10px;",
              sprintf("\u2713 Upload successful — %d events detected.", nrow(df_prev))),
          tags$small(style = "color:#666;",
                     paste("Columns:", paste(colnames(df_prev), collapse = ", "))),
          br(),
          DT::renderDataTable(
            head(df_prev, 6),
            options = list(dom = "t", ordering = FALSE, pageLength = 6),
            rownames = FALSE,
            class    = "compact"
          )
        )
      } else {
        div(style = "color:red; font-weight:bold; margin-top:10px;",
            paste("Upload failed:", error_msg))
      }
    })
  })

  # ---- Binding Discovery Mode: dynamic options shown after successful upload ----
  # NOTE: this used to nest uiOutput("binding_disc_target_ui") inside this
  # renderUI, with the target selectizeInput built in a SEPARATE renderUI
  # keyed off the same upload_ok_binding()/input$binding_eventtype. That
  # extra layer of dynamic UI costs a full additional client<->server
  # round-trip (render this panel -> browser requests the nested uiOutput ->
  # server responds) on top of the one this panel itself already needs --
  # the exact round-trip Splicing Discovery's single flat renderUI
  # (user_file_options_splice) doesn't pay, which is why upload options
  # there appear noticeably faster despite parsing an identical file.
  # Flattening into one renderUI (matching the Splicing pattern) removes
  # that extra round-trip.
  output$binding_discovery_options <- renderUI({
    if (!upload_ok_binding()) return(NULL)
    req(input$binding_eventtype)
    target_choices <- if (grepl("Intron Retention", input$binding_eventtype, ignore.case = TRUE)) {
      sort(ALL_BINDING_RBP_NAMES_IR)
    } else {
      sort(ALL_BINDING_RBP_NAMES_ES)
    }
    tagList(
      hr(),
      tags$h5("eCLIPSE Binding Map"),
      tags$p("Visualise where an RBP (or multiple RBPs) binds relative to splicing events in your uploaded data. Select one target for a full binding map, or multiple targets for a heatmap overview.",
             style = "font-size: 12px; color: #666; margin-top: -5px;"),
      selectizeInput(
        "binding_disc_target",
        "Target(s) — RBP binding profile to visualise:",
        choices  = c("All", target_choices),
        multiple = TRUE,
        options  = list(placeholder = "Select one or more targets, or \'All\'")
      ),
      selectInput(
        "binding_disc_psi_thresh",
        "\u0394PSI threshold:",
        choices  = c("0.01", "0.05", "0.10", "0.15", "0.20", "0.25", "0.30"),
        selected = "0.05"
      ),
      selectInput(
        "binding_disc_metric",
        "Metric:",
        choices  = c("FDR", "EffectSize"),
        selected = "FDR"
      ),
      div(
        style = "display: flex; align-items: center; margin-top: 15px;",
        actionButton(
          "binding_disc_plot_btn",
          tagList(fa("chart-line"), " Plot"),
          class = "btn btn-primary",
          style = "margin-right: 10px; border-radius: 20px;"
        ),
        actionButton(
          "binding_disc_reset_btn",
          tagList(fa("redo"), " Reset"),
          class = "btn btn-secondary",
          style = "border-radius: 20px;"
        )
      )
    )
  })

  
  # ---- Binding Discovery Mode: plot button ----
  observeEvent(input$binding_disc_plot_btn, {
    req(upload_ok_binding(), user_binding_df(),
        input$binding_disc_target,
        input$binding_eventtype)

    event_type   <- input$binding_eventtype
    psi_thresh   <- as.numeric(input$binding_disc_psi_thresh)
    metric       <- input$binding_disc_metric
    targets_sel  <- input$binding_disc_target

    rnamapfile <- if (grepl("Intron Retention", event_type, ignore.case = TRUE)) {
      eCLIPSE_Intron_full
    } else {
      eCLIPSE_BigExon_full
    }

    # Resolve "All" to every available target
    all_rbps <- if (grepl("Intron Retention", event_type, ignore.case = TRUE)) {
      ALL_BINDING_RBP_NAMES_IR
    } else {
      ALL_BINDING_RBP_NAMES_ES
    }
    if ("All" %in% targets_sel) targets_sel <- all_rbps

    n_targets <- length(targets_sel)

    if (n_targets == 1) {
      # Single target: full eCLIPSE line-plot
      output$binding_discovery_plot_ui <- renderUI({
        tagList(
          shinycssloaders::withSpinner(
            plotOutput("binding_disc_plot", height = "600px"),
            type = 6
          ),
          uiOutput("dl_ui_binding_disc")
        )
      })

      output$binding_disc_plot <- renderPlot({
        # Guard (Issue #4): confirm the uploaded betAS table still carries the
        # columns eCLIPSE_raw_user reads. The upload handler positionally maps
        # and renames the 4 columns to Event.ID/Gene/dPSI/PDiff, so the AllwSG
        # example (bare-\r line endings normalised by read_user_table) lands
        # here in the right shape; this surfaces a readable message if a
        # malformed file ever slips through instead of erroring in the analysis.
        shiny::validate(
          need(all(c("Event.ID", "dPSI") %in% names(user_binding_df())),
               "Uploaded file is missing required columns (Event.ID, dPSI).")
        )
        p <- withProgress(message = "Generating eCLIPSE binding map...", value = 0.1, {
          eCLIPSE_raw_user(
            rnamapfile   = rnamapfile,
            ASfile       = user_binding_df(),
            rnaBP        = targets_sel,
            event_type   = event_type,
            PSIthreshold = psi_thresh,
            metric       = metric,
            plot         = TRUE
          )
        })
        dl_store$binding_disc(p)
        p
      })

    } else {
      # Multiple targets: heatmap
      height_px <- min(900 + (n_targets - 1) * 10, 2000)

      output$binding_discovery_plot_ui <- renderUI({
        tagList(
          shinycssloaders::withSpinner(
            plotOutput("binding_disc_plot", height = paste0(height_px, "px")),
            type = 6
          ),
          uiOutput("dl_ui_binding_disc")
        )
      })

      output$binding_disc_plot <- renderPlot({
        # Guard (Issue #4): confirm the uploaded betAS table still carries the
        # columns eCLIPSE_raw_user reads. The upload handler positionally maps
        # and renames the 4 columns to Event.ID/Gene/dPSI/PDiff, so the AllwSG
        # example (bare-\r line endings normalised by read_user_table) lands
        # here in the right shape; this surfaces a readable message if a
        # malformed file ever slips through instead of erroring in the analysis.
        shiny::validate(
          need(all(c("Event.ID", "dPSI") %in% names(user_binding_df())),
               "Uploaded file is missing required columns (Event.ID, dPSI).")
        )
        p <- withProgress(message = "Generating heatmap...", value = 0.1, {
          build_binding_heatmap_user(
            rnamapfile   = rnamapfile,
            ASfile       = user_binding_df(),
            targets      = targets_sel,
            event_type   = event_type,
            PSIthreshold = psi_thresh,
            metric       = metric
          )
        })
        dl_store$binding_disc(p)
        p
      })
    }
  })
  # ---- Binding Discovery Mode: reset button ----
  observeEvent(input$binding_disc_reset_btn, {
    output$binding_discovery_plot_ui <- renderUI(NULL)
    dl_store$binding_disc(NULL)
  })
  
  # ---- Volcano plot helper ----
  make_volcano_plot <- function(tbl, rbp) {
    if (is.null(tbl) || nrow(tbl) == 0) {
      ggplot() + annotate("text", x = 0, y = 0, label = paste("No results for", rbp), family = CHARM_FONT) + theme_charm_void()
    } else {
      ggplot(tbl, aes(x = logFC, y = B,
                      text = paste0("Gene: ", gene,
                                    "<br>logFC: ", round(logFC,2),
                                    "<br>B: ", round(B,2),
                                    "<br>P: ", signif(P.Value,3)))) +
        geom_point(aes(color = highlight, size = highlight), alpha = 0.7) +
        scale_color_manual(values = c("None"="#CCCCCC",
                                      "RBP"="#A10702",
                                      "Selected"="#008057")) +
        # The highlighted "RBP" point (the searched RBP's own gene) renders
        # bigger than the background cloud, matching the on-screen
        # highcharter version below.
        scale_size_manual(values = c("None"=1.5, "RBP"=4, "Selected"=2.5)) +
        theme_charm() +
        labs(title=paste(rbp,"KD"), x="Log2 Fold-Change", y="B-statistic") +
        theme(legend.position = "none") +
        theme(legend.position = "none")
    }
  }

  # ---- Shared click handler for interactive highcharter scatter/volcano
  # plots ----
  # NOTE on the switch from plotly: we deliberately don't use highcharter's
  # own hc_add_event_point() helper here. Reading its source shows it always
  # reads `this.category.name`, which is only defined for category-type axes
  # (e.g. bar charts) -- for continuous numeric axes like ours, `this.category`
  # is undefined and that line throws a JS TypeError, silently killing the
  # click handler. This is a minimal replacement that only reads fields we
  # actually attach via hcaes() (x, y, gene, key), so it can't hit that bug.
  # Uses Shiny.setInputValue(..., {priority: "event"}) so re-clicking the same
  # point still fires the observer even when the payload is unchanged.
  hc_add_click_input <- function(hc, output_id) {
    hc %>%
      highcharter::hc_plotOptions(series = list(
        cursor = "pointer",
        point = list(events = list(click = htmlwidgets::JS(sprintf(
          "function() {
             var pt = {x: this.x, y: this.y, gene: this.gene, key: this.key};
             if (typeof Shiny !== 'undefined') {
               Shiny.setInputValue('%s_click', pt, {priority: 'event'});
             }
           }", output_id
        ))))
      ))
  }

  # ---- Volcano plot helper (interactive, highcharter) ----
  # Mirrors make_volcano_plot() above but renders directly with highcharter
  # instead of wrapping a ggplot with ggplotly(); make_volcano_plot() itself
  # is left untouched since it still feeds the PNG download handler.
  make_volcano_plot_hc <- function(tbl, rbp, output_id = "volcano_plot") {
    if (is.null(tbl) || nrow(tbl) == 0) {
      return(highcharter::highchart() %>% charm_hc_style() %>% highcharter::hc_title(text = paste("No results for", rbp)))
    }
    # Per-point hex color (rather than group=highlight + hc_colors()) so
    # coloring is exact regardless of which highlight categories happen to
    # be present in tbl -- group-based coloring is assigned positionally to
    # whichever groups survive dplyr::group_by()'s default unused-level
    # dropping, which can silently misalign if e.g. no row is "RBP" yet.
    # This also avoids a legend/series-toggle UI that the original
    # (legend.position = "none") never had.
    highlight_colors <- c("None" = "#CCCCCC", "RBP" = "#A10702", "Selected" = "#008057")
    plot_df <- tbl
    plot_df$point_color <- unname(highlight_colors[plot_df$highlight])
    plot_df$logfc_r <- round(plot_df$logFC, 2)
    plot_df$b_r     <- round(plot_df$B, 2)
    plot_df$p_r     <- signif(plot_df$P.Value, 3)

    # Highcharts only supports a per-point marker RADIUS via a nested
    # marker:{radius:} object on manually built point lists -- hcaes()'s flat
    # column mapping (how per-point *color* already works, e.g. point_color
    # above) can't express that. Splitting into two series -- background
    # cloud vs. the highlighted "RBP" point(s) -- lets each use its own fixed
    # series-level marker radius, so the RBP's own gene renders visibly
    # bigger than the rest, in addition to its red color.
    is_rbp <- plot_df$highlight == "RBP"
    bg_df  <- plot_df[!is_rbp, , drop = FALSE]
    rbp_df <- plot_df[ is_rbp, , drop = FALSE]

    hc <- highcharter::highchart() %>%
      charm_hc_style() %>% highcharter::hc_title(text = paste(rbp, "KD")) %>%
      highcharter::hc_xAxis(title = list(text = "Log2 Fold-Change")) %>%
      highcharter::hc_yAxis(title = list(text = "B-statistic")) %>%
      highcharter::hc_tooltip(pointFormat = "Gene: {point.gene}<br>logFC: {point.logfc_r}<br>B: {point.b_r}<br>P: {point.p_r}") %>%
      highcharter::hc_legend(enabled = FALSE) %>%
      hc_add_click_input(output_id)

    if (nrow(bg_df) > 0) {
      hc <- hc %>%
        highcharter::hc_add_series(
          data = bg_df, type = "scatter",
          highcharter::hcaes(x = logFC, y = B, color = point_color, gene = gene,
                             logfc_r = logfc_r, b_r = b_r, p_r = p_r),
          marker = list(radius = 5, lineWidth = 1, lineColor = "black"),
          showInLegend = FALSE
        )
    }
    if (nrow(rbp_df) > 0) {
      hc <- hc %>%
        highcharter::hc_add_series(
          data = rbp_df, type = "scatter",
          highcharter::hcaes(x = logFC, y = B, color = point_color, gene = gene,
                             logfc_r = logfc_r, b_r = b_r, p_r = p_r),
          marker = list(radius = 9, lineWidth = 1, lineColor = "black"),
          showInLegend = FALSE
        )
    }
    hc
  }

