from reportlab.lib.pagesizes import A4
from reportlab.lib import colors
from reportlab.lib.units import cm, mm
from reportlab.lib.styles import getSampleStyleSheet, ParagraphStyle
from reportlab.lib.enums import TA_CENTER, TA_LEFT, TA_JUSTIFY
from reportlab.platypus import (
    SimpleDocTemplate, Paragraph, Spacer, Table, TableStyle,
    HRFlowable, PageBreak, KeepTogether
)
from reportlab.platypus.flowables import Flowable
from reportlab.graphics.shapes import Drawing, Circle, Rect, String, Line, Polygon, Wedge, Arc
from reportlab.graphics.charts.piecharts import Pie
from reportlab.graphics import renderPDF
import math

# ── Colour Palette ──────────────────────────────────────────────────────────
DEEP_BLUE   = colors.HexColor("#1A3A5C")
MID_BLUE    = colors.HexColor("#2E6DA4")
LIGHT_BLUE  = colors.HexColor("#D6E8F7")
ACCENT      = colors.HexColor("#E8A020")
ACCENT2     = colors.HexColor("#2ECC71")
BG_LIGHT    = colors.HexColor("#F4F8FC")
PHASE_G1    = colors.HexColor("#3498DB")
PHASE_S     = colors.HexColor("#E74C3C")
PHASE_G2    = colors.HexColor("#9B59B6")
PHASE_M     = colors.HexColor("#27AE60")
PHASE_G0    = colors.HexColor("#95A5A6")
TEXT_DARK   = colors.HexColor("#1C2833")
TEXT_MED    = colors.HexColor("#2C3E50")
GOLD        = colors.HexColor("#F39C12")
PINK        = colors.HexColor("#E91E8C")

# ── Styles ───────────────────────────────────────────────────────────────────
def make_styles():
    base = getSampleStyleSheet()
    styles = {}

    styles['cover_title'] = ParagraphStyle(
        'cover_title', parent=base['Title'],
        fontSize=38, leading=46, textColor=colors.white,
        fontName='Helvetica-Bold', alignment=TA_CENTER, spaceAfter=8
    )
    styles['cover_sub'] = ParagraphStyle(
        'cover_sub', parent=base['Normal'],
        fontSize=15, leading=20, textColor=colors.HexColor("#D6E8F7"),
        fontName='Helvetica', alignment=TA_CENTER, spaceAfter=4
    )
    styles['cover_tag'] = ParagraphStyle(
        'cover_tag', parent=base['Normal'],
        fontSize=11, leading=14, textColor=colors.HexColor("#A8C8E8"),
        fontName='Helvetica-Oblique', alignment=TA_CENTER
    )
    styles['section_head'] = ParagraphStyle(
        'section_head', parent=base['Heading1'],
        fontSize=16, leading=20, textColor=colors.white,
        fontName='Helvetica-Bold', spaceBefore=14, spaceAfter=6,
        backColor=DEEP_BLUE, borderPad=8, leftIndent=-12, rightIndent=-12
    )
    styles['sub_head'] = ParagraphStyle(
        'sub_head', parent=base['Heading2'],
        fontSize=12, leading=16, textColor=DEEP_BLUE,
        fontName='Helvetica-Bold', spaceBefore=10, spaceAfter=4,
        borderPadding=(0, 0, 2, 0)
    )
    styles['body'] = ParagraphStyle(
        'body', parent=base['Normal'],
        fontSize=9.5, leading=14, textColor=TEXT_MED,
        fontName='Helvetica', spaceAfter=6, alignment=TA_JUSTIFY
    )
    styles['bullet'] = ParagraphStyle(
        'bullet', parent=base['Normal'],
        fontSize=9.5, leading=13, textColor=TEXT_MED,
        fontName='Helvetica', leftIndent=16, spaceAfter=3,
        bulletIndent=4
    )
    styles['caption'] = ParagraphStyle(
        'caption', parent=base['Normal'],
        fontSize=8.5, leading=11, textColor=colors.HexColor("#5D6D7E"),
        fontName='Helvetica-Oblique', alignment=TA_CENTER, spaceAfter=6
    )
    styles['table_hdr'] = ParagraphStyle(
        'table_hdr', parent=base['Normal'],
        fontSize=9, leading=12, textColor=colors.white,
        fontName='Helvetica-Bold', alignment=TA_CENTER
    )
    styles['table_cell'] = ParagraphStyle(
        'table_cell', parent=base['Normal'],
        fontSize=8.5, leading=11, textColor=TEXT_MED,
        fontName='Helvetica', alignment=TA_LEFT
    )
    styles['highlight_box'] = ParagraphStyle(
        'highlight_box', parent=base['Normal'],
        fontSize=9.5, leading=14, textColor=TEXT_MED,
        fontName='Helvetica', alignment=TA_JUSTIFY,
        backColor=LIGHT_BLUE, borderPad=10, leftIndent=8, rightIndent=8,
        spaceAfter=8
    )
    styles['key_point'] = ParagraphStyle(
        'key_point', parent=base['Normal'],
        fontSize=9, leading=13, textColor=DEEP_BLUE,
        fontName='Helvetica-Bold', leftIndent=20, spaceAfter=4
    )
    return styles