  # ---- Splicing volcano plot helper (interactive, highcharter) ----
  # Mirrors the ggplot built inline in the "Splicing" server blocks below
  # (dPSI vs Pdiff, colored by highlight, tooltip keyed by Event.ID).
  make_splice_volcano_plot_hc <- function(tbl, rbp, output_id = "plot_splice_volcano") {
    if (is.null(tbl) || nrow(tbl) == 0) {
      return(highcharter::highchart() %>% charm_hc_style() %>% highcharter::hc_title(text = paste("No results for", rbp)))
    }
    # See make_volcano_plot_hc() above for why this uses per-point hex
    # color instead of group=highlight + hc_colors().
    highlight_colors <- c("None" = "#CCCCCC", "RBP" = "#A10702", "Selected" = "#008057")
    plot_df <- tbl
    plot_df$point_color <- unname(highlight_colors[plot_df$highlight])

    highcharter::hchart(
      plot_df, "scatter",
      highcharter::hcaes(x = dPSI, y = Pdiff, color = point_color, key = Event.ID),
      fast = TRUE
    ) %>%
      charm_hc_style() %>% highcharter::hc_title(text = paste0("Volcano Plot: ", rbp, " KD")) %>%
      highcharter::hc_xAxis(title = list(text = "dPSI (shRNA - CTRL)")) %>%
      highcharter::hc_yAxis(title = list(text = "PDiff")) %>%
      highcharter::hc_tooltip(pointFormat = "Event: {point.key}") %>%
      highcharter::hc_plotOptions(scatter = list(marker = list(radius = 5, lineWidth = 1, lineColor = "black"))) %>%
      highcharter::hc_legend(enabled = FALSE) %>%
      hc_add_click_input(output_id)
  }

  # ---- React to clicking a point in the volcano ----
  # ed$gene comes straight from the clicked point's own data (attached via
  # hcaes(gene = gene) in make_volcano_plot_hc / hc_add_click_input), so this
  # is an exact match rather than the old plotly-era nearest-point-by-distance
  # heuristic.
  observeEvent(input$volcano_plot_click, {
    ed <- input$volcano_plot_click
    tbl <- display_table()
    if (!is.null(ed) && !is.null(ed$gene) && nrow(tbl) > 0) {
      clicked_gene <- ed$gene

      # Update highlights
      tbl$highlight <- ifelse(tbl$gene == clicked_gene, "Selected",
                              ifelse(tbl$gene == rbp_current(), "RBP", "None"))

      # Reorder table to bring selected gene on top
      tbl <- rbind(tbl[tbl$gene == clicked_gene, ], tbl[tbl$gene != clicked_gene, ])
      display_table(tbl)

      # Re-render volcano plot
      output$volcano_plot <- renderHighchart({
        make_volcano_plot_hc(display_table(), rbp_current())
      })
    }
  })

  # ---- React to selecting a row in the table ----
  observeEvent(input$volcano_table_rows_selected, {
    sel_row <- input$volcano_table_rows_selected
    if (is.null(sel_row)) return()
    tbl <- display_table()
    sel_gene <- tbl$gene[sel_row]

    # Update highlights
    tbl$highlight <- ifelse(tbl$gene == sel_gene, "Selected",
                            ifelse(tbl$gene == rbp_current(), "RBP", "None"))
    display_table(tbl)

    # Re-render volcano plot
    output$volcano_plot <- renderHighchart({
      make_volcano_plot_hc(display_table(), rbp_current())
    })
  })
  
  # ---- Main: search button triggers all plots ----
  observeEvent(input$search_btn_rbp, {
    req(input$expr_search_rbp)
    rbp_sel <- input$expr_search_rbp
    rbp_current(rbp_sel)
    
    # Auto-clear previous outputs before rendering new ones —
    # eliminates the need for the "please reset" warning banner
    output$expr_violin    <- renderPlot(NULL)
    output$shrna_plot     <- renderPlot(NULL)
    output$shrna_warning  <- renderUI(NULL)
    output$volcano_plot   <- renderHighchart(NULL)
    output$volcano_table  <- renderDT(NULL)
    output$gsea_plot      <- renderPlot(NULL)
    output$geneset_table  <- renderDT(NULL)
    display_table(NULL)
    
    # Searching the main RBP plot brings it back to the top: hide gene/hallmark panel
    expr_top_panel(NULL)
    
    charm_obj <- current_charm_expr()
    shrna_obj <- current_shrna_expr()
    
    # Checks data *validity*, not just name presence -- see
    # valid_expr_rbp_names(). An RBP can exist as a name in this dataset
    # variant while its corcounts/SampleType are missing/degenerate (e.g.
    # CPEB4 outside the K562 variant), which used to sail past a plain
    # names(charm_obj) check and crash further down.
    exp_list <- valid_expr_rbp_names(charm_obj)
    # (Also fixes a stale reference: this used to read input$cell_line,
    # an input ID that doesn't exist anywhere in the UI -- the dataset
    # selector's real ID is expr_dataset -- so the message always printed
    # blank.)
    if (is.null(exp_list) || !(rbp_sel %in% exp_list)) {
      showModal(modalDialog(
        title = "Warning",
        paste("This RBP has no information available for", input$expr_dataset),
        easyClose = TRUE,
        footer = NULL
      ))
      return(NULL)
    }
    
    show_status("Generating expression plots \u2014 please wait\u2026")
    
    output$expr_violin <- renderPlot({
      p <- violinplotter(charm_obj, rbp_sel)
      dl_store$expr_violin(p)
      p
    })
    
    output$shrna_plot <- renderPlot({
      p <- plot_shRNA_effect(shrna_obj, rbp_sel)
      dl_store$shrna(p)
      p
    })
    output$shrna_warning <- renderUI({
      # Indexing a data.frame by a row name that isn't present (e.g. an RBP
      # with no shRNA-efficiency data, such as CPEB4) silently returns a row
      # of NAs rather than erroring -- so guard explicitly via %in% and check
      # for NA before the if(), otherwise "if (NA || NA)" throws "missing
      # value where TRUE/FALSE needed" and crashes this render (and, since it
      # ran inline, can take the whole session down with it).
      if (is.null(shrna_obj) || !(rbp_sel %in% rownames(shrna_obj))) return(NULL)
      stats <- shrna_obj[rbp_sel,,drop=FALSE]
      if (is.null(stats) || nrow(stats)==0) return(NULL)
      logFC <- stats$logFC
      pval <- stats$P.Value
      if (is.na(pval) || is.na(logFC)) return(NULL)
      if (pval > 0.05 || logFC > -0.5) {
        div(style="margin-top:10px;font-size:16px;font-weight:bold;color:red;",
            "WARNING: The efficiency of this knockdown is uncertain. Proceed with caution.")
      } else NULL
    })
    
    result <- plot_rbp_volcano(charm_obj, rbp_sel)
    tbl <- build_volcano_table(result, rbp_sel)
    if (nrow(tbl) == 0) {
      hide_status()
      showModal(modalDialog(
        title = "No data",
        paste("No differential expression results are available for", rbp_sel,
              "in this cell line — its data may be incomplete."),
        easyClose = TRUE, footer = NULL
      ))
      return(NULL)
    }
    display_table(tbl)

    output$volcano_table <- renderDT({
      datatable(display_table(),
                filter = "none",
                selection = "single",
                rownames = FALSE,
                options = list(pageLength = 10, scrollX = TRUE, searching = TRUE))
    })
    
    output$volcano_plot <- renderHighchart({
      p <- make_volcano_plot(display_table(), rbp_sel)
      dl_store$volcano(p)
      make_volcano_plot_hc(display_table(), rbp_sel)
    })
    
    gsea_result <- plot_gsea(charm_obj, rbp_sel, thresh = 0.05)
    gsea_table_rv(gsea_result$geneset_table)
    output$gsea_plot <- renderPlot({
      # on.exit guarantees the "generating plots" banner clears even if
      # something in this render throws -- a plain hide_status() call at the
      # end never runs if an earlier line errors.
      on.exit(hide_status(), add = TRUE)
      p <- gsea_result$gsea_plot
      dl_store$gsea(p)
      p
    })
    output$geneset_table <- renderDT({
      datatable(gsea_result$geneset_table,
                filter = "none",
                rownames = FALSE,
                options = list(pageLength = 10, scrollX = TRUE))
    })
  })
  # ---- Gene Search ----
  observeEvent(input$search_btn_gene, {
    req(input$expr_search_gene)
    gene <- input$expr_search_gene
    charm_obj <- current_charm_expr()
    show_status("Generating gene plot \u2014 please wait\u2026")
    expr_top_panel("gene")
    
    output$expr_gene_plot <- renderPlot({
      # on.exit fires even when shiny::validate()/need() below stops execution (an
      # unrecognized gene) -- the plain hide_status() call after it would
      # never run in that case, leaving the status banner stuck up.
      on.exit(hide_status(), add = TRUE)
      shiny::validate(
        need(gene %in% unlist(lapply(charm_obj, function(x) rownames(x$DEGenes))),
             paste("Gene", gene, "not found in any RBP DEGenes tables."))
      )
      p <- plot_gene_t_barplot(charm_obj, gene)
      dl_store$expr_gene(p)
      p
    })
    
  })
  
  # ---- Hallmark Gene Set Search ----
  observeEvent(input$search_btn_hallmark, {
    req(input$expr_search_hallmark)
    geneset <- input$expr_search_hallmark
    charm_obj <- current_charm_expr()
    show_status("Generating hallmark plot \u2014 please wait\u2026")
    expr_top_panel("hallmark")
    
    output$expr_hallmark_plot <- renderPlot({
      on.exit(hide_status(), add = TRUE)
      shiny::validate(
        need(geneset %in% unlist(lapply(charm_obj, function(x) x$GSEA$pathway)),
             paste0("Geneset '", geneset, "' not found in any RBP GSEA tables."))
      )
      p <- plot_hallmark_nes_barplot(charm_obj, geneset)
      dl_store$expr_hallmark(p)
      p
    })
    
  })
  
  # Reactive values to store what the user selected
  similar_plot_inputs <- reactiveVal(list(
    rbp1 = NULL,
    selected_rbps = NULL,
    mode = NULL
  ))
  
  # ---- Populate Similar RBPs selectize inputs ----
  observe({
    req(ALL_RBP_NAMES)  # make sure the RBP name list exists
    rbp_names <- ALL_RBP_NAMES
    
    # Expression correlation selectize
    updateSelectizeInput(
      session,
      "similar_rbps_select_expr",
      choices = rbp_names,
      server = TRUE
    )
    
    # GSEA correlation selectize
    updateSelectizeInput(
      session,
      "similar_rbps_select_gsea",
      choices = rbp_names,
      server = TRUE
    )
  })
  # ---- Similar RBPs: Expression/GSEA correlation ----
  observeEvent(input$similar_plot_btn, {
    req(input$expr_dataset)
    if (input$expr_dataset != "Similar RBPs") return(NULL)
    req(input$expr_search_rbp)
    rbp1 <- input$expr_search_rbp
    mode <- input$similar_mode
    
    # Auto-clear previous output
    output$similar_expr_plots <- renderUI(NULL)
    
    # Datasets
    datasets <- list(
      "Both Cells" = if(mode == "expr") similar_expression_all else similar_gsea_all,
      "K562"       = if(mode == "expr") similar_expression_K562 else similar_gsea_K562,
      "HEPG2"      = if(mode == "expr") similar_expression_HEPG2 else similar_gsea_HEPG2
    )
    
    # Functions
    scatter_fun <- if(mode == "expr") correl_exp_rbp_hc else correl_scatter_gsea_hc
    heatmap_fun <- if(mode == "expr") exp_correl else gsea_correl
    
    # Inputs
    selected_rbps <- if(mode == "expr") input$similar_rbps_select_expr else input$similar_rbps_select_gsea
    correl_num <- if(mode == "expr") input$correl_num_expr else input$correl_num_gsea
    n_pos      <- if(mode == "expr") input$n_pos_expr else input$n_pos_gsea
    n_neg      <- if(mode == "expr") input$n_neg_expr else input$n_neg_gsea
    
    if(length(selected_rbps) == 0) selected_rbps <- NULL
    
    # Render plots UI
    output$similar_expr_plots <- renderUI({
      # Use lapply and wrap columns in tagList() properly
      tagList(
        lapply(names(datasets), function(ds_name) {
          # See the "userfile_plot_" block above for why this is sanitized.
          plotname <- paste0("similar_plot_", gsub("[^A-Za-z0-9_]+", "_", ds_name))
          
          if (!is.null(selected_rbps) && length(selected_rbps) == 1) {
            output[[plotname]] <- renderHighchart({
              scatter_fun(datasets[[ds_name]], rbp1, selected_rbps[1], plot_title = ds_name)
            })
            plot_ui <- highchartOutput(plotname, height = "500px")
          } else {
            output[[plotname]] <- renderPlot({
              heat_res <- heatmap_fun(
                datasets[[ds_name]], rbp1,
                correl_num = correl_num,
                n_pos = n_pos,
                n_neg = n_neg,
                other_rbps = if(!is.null(selected_rbps) && length(selected_rbps) > 1) selected_rbps else NULL,
                ref_key = corr_key(if (mode == "expr") "expr" else "gsea", ds_name)
              )
              # always return ggplot object
              heat_res$heatmap
            })
            plot_ui <- plotOutput(plotname, height = corr_plot_height(corr_key(if (mode == "expr") "expr" else "gsea", ds_name)))
          }
          
          # Return the column for renderUI
          column(
            width = 12,
            tags$h4(ds_name, style = "text-align:center;"),
            shinycssloaders::withSpinner(plot_ui)
          )
        }) %>% tagList()  # <-- flatten the list of columns
      )
    })
  })
  
  # ---- Main: Splicing Explore ----
  observeEvent(input$splice_search_btn, {
    req(input$splice_search)
    rbp_sel <- input$splice_search
    rbp_current(rbp_sel)
    
    # Auto-clear previous outputs before rendering new ones
    output$violin_splice_plot   <- renderPlot(NULL)
    output$plot_shrna_effect    <- renderPlot(NULL)
    output$shrna_warning_splice <- renderUI(NULL)
    output$plot_splice_volcano  <- renderHighchart(NULL)
    output$splice_volcano_table <- renderDT(NULL)
    
    # Searching the main RBP plot brings it back to the top: hide Event ID panel
    splice_top_panel(NULL)
    
    charm_obj <- current_charm_splice()
    shrna_obj <- current_shrna_splice()
    
    splice_list <- valid_splice_rbp_names(charm_obj)
    if (is.null(splice_list) || !(rbp_sel %in% splice_list)) {
      showModal(modalDialog(
        title = "Warning",
        paste("This RBP has no splicing information available."),
        easyClose = TRUE,
        footer = NULL
      ))
      return(NULL)
    }
    
    show_status("Generating splicing plots \u2014 please wait\u2026")
    
    
    
    # ---- Top row: Violin + shRNA knockdown plots ----
    output$violin_splice_plot <- renderPlot({
      on.exit(hide_status(), add = TRUE)
      p <- violin_splice_plot(charm_obj, rbp_sel)
      dl_store$splice_violin(p)
      p
    })
    
    output$plot_shrna_effect <- renderPlot({
      p <- plot_shRNA_effect(shrna_obj, rbp_sel)
      dl_store$shrna_splice(p)
      p
    })
    
    output$shrna_warning_splice <- renderUI({
      # Same NA-crash guard as the Expression tab's shrna_warning (see there
      # for the full explanation): an RBP absent from shrna_obj's rownames
      # returns a row of NAs, not an error, and if(NA || NA) is fatal.
      if (is.null(shrna_obj) || !(rbp_sel %in% rownames(shrna_obj))) return(NULL)
      stats <- shrna_obj[rbp_sel,,drop=FALSE]
      if (is.null(stats) || nrow(stats) == 0) return(NULL)
      logFC <- stats$logFC
      pval <- stats$P.Value
      if (is.na(pval) || is.na(logFC)) return(NULL)
      if (pval > 0.05 || logFC > -0.5) {
        div(style="margin-top:10px;font-size:16px;font-weight:bold;color:red;",
            "WARNING: The efficiency of this knockdown is uncertain. Proceed with caution.")
      } else NULL
    })
    
    # ---- Second row: Volcano plot ----
    splice_res <- plot_splice_volcano(charm_obj, rbp_sel)
    if (is.null(splice_res)) {
      output$plot_splice_volcano <- renderPlot({
        ggplot() + annotate("text", x = 0, y = 0, label = paste("No results for", rbp_sel), family = CHARM_FONT) + theme_charm_void()
      })
      output$splice_volcano_table <- DT::renderDataTable(NULL)
      return()
    }
    
    # Store results in reactiveVal
    result_splice(splice_res)
    
    # ---- Helper to render volcano ----
    render_volcano <- function(tbl) {
      p <- ggplot(tbl, aes(x = dPSI, y = Pdiff, key = Event.ID, color = highlight)) +
        geom_point(alpha = 0.7) +
        scale_color_manual(values = c("None"="#CCCCCC","RBP"="#A10702","Selected"="#008057")) +
        theme_charm() +
        theme(legend.position = "none") +
        labs(title = paste0("Volcano Plot: ", rbp_sel, " KD"), x = "dPSI (shRNA - CTRL)", y = "PDiff")
      dl_store$splice_volcano(p)
      make_splice_volcano_plot_hc(tbl, rbp_sel)
    }

    # ---- Render volcano plot ----
    output$plot_splice_volcano <- renderHighchart({
      req(result_splice())
      render_volcano(result_splice()$top_table)
    })
    
    # ---- Render table ----
    output$splice_volcano_table <- DT::renderDataTable({
      req(result_splice())
      result_splice()$top_table %>% select(-text)
    }, rownames = FALSE, selection = "single", options = list(pageLength = 10))
    
    # ---- Shared function to update highlights ----
    update_highlight <- function(selected_event) {
      if (is.null(selected_event) || length(selected_event) == 0) return(NULL)
      tbl <- result_splice()$top_table
      if (!selected_event %in% tbl$Event.ID) return(NULL)
      
      tbl$highlight <- ifelse(tbl$Event.ID == selected_event, "Selected",
                              ifelse(tbl$Event.ID %in% input$splice_search, "RBP", "None"))
      
      result_splice(list(
        top_table = tbl,
        volcano_plot = result_splice()$volcano_plot
      ))
      
      # Sync table selection
      proxy <- DT::dataTableProxy("splice_volcano_table")
      sel_idx <- which(tbl$highlight == "Selected")
      DT::selectRows(proxy, sel_idx)
    }
    
    # ---- React to selecting a row in the table ----
    observeEvent(input$splice_volcano_table_rows_selected, {
      sel_row <- input$splice_volcano_table_rows_selected
      if (is.null(sel_row)) return()
      selected_event <- result_splice()$top_table$Event.ID[sel_row]
      update_highlight(selected_event)
    })
    
    # ---- React to clicking a point in the volcano plot ----
    observeEvent(input$plot_splice_volcano_click, {
      click <- input$plot_splice_volcano_click
      if (is.null(click) || is.null(click$key)) return()
      clicked_event <- click$key
      update_highlight(clicked_event)
    })
    
  })
  
  # ---- Event ID Search ----
  observeEvent(input$splice_event_btn, {
    req(input$splice_event_search)
    event_id <- input$splice_event_search
    charm_obj <- current_charm_splice()
    
    output$heatmap_splicing_dpsi <- renderPlot({
      plot_event_dpsi_barplot(charm_obj, event_id)
    })
  })
  
  # ---- Similar RBPs: Splicing correlation ----
  observeEvent(input$similar_plot_btn_splice, {
    req(input$splice_dataset)
    if (input$splice_dataset != "Similar RBPs") return(NULL)
    req(input$splice_search)
    rbp1 <- input$splice_search

    # Loading feedback for the slow part: load_all_charm_variants() below reads
    # all 3 Charm.object variants from disk before any plot placeholder exists,
    # so without this the Similar RBPs panels show nothing during the wait (the
    # per-plot withSpinner only covers the fast render once the outputs exist).
    # Mirrors the Discovery-mode Similar RBPs observer.
    show_status("Loading comparison datasets — please wait…")
    on.exit(hide_status(), add = TRUE)

    # Auto-clear previous output
    output$similar_splice_plots <- renderUI(NULL)
    
    # Only one mode currently
    mode <- "splice"
    
    # Choose datasets. NOTE: compares all 3 cell lines side by side, so this
    # necessarily materializes all 3 Charm.object variants at once for the
    # duration of this action. Loaded via load_all_charm_variants() (direct
    # qload(), bypassing the single-slot get_charm_object() cache) so the 3
    # back-to-back loads don't evict-and-reload each other -- see its
    # definition for why that mattered.
    datasets <- load_all_charm_variants()
    
    scatter_fun <- correl_splicing_rbp_hc
    heatmap_fun <- splicing_correl
    
    selected_rbps <- input$similar_rbps_select_splice
    correl_num <- input$correl_num_splice
    n_pos      <- input$n_pos_splice
    n_neg      <- input$n_neg_splice
    
    if (length(selected_rbps) == 0) selected_rbps <- NULL
    
    output$similar_splice_plots <- renderUI({
      tagList(
        lapply(names(datasets), function(ds_name) {
          # See the "userfile_plot_" block above for why this is sanitized.
          # Type-specific id (see the discovery observer above): never reuse one
          # output id across the scatter (highchart) and bar (plot) render types.
          is_scatter <- !is.null(selected_rbps) && length(selected_rbps) == 1
          plotname <- paste0("similar_splice_plot_",
                             if (is_scatter) "scatter_" else "bar_",
                             gsub("[^A-Za-z0-9_]+", "_", ds_name))

          if (is_scatter) {
            output[[plotname]] <- renderHighchart({
              # Guard: the searched reference RBP and the single comparison
              # RBP must both exist in THIS cell line's Charm object -- an
              # RBP profiled in one line can be absent from another, which
              # would otherwise throw a hard error in just that panel.
              # shiny::validate() turns that into a readable message instead.
              shiny::validate(
                need(rbp1 %in% names(datasets[[ds_name]]),
                     paste0(rbp1, " is not available in ", ds_name, ".")),
                need(all(selected_rbps %in% names(datasets[[ds_name]])),
                     paste0("Selected RBP(s) not available in ", ds_name, "."))
              )
              scatter_fun(datasets[[ds_name]], rbp1, selected_rbps)
            })
            plot_ui <- highchartOutput(plotname, height = "500px")
          } else {
            output[[plotname]] <- renderPlot({
              # Same cross-cell-line guard as the scatter branch above.
              shiny::validate(
                need(rbp1 %in% names(datasets[[ds_name]]),
                     paste0(rbp1, " is not available in ", ds_name, "."))
              )
              # selected_rbps is a character vector here (multiple = TRUE)
              # and is passed straight through as other_rbps whenever >1 was
              # chosen, so splicing_correl receives a proper vector and the
              # multi-RBP comparison renders instead of collapsing to the
              # single-RBP path.
              heat_res <- heatmap_fun(
                datasets[[ds_name]], rbp1,
                correl_num = correl_num,
                n_pos = n_pos,
                n_neg = n_neg,
                other_rbps = if (!is.null(selected_rbps) && length(selected_rbps) > 1) selected_rbps else NULL,
                ref_key = corr_key("splice", ds_name)
              )
              heat_res$heatmap
            })
            plot_ui <- plotOutput(plotname, height = corr_plot_height(corr_key("splice", ds_name)))
          }
          
          column(
            width = 12,
            tags$h4(ds_name, style = "text-align:center;"),
            shinycssloaders::withSpinner(plot_ui)
          )
        }) %>% tagList()  # flatten
      )
    })
  })
  