# ── Custom Flowables ──────────────────────────────────────────────────────────

class CoverPage(Flowable):
    def __init__(self, w, h):
        Flowable.__init__(self)
        self.width = w
        self.height = h

    def draw(self):
        c = self.canv
        # Gradient background (approximated with bands)
        bands = 40
        for i in range(bands):
            ratio = i / bands
            r = int(26 + ratio * (46 - 26))
            g = int(58 + ratio * (90 - 58))
            b = int(92 + ratio * (140 - 92))
            c.setFillColorRGB(r/255, g/255, b/255)
            c.rect(0, self.height * i / bands,
                   self.width, self.height / bands + 1, stroke=0, fill=1)

        # Decorative circles (DNA-like bubbles)
        for cx, cy, r, alpha in [
            (50, self.height - 60, 80, 0.08),
            (self.width - 40, 80, 100, 0.07),
            (self.width / 2, self.height - 30, 120, 0.05),
            (30, self.height / 2, 60, 0.06),
        ]:
            c.setFillColorRGB(1, 1, 1, alpha)
            c.circle(cx, cy, r, stroke=0, fill=1)

        # Top accent bar
        c.setFillColor(ACCENT)
        c.rect(0, self.height - 8, self.width, 8, stroke=0, fill=1)

        # Bottom accent bar
        c.setFillColor(ACCENT)
        c.rect(0, 0, self.width, 6, stroke=0, fill=1)

        # Cell cycle wheel (decorative)
        cx = self.width / 2
        cy = self.height / 2 + 30
        R = 95
        # Sectors
        phases = [
            (PHASE_G1, 0, 90, "G1"),
            (PHASE_S, 90, 180, "S"),
            (PHASE_G2, 180, 270, "G2"),
            (PHASE_M, 270, 360, "M"),
        ]
        for col, a1, a2, label in phases:
            c.setFillColor(col)
            c.setStrokeColor(colors.white)
            c.setLineWidth(2)
            c.wedge(cx - R, cy - R, cx + R, cy + R, a1, a2 - a1, stroke=1, fill=1)
            # Label
            mid_a = math.radians((a1 + a2) / 2)
            lx = cx + (R * 0.60) * math.cos(mid_a)
            ly = cy + (R * 0.60) * math.sin(mid_a)
            c.setFillColor(colors.white)
            c.setFont("Helvetica-Bold", 13)
            c.drawCentredString(lx, ly - 5, label)

        # Centre circle (white)
        c.setFillColor(colors.white)
        c.setStrokeColor(DEEP_BLUE)
        c.setLineWidth(2)
        c.circle(cx, cy, R * 0.32, stroke=1, fill=1)
        c.setFillColor(DEEP_BLUE)
        c.setFont("Helvetica-Bold", 9)
        c.drawCentredString(cx, cy + 4, "CELL")
        c.drawCentredString(cx, cy - 8, "CYCLE")

        # Title text
        c.setFillColor(colors.white)
        c.setFont("Helvetica-Bold", 36)
        c.drawCentredString(self.width / 2, self.height * 0.82, "THE CELL CYCLE")
        c.setFont("Helvetica", 14)
        c.setFillColor(colors.HexColor("#A8D8EA"))
        c.drawCentredString(self.width / 2, self.height * 0.76,
                            "Growth • Division • Regulation • Clinical Relevance")