  
  # ---- Reset Similar RBPs Splicing plots ----
  observeEvent(input$similar_reset_btn_splice, {
    output$similar_splice_plots <- renderUI(NULL)
    updateSelectizeInput(session, "similar_rbps_select_splice", selected = "")
    updateNumericInput(session, "correl_num_splice", value = NA)
    updateNumericInput(session, "n_pos_splice", value = NA)
    updateNumericInput(session, "n_neg_splice", value = NA)
  })
  
  # ---- Reset buttons Expression ----
  observeEvent(input$similar_reset_btn, {
    output$similar_expr_plots <- renderUI(NULL)
    updateSelectizeInput(session, "similar_rbps_select_expr", selected = "")
    updateSelectizeInput(session, "similar_rbps_select_gsea", selected = "")
  })
  
  observeEvent(input$reset_btn_rbp, {
    output$expr_violin    <- renderPlot(NULL)
    output$shrna_plot     <- renderPlot(NULL)
    output$shrna_warning  <- renderUI(NULL)
    output$volcano_plot   <- renderHighchart(NULL)
    output$volcano_table  <- renderDT(NULL)
    output$gsea_plot      <- renderPlot(NULL)
    output$geneset_table  <- renderDT(NULL)
    display_table(NULL)
    rbp_current(NULL)
    gsea_table_rv(NULL)
    dl_store$expr_violin(NULL); dl_store$shrna(NULL)
    dl_store$volcano(NULL);     dl_store$gsea(NULL)
    updateSelectizeInput(session, "expr_search", selected = "")
  })
  observeEvent(input$reset_btn_gene, {
    output$expr_gene_plot <- renderPlot(NULL)
    if (identical(expr_top_panel(), "gene")) expr_top_panel(NULL)
  })
  
  observeEvent(input$reset_btn_hallmark, {
    output$expr_hallmark_plot <- renderPlot(NULL)
    if (identical(expr_top_panel(), "hallmark")) expr_top_panel(NULL)
  })
  # ---- Reset buttons for Splicing tab ----
  
  # 1️⃣ Similar RBPs reset
  observeEvent(input$similar_reset_btn_splice, {
    output$similar_splice_plots <- renderUI(NULL)
    updateSelectizeInput(session, "similar_rbps_select_splice", selected = "")
  })
  
  # 2️⃣ RBP search reset
  observeEvent(input$splice_reset_btn, {
    output$violin_splice_plot    <- renderPlot(NULL)
    output$plot_shrna_effect     <- renderPlot(NULL)
    output$shrna_warning_splice  <- renderUI(NULL)
    output$plot_splice_volcano   <- renderHighchart(NULL)
    output$splice_volcano_table  <- renderDT(NULL)
    result_splice(NULL)
    rbp_current(NULL)
    dl_store$splice_violin(NULL); dl_store$shrna_splice(NULL)
    dl_store$splice_volcano(NULL)
    updateSelectizeInput(session, "splice_search", selected = "")
  })
  
  # 3️⃣ Event ID search reset
  # Reset Event heatmap
  observeEvent(input$splice_event_reset_btn, {
    output$heatmap_splicing_dpsi <- renderPlot(NULL)  # clear plot
    dl_store$event_dpsi(NULL)
    splice_top_panel(NULL)  # hides the panel (and its now-stale download button)
    updateSelectizeInput(session, "splice_search_event", selected = "")  # clear search (matches the actual input ID)
  })
  
  # =========================
  # 1. Binding dataset selector
  # =========================
  binding_data <- reactive({
    req(input$binding_eventtype, input$binding_dataset)

    if (input$binding_eventtype %in% c("Exon Skipping", "Intron Retention")) {
      return(get_binding_object(input$binding_eventtype, input$binding_dataset))
    }

    NULL
  })
  
  
  
  # =========================
  # 2. RBP selector
  # =========================
  observeEvent(binding_data(), {
    data <- binding_data()
    if (!is.null(data)) {
      updateSelectizeInput(
        session, "binding_search",
        choices = names(data),
        server = TRUE
      )
    }
  })
  
  # =========================
  # 3. Target selector
  # =========================
  output$binding_target_ui <- renderUI({
    req(input$binding_search)
    data <- binding_data()
    rbp <- input$binding_search
    all_targets <- sort(names(data[[rbp]]))

    # If we're arriving here via cross-tab navigation, binding_nav_target()
    # already holds the target to pre-select. Bake it into `selected` at
    # creation time instead of updating it afterward via
    # updateSelectizeInput() -- that update message races the client-side
    # creation of this very widget and gets silently dropped if it arrives
    # first, which left binding_target (and the binding_dpsi UI that depends
    # on it) unset and results() never firing.
    nav_tgt <- binding_nav_target()
    preselected <- if (!is.null(nav_tgt) && nav_tgt %in% all_targets) nav_tgt else NULL

    selectizeInput(
      "binding_target",
      "Target(s):",
      choices = c("All", all_targets),
      selected = preselected,
      multiple = TRUE,
      options = list(placeholder = "Select one or more targets, or 'All'")
    )
  })
  
  # Warn when many targets selected — heatmap will be slow / unreadable
  output$binding_target_warning <- renderUI({
    tgts <- input$binding_target
    if (is.null(tgts) || length(tgts) == 0) return(NULL)
    n <- if ("All" %in% tgts) {
      data <- binding_data()
      rbp  <- input$binding_search
      length(names(data[[rbp]]))
    } else {
      length(tgts)
    }
    if (n > 10) {
      div(
        style = "background:#fff3cd; border:1px solid #ffc107; border-radius:6px;
                 padding:7px 10px; margin-top:5px; font-size:11px; color:#856404;",
        tags$b("\u26a0 Large selection:"),
        sprintf(" %d targets selected. Generating the heatmap may take
                 30\u201360 seconds. Consider selecting fewer targets for faster results.", n)
      )
    }
  })
  
  # =========================
  # 4. dPSI selector (corrected)
  # =========================
  
  
  output$binding_dpsi_ui <- renderUI({
    req(input$binding_search, input$binding_target)
    
    data <- binding_data()
    rbp <- input$binding_search
    targets <- input$binding_target
    
    # Cleanly handle "All"
    hide_labels <- FALSE
    
    if ("All" %in% targets) {
      targets <- names(data[[rbp]])
    }
    # Single-target mode
    if (length(targets) == 1) {
      dpsi_names <- names(data[[rbp]][[targets]])
      dpsi_nums  <- suppressWarnings(as.numeric(sub(" .*", "", dpsi_names)))
      selected   <- dpsi_names[which.min(abs(dpsi_nums))]
      
      return(selectInput(
        "binding_dpsi",
        "dPSI:",
        choices  = setNames(dpsi_names, dpsi_names),
        selected = selected
      ))
    }
    
    # Multi-target mode
    options_multi <- c(
      "0.05", "0.1",
      "maximised oddsratinc", "maximised oddsratdec",
      "maximised pvalinc", "maximised pvaldec"
    )
    
    selectInput(
      "binding_dpsi",
      "dPSI:",
      choices = setNames(options_multi, options_multi),
      selected = "0.05"
    )
  })
  
  # =========================
  # 5. Metric mapping
  # =========================
  binding_metric_name <- reactive({
    if (input$binding_metric == "FDR")        return("pval")
    if (input$binding_metric == "EffectSize") return("oddsrat")
  })
  
  
  # =========================
  # 6. RUN HEAVY FUNCTION WHEN SEARCH IS PRESSED (updated with metric fix)
  # =========================
  
  schematic_exon_skipping <- function() {
    list(
      rects = data.frame(
        xmin = c(0, 450, 950),
        xmax = c(50, 550, 1000),
        ymin = -0.8,
        ymax = -0.2,
        fill = c("#1B4F72", "#BA3B46", "#1B4F72")
      ),
      introns = data.frame(
        x = c(50, 550),
        xend = c(450, 950),
        y = -0.5,
        yend = -0.5
      ),
      arrow = data.frame(
        x = 50, xend = 950, y = -0.1, yend = -0.1
      ),max_x = 1000 
    )
  }
  
  
  schematic_intron_retention <- function() {
    list(
      rects = data.frame(
        xmin = c(0, 450),
        xmax = c(50, 500),
        ymin = -0.8,
        ymax = -0.2,
        fill = c("#1B4F72", "#1B4F72")
      ),
      intron_rect = data.frame(
        xmin = 50,
        xmax = 450,
        ymin = -0.7,
        ymax = -0.3
      ),max_x = 500
    )
  }
  
  
  # -------------------------------
  # Helper: pick dPSI per target
  # -------------------------------
  resolve_dpsi_key <- function(dpsi_names, choice){
    if (is.null(dpsi_names) || length(dpsi_names) == 0 || is.null(choice)) return(NULL)
    
    # ---- 1. Exact match (this covers single-target mode, where `choice` IS
    #         one of the real keys, e.g. "0.02 (maximised pvaldec)") ----
    if (choice %in% dpsi_names) return(list(key = choice, fallback = FALSE))
    
    choice_lc <- tolower(choice)
    
    # ---- 2. Plain numeric threshold choice, e.g. "0.05" or "0.1" ----
    # Keys look like "0.05 (oddsratinc)" -- match the number exactly (escaped),
    # followed by a space or open-paren, and make sure it is NOT a "maximised" key.
    if (grepl("^[0-9.]+$", choice)) {
      pattern <- paste0("^", gsub("\\.", "\\\\.", choice), "[ (]")
      hits <- dpsi_names[grepl(pattern, dpsi_names) & !grepl("maximised", tolower(dpsi_names))]
      if (length(hits) > 0) return(list(key = hits[1], fallback = FALSE))
      return(NULL)  # that exact threshold isn't available for this target
    }
    
    # ---- 3. "maximised <metric><direction>" choice, e.g. "maximised pvaldec" ----
    # The metric+direction suffix (oddsratinc/oddsratdec/pvalinc/pvaldec) must
    # match exactly -- the leading number is target-specific and not part of
    # the match (that's the whole point of "maximised").
    if (grepl("^maximised", choice_lc)) {
      suffix <- trimws(sub("^maximised", "", choice_lc))  # e.g. "pvaldec", "oddsratinc"
      # Match keys containing "maximised <suffix>" specifically (parenthesised or not)
      pattern <- paste0("maximised\\s+", suffix, "\\b")
      hits <- dpsi_names[grepl(pattern, tolower(dpsi_names))]
      if (length(hits) > 0) return(list(key = hits[1], fallback = FALSE))
      
      # Fallback: this target has no "maximised <suffix>" key -- use its 0.1 entry instead
      hits_01 <- dpsi_names[grepl("^0\\.1[ (]", dpsi_names) & !grepl("maximised", tolower(dpsi_names))]
      if (length(hits_01) > 0) return(list(key = hits_01[1], fallback = TRUE))
      return(NULL)  # neither the maximised key nor a 0.1 fallback is available
    }
    
    # ---- 4. Unrecognised choice: no safe fallback: 4 maximised options and the two
    #         numeric ones are mutually exclusive categories, so silently picking a
    #         different one would be misleading. ----
    NULL
  }
  
  # -------------------------------
  # build_binding_heatmap (refactored)
  # -------------------------------
  build_binding_heatmap <- function(data, rbp, targets, dpsi_choice, metric, hide_row_labels = FALSE) {
    
    # -----------------------------
    # 1. Helper: pad list to matrix
    # -----------------------------
    pad_and_rbind <- function(lst) {
      if (length(lst) == 0) return(NULL)
      lengths <- sapply(lst, length)
      maxlen <- max(lengths)
      mat <- t(sapply(lst, function(v) {
        if (is.null(v)) return(rep(NA_real_, maxlen))
        if (length(v) < maxlen) return(c(v, rep(NA_real_, maxlen - length(v))))
        v
      }))
      rownames(mat) <- names(lst)
      
      # Drop rows that are entirely NA
      mat <- mat[rowSums(!is.na(mat)) > 0, , drop = FALSE]
      mat
    }
    
    # -----------------------------
    # 2. Build numeric vectors
    # -----------------------------
    inc_list <- list()
    dec_list <- list()
    fallback_targets <- character(0)  # targets that fell back to 0.1 (no maximised key)
    
    # Totals depend only on the shRNA (rbp) + dPSI threshold, not on target,
    # so we grab them once from the first target that has valid data (see the
    # "maximised" handling below for why that threshold isn't always `key`).
    inc_total <- NA
    maint_total <- NA
    dec_total <- NA
    totals_captured <- FALSE
    
    get_value <- function(df) {
      if (is.null(df) || nrow(df) == 0) return(NA)
      if ("Value" %in% names(df)) return(df$Value[1])
      as.numeric(df[1,1])
    }
    
    # For "maximised" dPSI choices, the threshold (and therefore the totals)
    # genuinely differs per target, so there is no single shared total. In
    # that case we always report the totals from the 0.1 threshold instead,
    # which is target-independent and stable.
    is_maximised_choice <- grepl("^maximised", tolower(dpsi_choice))
    
    for (tgt in targets) {
      if (is.null(data[[rbp]][[tgt]])) next
      dpsi_names <- names(data[[rbp]][[tgt]])
      resolved <- resolve_dpsi_key(dpsi_names, dpsi_choice)
      if (is.null(resolved)) next
      key <- resolved$key
      if (isTRUE(resolved$fallback)) fallback_targets <- c(fallback_targets, tgt)
      
      if (metric == "FDR") {
        inc_raw <- tryCatch(data[[rbp]][[tgt]][[key]]$pval$pvalinc, error = function(e) NULL)
        dec_raw <- tryCatch(data[[rbp]][[tgt]][[key]]$pval$pvaldec, error = function(e) NULL)
      } else {
        inc_raw <- tryCatch(data[[rbp]][[tgt]][[key]]$oddsrat$oddsratinc, error = function(e) NULL)
        dec_raw <- tryCatch(data[[rbp]][[tgt]][[key]]$oddsrat$oddsratdec, error = function(e) NULL)
      }
      
      inc_vec <- if (is.data.frame(inc_raw) && "Value" %in% names(inc_raw)) as.numeric(inc_raw$Value) else suppressWarnings(as.numeric(inc_raw))
      dec_vec <- if (is.data.frame(dec_raw) && "Value" %in% names(dec_raw)) as.numeric(dec_raw$Value) else suppressWarnings(as.numeric(dec_raw))
      
      if (!is.null(inc_vec) && !all(is.na(inc_vec))) inc_list[[tgt]] <- inc_vec
      if (!is.null(dec_vec) && !all(is.na(dec_vec))) dec_list[[tgt]] <- dec_vec
      
      # Capture the shRNA-level totals once (same for every target/dPSI key).
      # For "maximised" choices, always pull the totals from the 0.1 key
      # specifically, since the actual maximised threshold is target-specific
      # and there's no single shared total across targets in that case.
      if (!totals_captured) {
        totals_key <- key
        if (is_maximised_choice) {
          totals_resolved <- resolve_dpsi_key(dpsi_names, "0.1")
          if (!is.null(totals_resolved)) totals_key <- totals_resolved$key else totals_key <- NULL
        }
        if (!is.null(totals_key)) {
          this_data_tot <- tryCatch(data[[rbp]][[tgt]][[totals_key]], error = function(e) NULL)
          if (!is.null(this_data_tot)) {
            inc_total_tmp   <- get_value(this_data_tot$raw$TotalIncreasedEvents)
            maint_total_tmp <- get_value(this_data_tot$raw$TotalMaintainedEvents)
            dec_total_tmp   <- get_value(this_data_tot$raw$TotalDecreasedEvents)
            if (!is.na(inc_total_tmp) || !is.na(maint_total_tmp) || !is.na(dec_total_tmp)) {
              inc_total   <- inc_total_tmp
              maint_total <- maint_total_tmp
              dec_total   <- dec_total_tmp
              totals_captured <- TRUE
            }
          }
        }
      }
    }
    
    if (length(inc_list) == 0 && length(dec_list) == 0) {
      return(ggplot() + theme_charm_void() + ggtitle("No heatmap data"))
    }
    
    inc_mat <- pad_and_rbind(inc_list)
    dec_mat <- pad_and_rbind(dec_list)
    
    # Mark fallback targets in row names with an asterisk so it's visible on the
    # heatmap y-axis (no "maximised" key was available; used 0.1 instead)
    mark_fallback <- function(mat) {
      if (is.null(mat)) return(NULL)
      rn <- rownames(mat)
      rownames(mat) <- ifelse(rn %in% fallback_targets, paste0(rn, " *"), rn)
      mat
    }
    inc_mat <- mark_fallback(inc_mat)
    dec_mat <- mark_fallback(dec_mat)
    
    # -----------------------------
    # 3. Determine color limits
    # -----------------------------
    all_vals <- c(as.numeric(inc_mat), as.numeric(dec_mat))
    all_vals <- all_vals[is.finite(all_vals)]
    lim <- if (length(all_vals) == 0) c(-1,1) else { mx <- max(abs(all_vals)); if(mx==0) c(-1,1) else c(-mx,mx) }
    
    fill_label <- if(metric=="FDR") "FDR" else "Chi-Squared\nStatistic"
    
    # -----------------------------
    # 4. Determine event type & schematic
    # -----------------------------
    etype <- NULL
    try({
      if (exists("input", envir = parent.frame())) {
        pf_input <- get("input", envir = parent.frame())
        if (!is.null(pf_input$binding_eventtype)) etype <- pf_input$binding_eventtype
      }
    }, silent = TRUE)
    if (is.null(etype)) etype <- "Exon Skipping"
    
    schem <- if (grepl("Intron Retention", etype, ignore.case = TRUE)) {
      schematic_intron_retention()
    } else {
      schematic_exon_skipping()
    }
    
    # -----------------------------
    # 5. Plot matrix helper
    # -----------------------------
    plot_matrix <- function(mat, title_text, schematic) {
      if (is.null(mat)) return(NULL)
      
      mdf <- reshape2::melt(mat)
      colnames(mdf) <- c("Target","Position","Value")
      mdf$Position <- as.numeric(mdf$Position)
      
      # Preserve matrix row order for y-axis
      mdf$Target <- factor(mdf$Target, levels = rownames(mat))
      
      max_pos <- max(mdf$Position, na.rm = TRUE)
      n_rows <- nrow(mat)
      
      # Dashed vertical lines depending on event type
      vlines_raw <- if (grepl("Intron Retention", etype, ignore.case = TRUE)) {
        c(50, 250, 450)
      } else {
        c(50, 250, 450, 500, 550, 750, 950)
      }
      vlines_scaled <- vlines_raw * (max_pos / schematic$max_x)
      
      # Use geom_segment to restrict vertical lines to actual rows
      vline_df <- data.frame(x = vlines_scaled)
      
      p <- ggplot(mdf, aes(x=Position, y=Target, fill=Value)) +
        geom_tile() +
        scale_fill_gradient2(low="#A6B1E1", mid="#EEEEEE", high="#B07156", limits=lim, oob=scales::squish) +
        labs(x="Genomic position", y="", fill=fill_label, title=title_text) +
        theme_charm() +
        theme(axis.line = element_blank(), axis.ticks = element_blank(),
        axis.text.y = if(hide_row_labels) element_blank() else element_text()) +
        geom_segment(data=vline_df,
                     aes(x=x, xend=x, y=1, yend=n_rows),
                     linetype="dashed", color="black", linewidth=0.4,
                     inherit.aes=FALSE) +
        scale_y_discrete(expand = expansion(mult=c(0, 0)))+
        coord_cartesian(clip="off")
      
      # Add schematic under heatmap
      if (!is.null(schematic$rects)) {
        rects <- schematic$rects
        rects$xmin <- rects$xmin * (max_pos / schematic$max_x)
        rects$xmax <- rects$xmax * (max_pos / schematic$max_x)
        p <- p + geom_rect(data=rects,
                           aes(xmin=xmin, xmax=xmax, ymin=ymin, ymax=ymax),
                           fill=rects$fill, color="black", linewidth=0.3,
                           inherit.aes=FALSE)
      }
      if (!is.null(schematic$intron_rect)) {
        ir <- schematic$intron_rect
        ir$xmin <- ir$xmin * (max_pos / schematic$max_x)
        ir$xmax <- ir$xmax * (max_pos / schematic$max_x)
        p <- p + geom_rect(data=ir,
                           aes(xmin=xmin, xmax=xmax, ymin=ymin, ymax=ymax),
                           fill="#E5E7E9", color="black", linewidth=0.3,
                           inherit.aes=FALSE)
      }
      if (!is.null(schematic$introns)) {
        intr <- schematic$introns
        intr$x   <- intr$x   * (max_pos / schematic$max_x)
        intr$xend <- intr$xend * (max_pos / schematic$max_x)
        p <- p + geom_segment(data=intr,
                              aes(x=x, xend=xend, y=y, yend=yend),
                              linewidth=0.8, inherit.aes=FALSE)
      }
      
      return(p)
    }
    
    # -----------------------------
    # 6. Build plots
    # -----------------------------
    heat_inc_plot <- plot_matrix(inc_mat, "Increased Events", schem)
    heat_dec_plot <- plot_matrix(dec_mat, "Decreased Events", schem)
    
    # -----------------------------
    # 6b. Labels row (shRNA-level totals, shared across all targets)
    # -----------------------------
    inc_color   <- "#de425b"
    dec_color   <- "#769fca"
    maint_color <- "black"
    
    labels_plot <- ggplot() +
      annotate("text", x = 1, y = 0,
               label = paste0("Increased: ", inc_total, "\n"),
               color = inc_color, size = CHARM_GEOM_TEXT, fontface = "bold", hjust = -0.75, family = CHARM_FONT) +
      annotate("text", x = 1, y = 0,
               label = paste0("Maintained: ", maint_total, "\n"),
               color = maint_color, size = CHARM_GEOM_TEXT, fontface = "bold", hjust = 0.5, family = CHARM_FONT) +
      annotate("text", x = 1, y = 0,
               label = paste0("Decreased: ", dec_total, "\n"),
               color = dec_color, size = CHARM_GEOM_TEXT, fontface = "bold", hjust = 1.75, family = CHARM_FONT) +
      theme_charm_void() +
      theme(plot.margin = margin(t = 0, r = 0, b = 0, l = 0))
    
    # -----------------------------
    # 7. Combine side-by-side
    # -----------------------------
    heat_row <- NULL
    if (!is.null(heat_dec_plot) && !is.null(heat_inc_plot)) {
      heat_row <- ggpubr::ggarrange(heat_dec_plot, heat_inc_plot, ncol=2, widths=c(0.5,0.5))
    } else if (!is.null(heat_dec_plot)) {
      heat_row <- heat_dec_plot
    } else if (!is.null(heat_inc_plot)) {
      heat_row <- heat_inc_plot
    }
    
    if (!is.null(heat_row)) {
      footnote_lines <- character(0)
      if (is_maximised_choice) {
        footnote_lines <- c(footnote_lines,
          "Increased/Maintained/Decreased totals above use the 0.1 threshold (no single shared total exists across targets for 'maximised' choices).")
      }
      if (length(fallback_targets) > 0) {
        footnote_lines <- c(footnote_lines,
          "* No 'maximised' dPSI value available for this target — showing its 0.1 threshold instead.")
      }
      
      if (length(footnote_lines) > 0) {
        footnote <- ggplot() +
          annotate("text", x = 0.5, y = 0.5,
                   label = paste(footnote_lines, collapse = "\n"),
                   size = CHARM_GEOM_TEXT, fontface = "italic", hjust = 0.5, family = CHARM_FONT) +
          theme_charm_void()
        return(ggpubr::ggarrange(labels_plot, heat_row, footnote, ncol = 1, heights = c(0.05, 0.88, 0.07)))
      }
      return(ggpubr::ggarrange(labels_plot, heat_row, ncol = 1, heights = c(0.06, 0.94)))
    }
    
    ggplot() + theme_charm_void() + ggtitle("No heatmap data")
  }
  
  
  # -------------------------------
  # results reactive
  # -------------------------------
  results <- eventReactive(input$search_btn, {
    withProgress(message = "Generating Plot...", value = 0, {
      incProgress(0.05)

      # Use binding_nav_target if set (navigation case), otherwise read from UI
      nav_tgt <- binding_nav_target()
      targets <- if (!is.null(nav_tgt)) {
        binding_nav_target(NULL)   # consume and clear
        nav_tgt
      } else {
        input$binding_target
      }