        # Bottom info strip
        c.setFillColorRGB(0, 0, 0, 0.25)
        c.rect(0, 28, self.width, 36, stroke=0, fill=1)
        c.setFillColor(colors.HexColor("#A8C8E8"))
        c.setFont("Helvetica", 10)
        c.drawCentredString(self.width / 2, 42,
            "Source: Histology – A Text and Atlas | Berek & Novak's Gynecology | Scott-Brown's Otorhinolaryngology")


class CellCycleWheel(Flowable):
    """Annotated cell-cycle diagram."""
    def __init__(self, size=260):
        Flowable.__init__(self)
        self.size = size
        self.width = size
        self.height = size + 30

    def draw(self):
        c = self.canv
        cx = self.size / 2
        cy = self.size / 2 + 10
        R = self.size * 0.38
        inner_R = R * 0.42

        phases = [
            (PHASE_G1, 90,  180, "G1 Phase", "9-12 h"),
            (PHASE_S,  180, 270, "S Phase",  "10 h"),
            (PHASE_G2, 270, 340, "G2 Phase", "5 h"),
            (PHASE_M,  340, 360+90, "M Phase", "1 h"),
        ]
        for col, a1, a2, label, dur in phases:
            c.setFillColor(col)
            c.setStrokeColor(colors.white)
            c.setLineWidth(2.5)
            c.wedge(cx - R, cy - R, cx + R, cy + R, a1, a2 - a1, stroke=1, fill=1)
            mid_a = math.radians((a1 + a2) / 2)
            lx = cx + (R * 0.67) * math.cos(mid_a)
            ly = cy + (R * 0.67) * math.sin(mid_a)
            c.setFillColor(colors.white)
            c.setFont("Helvetica-Bold", 8)
            c.drawCentredString(lx, ly + 4, label)
            c.setFont("Helvetica", 7)
            c.drawCentredString(lx, ly - 6, dur)

        # Inner white circle
        c.setFillColor(colors.white)
        c.setStrokeColor(DEEP_BLUE)
        c.setLineWidth(2)
        c.circle(cx, cy, inner_R, stroke=1, fill=1)
        c.setFillColor(DEEP_BLUE)
        c.setFont("Helvetica-Bold", 8)
        c.drawCentredString(cx, cy + 6, "INTER-")
        c.drawCentredString(cx, cy - 6, "PHASE")

        # G0 branch arrow
        g0_start_angle = math.radians(135)  # mid G1
        ax = cx + R * math.cos(g0_start_angle)
        ay = cy + R * math.sin(g0_start_angle)
        ex = ax - 38
        ey = ay + 22
        c.setStrokeColor(PHASE_G0)
        c.setFillColor(PHASE_G0)
        c.setLineWidth(1.5)
        c.line(ax, ay, ex, ey)
        c.circle(ex, ey, 12, stroke=1, fill=1)
        c.setFillColor(colors.white)
        c.setFont("Helvetica-Bold", 8)
        c.drawCentredString(ex, ey - 3, "G0")

        # Checkpoint markers (small diamonds)
        checkpoints = [
            (math.radians(180), "R"),   # Restriction checkpoint G1/S
            (math.radians(270), "S-CP"),
            (math.radians(340), "G2/M"),
        ]
        for angle, label in checkpoints:
            px = cx + R * math.cos(angle)
            py = cy + R * math.sin(angle)
            c.setFillColor(GOLD)
            c.setStrokeColor(colors.white)
            c.setLineWidth(1)
            size = 7
            p = c.beginPath()
            p.moveTo(px, py + size)
            p.lineTo(px + size, py)
            p.lineTo(px, py - size)
            p.lineTo(px - size, py)
            p.close()
            c.drawPath(p, stroke=1, fill=1)

        # Legend
        legend_items = [
            (PHASE_G1, "G1 – Gap 1 (growth)"),
            (PHASE_S,  "S  – DNA Synthesis"),
            (PHASE_G2, "G2 – Gap 2 (prep)"),
            (PHASE_M,  "M  – Mitosis"),
            (PHASE_G0, "G0 – Resting"),
            (GOLD,     "Checkpoints"),
        ]
        lx0 = 4
        ly0 = 18
        for col, txt in legend_items:
            c.setFillColor(col)
            c.rect(lx0, ly0, 10, 8, stroke=0, fill=1)
            c.setFillColor(TEXT_MED)
            c.setFont("Helvetica", 6.5)
            c.drawString(lx0 + 13, ly0 + 1, txt)
            lx0 += 82