      # Only binding_search/targets are hard requirements. binding_dpsi and
      # binding_metric both already have graceful fallback handling below
      # (metric defaults to "FDR"; a missing/invalid dpsi produces a "not
      # available" message plot via resolve_dpsi_key()) -- req()'ing them
      # here contradicted that and silently killed this whole reactive
      # whenever they weren't populated yet, which is exactly what happens
      # during cross-tab navigation: the simulated Search click can fire
      # before the Binding sidebar's cascading dpsi/metric inputs have
      # rendered. When that happened, results() never resolved, so
      # eclipse_plot's hide_status() (which only runs once results()
      # succeeds) never ran either -- the "Loading binding data..." status
      # stayed up forever with nothing to clear it.
      req(input$binding_search, targets)
      
      data <- binding_data()
      rbp  <- input$binding_search
      
      # NEW: define hide_labels
      hide_labels <- FALSE
      
      if ("All" %in% targets) {
        targets <- names(data[[rbp]])
      }
      
      metric <- input$binding_metric
      if (is.null(metric) || !(metric %in% c("FDR","EffectSize"))) metric <- "FDR"
      
      incProgress(0.2)
      
      if (length(targets) == 1) {
        # Single target: regular eCLIPSE plot
        dpsi_names <- names(data[[rbp]][[targets]])
        dpsi_resolved <- resolve_dpsi_key(dpsi_names, input$binding_dpsi)
        if (is.null(dpsi_resolved)) {
          return(ggplot() +
                   annotate("text", x = 0.5, y = 0.5,
                            label = paste0("dPSI option '", input$binding_dpsi,
                                           "' is not available for ", rbp, " - ", targets, "."),
                            size = CHARM_GEOM_TEXT, hjust = 0.5, family = CHARM_FONT) +
                   theme_charm_void())
        }
        dpsi_key   <- dpsi_resolved$key
        dpsi_value <- suppressWarnings(as.numeric(sub(" .*", "", dpsi_key)))
        # eCLIPSE_full() builds its own "<target> Binding Profile - Upon
        # <rnaBP> KD" title from its rnaBP/target arguments -- plot_title
        # here is only an optional appended note (e.g. the dPSI fallback
        # warning), not the main title text.
        plot_title <- NULL
        if (isTRUE(dpsi_resolved$fallback)) {
          plot_title <- "[* fell back to 0.1, no maximised value available]"
        }
        p <- eCLIPSE_full(
          bindingvalues_nested = data,
          rnaBP = rbp,
          target = targets,
          dPSI = dpsi_value,
          metric = metric,
          title = plot_title,
          schematic_exon_skipping = schematic_exon_skipping,
          schematic_intron_retention = schematic_intron_retention
        )
        return(p)
      } else {
        # Multiple targets: heatmap
        return(build_binding_heatmap(
          data,
          rbp,
          targets,
          input$binding_dpsi,
          metric,
          hide_row_labels = hide_labels   # FIXED
        ))
      }
      
      incProgress(1)
    })
  })
  
  # ---- Helper reactive: pick the correct binding similarity object list ----
  binding_sim_objects <- reactive({
    req(input$binding_eventtype)
    is_IR  <- grepl("Intron Retention", input$binding_eventtype, ignore.case = TRUE)
    prefix <- if (is_IR) "IR" else "ES"
    cache  <- binding_sim_cache()   # triggers lazy load on first call
    
    list(
      "Both Cells" = list(
        inc = cache[[paste0("similar_binding_", prefix, "_both_inc")]],
        dec = cache[[paste0("similar_binding_", prefix, "_both_dec")]]
      ),
      "K562" = list(
        inc = cache[[paste0("similar_binding_", prefix, "_K562_inc")]],
        dec = cache[[paste0("similar_binding_", prefix, "_K562_dec")]]
      ),
      "HEPG2" = list(
        inc = cache[[paste0("similar_binding_", prefix, "_HEPG2_inc")]],
        dec = cache[[paste0("similar_binding_", prefix, "_HEPG2_dec")]]
      )
    )
  })
  
  # ─────────────────────────────────────────────────────────────────────────────
  # EXPLORE MODE — Similar Profiles (binding_dataset == "Similar Profiles")
  #
  # SUPERSEDED: this original implementation (query auto-derived from the
  # currently-searched RBP+target, single direction, 3 result panels) has
  # been replaced in the UI by the more flexible query-profile picker below
  # (output$binding_similar_profiles_options / the "PATCH 8/9" plot+reset
  # observers, 6 result panels) -- that UI used to live under Discovery mode
  # by mistake and has been moved into this Explore-mode panel instead. The
  # inputs below (binding_explore_sim_target_ui/_plot_btn/_reset_btn) no
  # longer have any UI element bound to them, so this code is inert; left
  # in place rather than deleted in case any of the plotting logic is
  # wanted again later.
  # ─────────────────────────────────────────────────────────────────────────────

  # ---- Target selector: targets available for the chosen RBP, current event type ----
  output$binding_explore_sim_target_ui <- renderUI({
    req(input$binding_search, input$binding_dataset == "Similar Profiles")
    
    sim_objs <- binding_sim_objects()
    # Use "Both Cells" / "inc" as the universe of profile IDs (RBP__Target pairs
    # are the same set across inc/dec for a given event type + cell line).
    all_ids <- rownames(sim_objs[["Both Cells"]]$inc$mean_profiles)
    if (is.null(all_ids)) all_ids <- character(0)
    
    rbp <- input$binding_search
    rbp_targets <- sort(unique(sub("^[^_]*__", "", all_ids[startsWith(all_ids, paste0(rbp, "__"))])))
    
    selectizeInput(
      "binding_explore_sim_target",
      "Target:",
      choices  = rbp_targets,
      multiple = FALSE,
      options  = list(placeholder = "Select a target")
    )
  })
  
  # ---- Plot button: render the 3 cell-line panels for the chosen pair/direction ----
  observeEvent(input$binding_explore_sim_plot_btn, {
    req(input$binding_dataset == "Similar Profiles",
        input$binding_search,
        input$binding_explore_sim_target,
        input$binding_eventtype)
    
    rbp      <- input$binding_search
    target   <- input$binding_explore_sim_target
    query_id <- paste0(rbp, "__", target)
    dir_sel  <- input$binding_explore_sim_direction   # "inc" or "dec"
    
    topN    <- input$binding_explore_sim_topN
    n_close <- input$binding_explore_sim_n_close
    n_far   <- input$binding_explore_sim_n_far
    
    # If the user left every filter blank, default to the top 10 closest
    # profiles instead of plotting every profile in the dataset.
    if (is.na(topN) && is.na(n_close) && is.na(n_far)) n_close <- 10
    
    sim_objs      <- binding_sim_objects()
    dataset_names <- c("Both Cells", "K562", "HEPG2")
    
    output$binding_explore_similar_plot_ui <- renderUI({
      tagList(
        tags$h4(paste0("Similar Profiles to ", query_id,
                       " (", if (dir_sel == "inc") "Increased" else "Decreased",
                       " Events)"),
                style = "text-align:center;"),
        lapply(dataset_names, function(ds_name) {
          fluidRow(
            column(width = 12,
                   tags$h5(ds_name, style = "text-align:center;"),
                   shinycssloaders::withSpinner(
                     plotOutput(paste0("binding_explore_sim_plot_", gsub(" ", "", ds_name)),
                                height = "450px"),
                     type = 6
                   )
            )
          )
        }) %>% tagList()
      )
    })
    
    for (ds in dataset_names) {
      local({
        ds_local <- ds
        plot_id  <- paste0("binding_explore_sim_plot_", gsub(" ", "", ds_local))
        
        output[[plot_id]] <- renderPlot({
          sim_obj <- sim_objs[[ds_local]][[dir_sel]]
          res <- binding_profile_correl(
            sim_obj       = sim_obj,
            query_id      = query_id,
            top_n         = if (!is.na(topN))    topN    else NULL,
            n_close       = if (!is.na(n_close)) n_close else NULL,
            n_far         = if (!is.na(n_far))   n_far   else NULL,
            other_ids     = NULL,
            direction     = dir_sel,
            dataset_label = ds_local
          )
          res$heatmap
        })
      })
    }
  })
  
  # ---- Reset button ----
  observeEvent(input$binding_explore_sim_reset_btn, {
    output$binding_explore_similar_plot_ui <- renderUI(NULL)
    updateSelectizeInput(session, "binding_explore_sim_target", selected = "")
    updateNumericInput(session,   "binding_explore_sim_topN",    value = NA)
    updateNumericInput(session,   "binding_explore_sim_n_close", value = NA)
    updateNumericInput(session,   "binding_explore_sim_n_far",   value = NA)
  })
  
  # -------------------------------
  # Render plot
  # -------------------------------
  output$eclipse_plot <- renderPlot({
    # on.exit fires even when req() below silently aborts this render (e.g.
    # results() isn't ready yet) -- a hide_status() placed only after the
    # req() would otherwise never run, leaving the status banner stuck up.
    on.exit(hide_status(), add = TRUE)
    req(results())
    p <- results()
    if (inherits(p, "ggplot") || inherits(p, "ggarrange")) {
      dl_store$binding(p)
      print(p)
    }
  })
  
  # Track plot visibility
  show_plot <- reactiveVal(FALSE)
  
  # When search button is pressed, show plot
  observeEvent(input$search_btn, {
    show_status("Generating binding map \u2014 this may take a moment\u2026")
    show_plot(TRUE)
  })
  
  # When reset button is pressed, hide plot
  observeEvent(input$reset_btn, {
    show_plot(FALSE)
    dl_store$binding(NULL)
    binding_nav_target(NULL)
  })
  output$binding_plot_ui <- renderUI({
    req(show_plot())
    
    targets <- input$binding_target
    data <- binding_data()
    rbp <- input$binding_search
    
    if ("All" %in% targets) {
      n_targets <- length(names(data[[rbp]]))
    } else {
      n_targets <- length(targets)
    }
    
    height_px <- min(900 + (n_targets - 1) * 10, 2000)
    
    tagList(
      plotOutput("eclipse_plot", height = paste0(height_px, "px")),
      uiOutput("dl_ui_binding")
    )
  })
  
  
  output$binding_similar_profiles_options <- renderUI({
    # Explore mode's "Similar Profiles" option. Built UNCONDITIONALLY (no
    # longer gated on input$binding_dataset) and rendered eagerly via
    # outputOptions(suspendWhenHidden = FALSE) just below, so the query /
    # compare selectizes exist in the DOM from app startup. That is what
    # lets the server-side updateSelectizeInput() populate step (the
    # observe() below) reliably land its choices: when this panel was
    # (re)built lazily on switching to "Similar Profiles", the populate
    # observe raced the input creation and the dropdowns came up empty.
    # Visibility is handled by the conditionalPanel that wraps
    # uiOutput("binding_similar_profiles_options") in the Binding UI.
    tagList(
      hr(),
      tags$h5("Similar Profiles"),
      tags$p(
        "Find RBP–Target binding profiles that are most similar to a chosen query profile.",
        style = "font-size: 12px; color: #666; margin-top: -5px;"
      ),

      # Query profile selector. Each profile ID is "<shRNA-knockdown
      # RBP>__<CLIP-profiled target RBP>" -- NOT an RBP paired with a
      # splicing event ID, which the previous placeholder wrongly implied.
      #
      # choices start empty and are filled in server-side (see the
      # binding_sim_query_id/binding_sim_compare observe() below) -- there
      # are 20,000+ profile IDs for "Both Cells", and handing that whole
      # vector to a client-side selectize (as this used to do) makes the
      # browser build a 20k-option dropdown DOM on every render of this
      # panel, which can lock up the tab for a long time. This mirrors the
      # server=TRUE pattern already used for expr_search_rbp/splice_search/
      # binding_search elsewhere in the app.
      selectizeInput(
        "binding_sim_query_id",
        "Query profile (shRNA RBP__Target RBP):",
        choices  = NULL,
        multiple = FALSE,
        options  = list(placeholder = "e.g. RBFOX2__HNRNPC")
      ),

      # Compare with specific profiles (optional)
      selectizeInput(
        "binding_sim_compare",
        "Compare with specific profiles (optional):",
        choices  = NULL,
        multiple = TRUE,
        options  = list(placeholder = "Select one or more profiles")
      ),
      
      numericInput(
        "binding_sim_topN",
        "Show top N most similar profiles (optional):",
        value = NA, min = 1
      ),
      helpText("Tip: selecting a number here takes precedence over the two below."),
      numericInput(
        "binding_sim_n_close",
        "Show top N closest profiles (optional):",
        value = NA, min = 1
      ),
      numericInput(
        "binding_sim_n_far",
        "Show top N most dissimilar profiles (optional):",
        value = NA, min = 1
      ),
      checkboxInput("binding_sim_zoom", "Zoom the density plots to the data range", value = TRUE),
      
      div(
        style = "display: flex; align-items: center; margin-top: 15px;",
        actionButton(
          "binding_sim_plot_btn",
          tagList(fa("chart-line"), " Plot"),
          class = "btn btn-primary",
          style = "margin-right: 10px; border-radius: 20px;"
        ),
        actionButton(
          "binding_sim_reset_btn",
          tagList(fa("redo"), " Reset"),
          class = "btn btn-secondary",
          style = "border-radius: 20px;"
        )
      )
    )
  })
  # Render this panel even while the conditionalPanel is hiding it, so its
  # inputs are registered client-side before the populate observe() fires.
  outputOptions(output, "binding_similar_profiles_options", suspendWhenHidden = FALSE)

  # ---- Server-side choices for the Similar Profiles query/compare pickers ----
  # Populates binding_sim_query_id / binding_sim_compare AFTER they're created
  # by the renderUI above, using server=TRUE so selectize only ever sends the
  # matches for what the user has typed so far instead of the full 20k+-item
  # profile list to the browser in one shot.
  observe({
    req(identical(input$binding_dataset, "Similar Profiles"), input$binding_eventtype)

    sim_objs <- binding_sim_objects()
    all_profile_ids <- rownames(sim_objs[["Both Cells"]]$inc$mean_profiles)
    if (is.null(all_profile_ids)) all_profile_ids <- character(0)

    all_profile_ids <- sort(all_profile_ids)
    updateSelectizeInput(session, "binding_sim_query_id", choices = all_profile_ids, server = TRUE)
    updateSelectizeInput(session, "binding_sim_compare",  choices = all_profile_ids, server = TRUE)
  })


  # ─────────────────────────────────────────────────────────────────────────────
  # PATCH 8 — SERVER: plot button for Similar Profiles (6 plots)
  # ─────────────────────────────────────────────────────────────────────────────
  
  observeEvent(input$binding_sim_plot_btn, {
    req(input$binding_dataset == "Similar Profiles",
        input$binding_sim_query_id,
        input$binding_eventtype)
    # This can trigger the first (lazy) load of all 12 similar_binding_*
    # objects via binding_sim_cache() below, which had no loading feedback
    # at all -- give the user something while that (and the "Both Cells"
    # correlation, the larger of the three) computes.
    show_status("Computing similar binding profiles — please wait…")
    on.exit(hide_status(), add = TRUE)

    query_id    <- input$binding_sim_query_id
    compare_ids <- if (length(input$binding_sim_compare) > 0) input$binding_sim_compare else NULL
    topN        <- input$binding_sim_topN
    n_close     <- input$binding_sim_n_close
    n_far       <- input$binding_sim_n_far

    # If the user left every filter blank, default to the top 10 closest
    # profiles instead of plotting every profile in the dataset -- matches
    # the "Explore" mode Similar Profiles panel (binding_explore_sim_plot_btn
    # above), which had this fallback but this panel didn't.
    if (is.na(topN) && is.na(n_close) && is.na(n_far)) n_close <- 10

    sim_objs <- binding_sim_objects()
    dataset_names <- c("Both Cells", "K562", "HEPG2")
    directions    <- c("inc", "dec")
    ev_prefix     <- if (grepl("Intron Retention", input$binding_eventtype, ignore.case = TRUE)) "IR" else "ES"
    
    # One full-width row per cell line: increased and decreased events pooled in one density plot
    bind_combined_ui <- function(ds_label, ds_key) {
      if (is.null(BIND_REF)) return(NULL)
      fluidRow(column(12,
        tags$h5(paste0(ds_label, " \u2014 Increased and Decreased Events together"), style = "text-align:center;"),
        shinycssloaders::withSpinner(
          plotOutput(paste0("binding_sim_plot_", ds_key, "_comb"), height = "340px"), type = 6),
        div(style = "text-align:center; margin-top:5px;",
            downloadButton(paste0("dl_binding_sim_plot_", ds_key, "_comb"), "\u2193 Download plot",
                           class = "btn btn-sm btn-default"))
      ))
    }

    output$binding_similar_profiles_plot_ui <- renderUI({
      tagList(
        hr(),
        tags$h4("Similar Profiles Results",
                style = "font-weight:bold; color:#A10702; margin-bottom:15px;"),
        
        # Row 1 — Both Cells
        fluidRow(
          column(6,
                 tags$h5("Both Cells — Increased Events", style = "text-align:center;"),
                 shinycssloaders::withSpinner(
                   plotOutput("binding_sim_plot_both_inc", height = bind_plot_height()), type = 6),
                 div(style = "text-align:center; margin-top:5px;",
                     downloadButton("dl_binding_sim_plot_both_inc", "↓ Download plot",
                                    class = "btn btn-sm btn-default"))
          ),
          column(6,
                 tags$h5("Both Cells — Decreased Events", style = "text-align:center;"),
                 shinycssloaders::withSpinner(
                   plotOutput("binding_sim_plot_both_dec", height = bind_plot_height()), type = 6),
                 div(style = "text-align:center; margin-top:5px;",
                     downloadButton("dl_binding_sim_plot_both_dec", "↓ Download plot",
                                    class = "btn btn-sm btn-default"))
          )
        ),
        
        bind_combined_ui("Both Cells", "both"),

        # Row 2 — K562
        fluidRow(
          column(6,
                 tags$h5("K562 — Increased Events", style = "text-align:center;"),
                 shinycssloaders::withSpinner(
                   plotOutput("binding_sim_plot_K562_inc", height = bind_plot_height()), type = 6),
                 div(style = "text-align:center; margin-top:5px;",
                     downloadButton("dl_binding_sim_plot_K562_inc", "↓ Download plot",
                                    class = "btn btn-sm btn-default"))
          ),
          column(6,
                 tags$h5("K562 — Decreased Events", style = "text-align:center;"),
                 shinycssloaders::withSpinner(
                   plotOutput("binding_sim_plot_K562_dec", height = bind_plot_height()), type = 6),
                 div(style = "text-align:center; margin-top:5px;",
                     downloadButton("dl_binding_sim_plot_K562_dec", "↓ Download plot",
                                    class = "btn btn-sm btn-default"))
          )
        ),
        
        bind_combined_ui("K562", "K562"),

        # Row 3 — HEPG2
        fluidRow(
          column(6,
                 tags$h5("HEPG2 — Increased Events", style = "text-align:center;"),
                 shinycssloaders::withSpinner(
                   plotOutput("binding_sim_plot_HEPG2_inc", height = bind_plot_height()), type = 6),
                 div(style = "text-align:center; margin-top:5px;",
                     downloadButton("dl_binding_sim_plot_HEPG2_inc", "↓ Download plot",
                                    class = "btn btn-sm btn-default"))
          ),
          column(6,
                 tags$h5("HEPG2 — Decreased Events", style = "text-align:center;"),
                 shinycssloaders::withSpinner(
                   plotOutput("binding_sim_plot_HEPG2_dec", height = bind_plot_height()), type = 6),
                 div(style = "text-align:center; margin-top:5px;",
                     downloadButton("dl_binding_sim_plot_HEPG2_dec", "↓ Download plot",
                                    class = "btn btn-sm btn-default"))
          )
        ),
        bind_combined_ui("HEPG2", "HEPG2")
      )
    })
    
    # Render each of the 6 plots
    for (ds in dataset_names) {
      for (dir in directions) {
        local({
          ds_local  <- ds
          dir_local <- dir
          # The UI (plotOutput ids above) uses the key "both" for "Both Cells",
          # but gsub(" ", "", "Both Cells") yields "BothCells" -- so the two
          # Both Cells outputs were bound to ids the UI never rendered, leaving
          # their spinners running forever while K562/HEPG2 (no spaces, exact
          # case) matched fine. Map each dataset name to the exact UI key.
          ds_key    <- c("Both Cells" = "both", "K562" = "K562", "HEPG2" = "HEPG2")[[ds_local]]
          plot_id   <- paste0("binding_sim_plot_", ds_key, "_", dir_local)
          
          output[[plot_id]] <- renderPlot({
            sim_obj <- sim_objs[[ds_local]][[dir_local]]
            res <- binding_profile_correl(
              sim_obj       = sim_obj,
              query_id      = query_id,
              top_n         = if (!is.na(topN))    topN    else NULL,
              n_close       = if (!is.na(n_close)) n_close else NULL,
              n_far         = if (!is.na(n_far))   n_far   else NULL,
              other_ids     = compare_ids,
              direction     = dir_local,
              dataset_label = ds_local,
              ref_key       = bind_key(ev_prefix, ds_local, dir_local),
              zoom          = !isFALSE(input$binding_sim_zoom)
            )
            dyn_dl_store[[plot_id]] <- res$heatmap
            res$heatmap
          })

          dl_id <- paste0("dl_", plot_id)
          output[[dl_id]] <- make_dyn_dl_handler(
            plot_id,
            paste0("binding_similar_profile_", ds_key, "_", dir_local)
          )
        })
      }
    }

    # Increased + decreased events together: one pooled plot per cell line
    if (!is.null(BIND_REF)) {
      for (ds in dataset_names) {
        local({
          ds_local <- ds
          ds_key   <- c("Both Cells" = "both", "K562" = "K562", "HEPG2" = "HEPG2")[[ds_local]]
          plot_id  <- paste0("binding_sim_plot_", ds_key, "_comb")
          output[[plot_id]] <- renderPlot({
            profiles_of <- function(d) {
              mp <- sim_objs[[ds_local]][[d]]$mean_profiles
              if (is.null(mp)) NULL else mp[!duplicated(rownames(mp)), , drop = FALSE]
            }
            p <- bind_density_panel_combined(
              query_id,
              bind_pool_key(ev_prefix, ds_local),
              profiles_of("inc"), profiles_of("dec"),
              zoom = !isFALSE(input$binding_sim_zoom)
            )
            dyn_dl_store[[plot_id]] <- p
            p
          })
          output[[paste0("dl_", plot_id)]] <- make_dyn_dl_handler(
            plot_id, paste0("binding_similar_profile_", ds_key, "_together")
          )
        })
      }
    }
  })
  
  
  # ─────────────────────────────────────────────────────────────────────────────
  # PATCH 9 — SERVER: reset button for Similar Profiles
  # ─────────────────────────────────────────────────────────────────────────────
  
  observeEvent(input$binding_sim_reset_btn, {
    output$binding_similar_profiles_plot_ui <- renderUI(NULL)
    updateSelectizeInput(session, "binding_sim_query_id", selected = "")
    updateSelectizeInput(session, "binding_sim_compare",  selected = "")
    updateNumericInput(session,   "binding_sim_topN",     value    = NA)
    updateNumericInput(session,   "binding_sim_n_close",  value    = NA)
    updateNumericInput(session,   "binding_sim_n_far",    value    = NA)
  })

  # ─────────────────────────────────────────────────────────────────────────────
  # NETWORK TAB — MDS of RBP binding-profile similarity
  # ─────────────────────────────────────────────────────────────────────────────

  # ── Helper: base scatter ggplot ────────────────────────────────────────
  # hl_valid is passed in from the (cheap, un-isolated) render step below
  # rather than computed here, so restyling for a highlight change never
  # needs to re-run the expensive stuff above this point.
  make_scatter <- function(df, xlab, ylab, title, subtitle, caption, hl_valid) {
    df$Highlight <- ifelse(df$RBP %in% hl_valid, "Highlighted", "Other")
    df$Fontface  <- ifelse(df$Highlight == "Highlighted", "bold", "plain")
    has_hl       <- length(hl_valid) > 0

    p <- ggplot(df, aes(x = Dim1, y = Dim2)) +
      # Points: colour and size driven by Highlight column
      geom_point(
        aes(color = Highlight, size = Highlight),
        alpha = 0.8
      ) +
      scale_color_manual(values = c("Highlighted" = "#BA3B46", "Other" = "#2c3e50")) +
      scale_size_manual( values = c("Highlighted" = 4,         "Other" = 2.5)) +
      labs(title = title, subtitle = subtitle,
           x = xlab, y = ylab, caption = caption) +
      theme_charm() +
      theme(legend.position = if (has_hl) "right" else "none")