        # Caption
        c.setFillColor(colors.HexColor("#5D6D7E"))
        c.setFont("Helvetica-Oblique", 7.5)
        c.drawCentredString(cx, 6, "Figure 1. The Eukaryotic Cell Cycle with Checkpoints and Timing")


class CheckpointDiagram(Flowable):
    """Horizontal checkpoint strip."""
    def __init__(self, w=480, h=70):
        Flowable.__init__(self)
        self.width = w
        self.height = h

    def draw(self):
        c = self.canv
        phases = [
            (PHASE_G0, "G0", 0.08),
            (PHASE_G1, "G1 Phase\n9-12 h", 0.24),
            (PHASE_S,  "S Phase\n10 h", 0.24),
            (PHASE_G2, "G2 Phase\n5 h", 0.20),
            (PHASE_M,  "M Phase\n1 h", 0.16),
        ]
        x = 4
        bar_h = 36
        bar_y = self.height / 2 - bar_h / 2 + 8
        total_w = self.width - 8

        for col, label, frac in phases:
            seg_w = total_w * frac
            c.setFillColor(col)
            c.setStrokeColor(colors.white)
            c.setLineWidth(1.5)
            c.roundRect(x, bar_y, seg_w - 2, bar_h, 4, stroke=1, fill=1)
            c.setFillColor(colors.white)
            c.setFont("Helvetica-Bold", 7.5)
            lines = label.split('\n')
            for i, line in enumerate(lines):
                c.drawCentredString(x + (seg_w - 2) / 2,
                                    bar_y + bar_h / 2 + 4 - i * 10, line)
            x += seg_w

        # Checkpoint diamonds
        cps = [
            (0.32 * total_w + 4, "Restriction\nPoint"),
            (0.56 * total_w + 4, "S-phase\nCheckpoint"),
            (0.76 * total_w + 4, "G2/M\nCheckpoint"),
        ]
        for cpx, lbl in cps:
            dy = 7
            c.setFillColor(GOLD)
            c.setStrokeColor(DEEP_BLUE)
            c.setLineWidth(1)
            p = c.beginPath()
            p.moveTo(cpx, bar_y + bar_h + dy + 6)
            p.lineTo(cpx + 7, bar_y + bar_h + dy)
            p.lineTo(cpx, bar_y + bar_h + dy - 6)
            p.lineTo(cpx - 7, bar_y + bar_h + dy)
            p.close()
            c.drawPath(p, stroke=1, fill=1)
            c.setFillColor(TEXT_MED)
            c.setFont("Helvetica", 6)
            lines = lbl.split('\n')
            for i, line in enumerate(lines):
                c.drawCentredString(cpx, bar_y + bar_h + dy + 18 + i * 8, line)

        # Caption
        c.setFillColor(colors.HexColor("#5D6D7E"))
        c.setFont("Helvetica-Oblique", 7)
        c.drawCentredString(self.width / 2, 4, "Figure 2. Linear representation of the cell cycle with checkpoint positions")


class MitosisSteps(Flowable):
    """Simplified mitosis stage strip."""
    def __init__(self, w=480, h=90):
        Flowable.__init__(self)
        self.width = w
        self.height = h

    def _draw_cell(self, c, cx, cy, r, stage, col, chrom_lines):
        # Outer cell
        c.setFillColor(colors.HexColor("#EBF5FB"))
        c.setStrokeColor(col)
        c.setLineWidth(1.5)
        c.circle(cx, cy, r, stroke=1, fill=1)
        # Nucleus or chromosomes
        c.setStrokeColor(col)
        c.setLineWidth(1.2)
        for lx1, ly1, lx2, ly2 in chrom_lines:
            c.setFillColor(col)
            c.line(cx + lx1, cy + ly1, cx + lx2, cy + ly2)
        # Label
        c.setFillColor(TEXT_DARK)
        c.setFont("Helvetica-Bold", 7)
        c.drawCentredString(cx, cy - r - 10, stage)

    def draw(self):
        c = self.canv
        stages = [
            ("Prophase",     [(−8, 4, −4, 10), (−2, 6, 2, 12), (4, 4, 8, 10),
                              (−8,−10, −4,−4), (−2,−12, 2,−6), (4,−10, 8,−4)]),
            ("Metaphase",    [(−10, 0, −4, 0), (−2, 0, 4, 0), (6, 0, 12, 0),
                              (−10, 4, −4, 4), (−2, 4, 4, 4), (6, 4, 12, 4)]),
            ("Anaphase",     [(−8, 7, −4, 12), (−2, 8, 2, 13),
                              (−8,−12, −4,−7), (−2,−13, 2,−8)]),
            ("Telophase",    [(−6, 5, −2, 5), (0, 7, 4, 7),
                              (−6,−7, −2,−7), (0,−5, 4,−5)]),
            ("Cytokinesis",  [(−5, 3, 5, 3), (−5,−3, 5,−3)]),
        ]
        n = len(stages)
        step = self.width / n
        r = 28
        cy = self.height / 2 + 6
        for i, (stage, lines) in enumerate(stages):
            cx = step * i + step / 2
            self._draw_cell(c, cx, cy, r, stage, PHASE_M, lines)
            # Arrow between cells
            if i < n - 1:
                ax = cx + r + 4
                ay = cy
                c.setStrokeColor(PHASE_M)
                c.setLineWidth(1)
                c.line(ax, ay, ax + step - 2 * r - 8, ay)
                # arrowhead
                ex = ax + step - 2 * r - 8
                c.line(ex, ay, ex - 5, ay + 3)
                c.line(ex, ay, ex - 5, ay - 3)