    # Label every RBP regardless of highlight status (highlighting should
    # only recolor points red, not remove everyone else's labels) --
    # color/weight the text the same way as its point via the Highlight
    # aesthetic instead of only repelling a filtered subset.
    p <- p + ggrepel::geom_text_repel(
      aes(label = RBP, color = Highlight, fontface = Fontface),
      size         = CHARM_GEOM_TEXT,
      max.overlaps = 30,
      show.legend  = FALSE
    , family = CHARM_FONT)
    p
  }

  # \u2500\u2500 Heavy computation: correlation matrices + ordination \u2500\u2500\u2500\u2500\u2500\u2500\u2500\u2500\u2500\u2500\u2500\u2500\u2500\u2500\u2500\u2500\u2500\u2500\u2500
  # This used to live directly inside output$network_mds_plot's renderPlot,
  # gated only by `input$network_plot_btn; isolate({...})`. Highlighting
  # (input$network_highlight_rbps) was read inside that same isolate(), so it
  # could only ever take effect by the user clicking "Plot" again -- which
  # re-ran this ENTIRE expensive block (rebuilding every correlation matrix
  # from scratch, re-running MDS/PCA/t-SNE/hclust) just to recolor some
  # points. Splitting the expensive part into its own eventReactive (still
  # gated on the Plot button) and applying highlighting afterwards in a
  # separate, cheap render step means changing the highlight selection no
  # longer forces a full recompute -- see output$network_mds_plot below.
  network_result <- eventReactive(input$network_plot_btn, {
    show_status("Building RBP similarity network \u2014 please wait\u2026")
    on.exit(hide_status(), add = TRUE)  # guarantee the status banner clears
                                         # even if something below errors
    layers    <- input$network_layers
    cell      <- input$network_cellline
    # Display-only label for plot titles below -- "Both" on its own reads
    # ambiguously (both... what?), so titles say "Both cell lines" instead.
    # `cell` itself must stay the raw "Both"/"K562"/"HEPG2" value: it drives
    # real data lookups downstream (get_charm_object(cell), switch(cell, ...)).
    cell_label <- if (identical(cell, "Both")) "Both cell lines" else cell
    btypes    <- input$network_binding_type
    dirs      <- input$network_binding_dir
    plot_type <- input$network_plot_type

    if (is.null(layers) || length(layers) == 0) {
      return(list(error = "Please select at least one data layer."))
    }

    withProgress(message = "Building RBP similarity network\u2026", value = 0, {

      # ── Cell line mapping ──────────────────────────────────────────────────
      cell_key_binding <- switch(cell, "Both" = "both", "K562" = "K562", "HEPG2" = "HEPG2")
      charm_obj <- get_charm_object(cell)
      expr_obj  <- switch(cell,
                          "Both"  = similar_expression_all,
                          "K562"  = similar_expression_K562,
                          "HEPG2" = similar_expression_HEPG2)

      # ── Weights ───────────────────────────────────────────────────────────
      raw_weights <- c()
      if ("Expression" %in% layers)
        raw_weights["Expression"] <- max(0, if (is.null(input$network_weight_expr))    1 else input$network_weight_expr)
      if ("Splicing"   %in% layers)
        raw_weights["Splicing"]   <- max(0, if (is.null(input$network_weight_splice))  1 else input$network_weight_splice)
      if ("Binding"    %in% layers)
        raw_weights["Binding"]    <- max(0, if (is.null(input$network_weight_binding)) 1 else input$network_weight_binding)
      total_w <- sum(raw_weights)
      if (total_w == 0) raw_weights[] <- 1 / length(raw_weights)
      weights <- raw_weights / total_w

      # ── Build correlation matrices per layer ───────────────────────────────
      cor_matrices <- list()
      n_layers <- length(layers)
      step_size <- 0.6 / max(n_layers, 1)

      if ("Expression" %in% layers) {
        incProgress(step_size, message = "Computing expression correlations\u2026")
        cm <- network_cor_matrix(type = "expression", rbp_list = expr_obj)
        if (!is.null(cm) && nrow(cm) >= 3) cor_matrices[["Expression"]] <- cm
      }

      if ("Splicing" %in% layers) {
        incProgress(step_size, message = "Computing splicing correlations\u2026")
        cm <- network_cor_matrix(type = "splicing", rbp_list = charm_obj)
        if (!is.null(cm) && nrow(cm) >= 3) cor_matrices[["Splicing"]] <- cm
      }

      if ("Binding" %in% layers) {
        incProgress(step_size, message = "Computing binding correlations\u2026")
        if (!is.null(btypes) && length(btypes) > 0 &&
            !is.null(dirs)   && length(dirs)   > 0) {

          type_keys <- c()
          if ("Exon Skipping"    %in% btypes) type_keys <- c(type_keys, "ES")
          if ("Intron Retention" %in% btypes) type_keys <- c(type_keys, "IR")
          dir_keys <- c()
          if ("Increased" %in% dirs) dir_keys <- c(dir_keys, "inc")
          if ("Decreased" %in% dirs) dir_keys <- c(dir_keys, "dec")

          binding_cor_list <- list()
          cache <- binding_sim_cache()
          for (tk in type_keys) {
            for (dk in dir_keys) {
              obj_name <- paste0("similar_binding_", tk, "_", cell_key_binding, "_", dk)
              obj <- cache[[obj_name]]
              if (is.null(obj) || is.null(obj$mean_profiles)) next
              mat       <- obj$mean_profiles
              rbp_names <- sub("__.*", "", rownames(mat))
              unique_rbps <- unique(rbp_names)
              agg <- do.call(rbind, lapply(unique_rbps, function(r) {
                colMeans(mat[which(rbp_names == r), , drop = FALSE], na.rm = TRUE)
              }))
              rownames(agg) <- unique_rbps
              cm <- network_cor_matrix(type = "binding", rbp_mat = agg)
              if (!is.null(cm) && nrow(cm) >= 3)
                binding_cor_list[[paste0(tk, "_", dk)]] <- cm
            }
          }

          if (length(binding_cor_list) > 0) {
            common_b <- Reduce(intersect, lapply(binding_cor_list, rownames))
            avg_b <- Reduce("+", lapply(binding_cor_list, function(m) m[common_b, common_b])) /
                     length(binding_cor_list)
            cor_matrices[["Binding"]] <- avg_b
          }
        }
      }

      if (length(cor_matrices) == 0) {
        return(list(error = "No data available for the selected combination."))
      }

      # ── Common RBPs ───────────────────────────────────────────────────────
      common_rbps <- Reduce(intersect, lapply(cor_matrices, rownames))
      if (length(common_rbps) < 3) {
        return(list(error = paste0("Only ", length(common_rbps),
                                    " RBP(s) shared across all layers. Need \u2265 3.")))
      }

      # ── Weighted average correlation → dissimilarity ───────────────────────
      active_layers <- names(cor_matrices)
      w <- weights[active_layers]; w <- w / sum(w)

      avg_cor <- Reduce("+", mapply(
        function(cm, wi) cm[common_rbps, common_rbps] * wi,
        cor_matrices[active_layers], w, SIMPLIFY = FALSE
      ))
      diss_mat <- 1 - avg_cor   # dissimilarity in [0, 2]

      weight_str <- paste(
        sapply(active_layers, function(l) sprintf("%s (%.2f)", l, w[l])),
        collapse = " | "
      )
      caption_base <- paste0("Dissimilarity = 1 \u2212 weighted Spearman r  |  n = ",
                             length(common_rbps), " RBPs")


      # ── Plot type dispatch ─────────────────────────────────────────────────

      incProgress(0.2, message = "Running ordination\u2026")

      if (plot_type == "MDS") {
        fit     <- cmdscale(as.dist(diss_mat), k = 2, eig = TRUE)
        eig_pos <- pmax(fit$eig, 0)
        ve      <- round(eig_pos[1:2] / sum(eig_pos) * 100, 1)
        df <- data.frame(RBP = common_rbps,
                         Dim1 = fit$points[,1], Dim2 = fit$points[,2])
        return(list(
          plot_type = "MDS", df = df, common_rbps = common_rbps,
          xlab = paste0("MDS Dim 1 (", ve[1], "% var.)"),
          ylab = paste0("MDS Dim 2 (", ve[2], "% var.)"),
          title = paste0("RBP Similarity — MDS (", cell_label, ")"),
          weight_str = weight_str,
          caption_base = caption_base
        ))
      }

      if (plot_type == "PCA") {
        pca <- prcomp(avg_cor[common_rbps, common_rbps], scale. = TRUE, center = TRUE)
        ve  <- round(summary(pca)$importance[2, 1:2] * 100, 1)
        df  <- data.frame(RBP  = common_rbps,
                          Dim1 = pca$x[, 1],
                          Dim2 = pca$x[, 2])
        return(list(
          plot_type = "PCA", df = df, common_rbps = common_rbps,
          xlab = paste0("PC1 (", ve[1], "% var.)"),
          ylab = paste0("PC2 (", ve[2], "% var.)"),
          title = paste0("RBP Similarity — PCA (", cell_label, ")"),
          weight_str = weight_str,
          caption_base = caption_base
        ))
      }

      if (plot_type == "t-SNE") {
        if (!requireNamespace("Rtsne", quietly = TRUE)) {
          return(list(error = "Package 'Rtsne' is required for t-SNE.\nInstall it with: install.packages('Rtsne')"))
        }
        set.seed(42)
        tsne <- Rtsne::Rtsne(as.dist(diss_mat), is_distance = TRUE,
                              perplexity = min(30, floor((length(common_rbps) - 1) / 3)))
        df   <- data.frame(RBP  = common_rbps,
                           Dim1 = tsne$Y[, 1],
                           Dim2 = tsne$Y[, 2])
        return(list(
          plot_type = "t-SNE", df = df, common_rbps = common_rbps,
          xlab = "t-SNE 1", ylab = "t-SNE 2",
          title = paste0("RBP Similarity — t-SNE (", cell_label, ")"),
          weight_str = weight_str,
          caption_base = caption_base
        ))
      }

      if (plot_type == "Dendrogram") {
        hc   <- hclust(as.dist(diss_mat), method = "ward.D2")
        dend <- as.dendrogram(hc)
        return(list(
          plot_type = "Dendrogram", dend = dend, common_rbps = common_rbps,
          cell = cell_label, weight_str = weight_str
        ))
      }

      list(error = paste("Unknown plot type:", plot_type))

      }) # end withProgress
  })

  # Cheap render step: apply the CURRENT highlight selection to whatever
  # network_result() last computed. input$network_highlight_rbps is read
  # here directly (not isolate()'d), so changing it re-triggers only this
  # lightweight restyle -- not the whole correlation/ordination pipeline.
  output$network_mds_plot <- renderPlot({
    res <- network_result()
    req(res)
    on.exit(hide_status(), add = TRUE)

    if (!is.null(res$error)) {
      return(ggplot() +
               annotate("text", x = 0.5, y = 0.5, label = res$error,
                        size = CHARM_GEOM_TEXT, hjust = 0.5, family = CHARM_FONT) + theme_charm_void())
    }

    hl_valid <- intersect(input$network_highlight_rbps, res$common_rbps)

    if (res$plot_type == "Dendrogram") {
      dend <- res$dend
      if (length(hl_valid) > 0) {
        color_leaf <- function(node) {
          if (is.leaf(node)) {
            lbl <- attr(node, "label")
            if (lbl %in% hl_valid) {
              attr(node, "nodePar") <- list(lab.col = "#BA3B46",
                                            lab.font = 2, pch = NA)
            }
          }
          node
        }
        dend <- dendrapply(dend, color_leaf)
      }

      par(mar = c(12, 4, 4, 2))
      plot(dend, main = paste0("RBP Similarity \u2014 Dendrogram (", res$cell, ")"),
           sub  = res$weight_str,
           ylab = "Height (1 \u2212 Spearman r)",
           cex.main = 1.3, font.main = 2,
           cex.sub  = 0.9, col.sub  = "#555555",
           cex.lab  = 1.0, cex.axis = 0.9)
      if (length(hl_valid) > 0)
        legend("topright", legend = "Highlighted RBPs",
               text.col = "#BA3B46", text.font = 2, bty = "n", cex = 0.9)
      return(invisible(NULL))
    }

    p <- make_scatter(res$df, res$xlab, res$ylab, res$title, res$weight_str, res$caption_base, hl_valid)
    dl_store$network(p)
    p
  })

}


# end server


shinyApp(ui, server)