        c.setFillColor(colors.HexColor("#5D6D7E"))
        c.setFont("Helvetica-Oblique", 7)
        c.drawCentredString(self.width / 2, 4,
            "Figure 3. Stages of Mitosis (M Phase)")


class CyclinCDKBar(Flowable):
    """Cyclin-CDK activity bar chart across cell cycle."""
    def __init__(self, w=480, h=90):
        Flowable.__init__(self)
        self.width = w
        self.height = h

    def draw(self):
        c = self.canv
        pairs = [
            ("Cyclin D/CDK4,6", PHASE_G1,   [(0.05,0.3),(0.20,0.85),(0.32,0.70),(0.40,0.10)]),
            ("Cyclin E/CDK2",   PHASE_S,    [(0.20,0.10),(0.32,0.95),(0.40,0.80),(0.50,0.10)]),
            ("Cyclin A/CDK2",   PHASE_G2,   [(0.35,0.10),(0.50,0.90),(0.65,0.85),(0.72,0.10)]),
            ("Cyclin B/CDK1",   PHASE_M,    [(0.60,0.10),(0.72,0.95),(0.82,0.85),(0.90,0.05)]),
        ]
        bar_y = 22
        chart_h = self.height - 38
        chart_w = self.width - 60
        x0 = 55

        # Axis
        c.setStrokeColor(TEXT_MED)
        c.setLineWidth(0.8)
        c.line(x0, bar_y, x0, bar_y + chart_h)
        c.line(x0, bar_y, x0 + chart_w, bar_y)
        c.setFillColor(TEXT_MED)
        c.setFont("Helvetica", 6.5)
        c.drawString(2, bar_y + chart_h / 2 - 4, "Activity")
        # Phase labels on x axis
        for label, frac, col in [("G0/G1", 0.13, PHASE_G1), ("S", 0.43, PHASE_S),
                                  ("G2", 0.65, PHASE_G2), ("M", 0.83, PHASE_M)]:
            c.setFillColor(col)
            c.setFont("Helvetica-Bold", 7)
            c.drawCentredString(x0 + frac * chart_w, bar_y - 8, label)

        # Draw curves
        for name, col, pts in pairs:
            c.setStrokeColor(col)
            c.setLineWidth(1.8)
            path = c.beginPath()
            first = True
            for fx, fy in pts:
                px = x0 + fx * chart_w
                py = bar_y + fy * chart_h
                if first:
                    path.moveTo(px, py)
                    first = False
                else:
                    path.lineTo(px, py)
            c.drawPath(path, stroke=1, fill=0)

        # Legend
        lx = x0
        for name, col, _ in pairs:
            c.setFillColor(col)
            c.rect(lx, self.height - 12, 10, 8, stroke=0, fill=1)
            c.setFillColor(TEXT_MED)
            c.setFont("Helvetica", 6.5)
            c.drawString(lx + 12, self.height - 11, name)
            lx += 115

        c.setFillColor(colors.HexColor("#5D6D7E"))
        c.setFont("Helvetica-Oblique", 7)
        c.drawCentredString(self.width / 2, 4,
            "Figure 4. Cyclin-CDK Complex Activity Across the Cell Cycle")


# ── Section Header Helper ─────────────────────────────────────────────────────
class SectionHeader(Flowable):
    def __init__(self, text, w=480, num=None):
        Flowable.__init__(self)
        self.text = text
        self.width = w
        self.height = 28
        self.num = num

    def draw(self):
        c = self.canv
        # Background
        c.setFillColor(DEEP_BLUE)
        c.roundRect(0, 0, self.width, self.height, 4, stroke=0, fill=1)
        # Left accent strip
        c.setFillColor(ACCENT)
        c.roundRect(0, 0, 6, self.height, 3, stroke=0, fill=1)
        # Number badge
        if self.num:
            c.setFillColor(ACCENT)
            c.circle(20, self.height / 2, 10, stroke=0, fill=1)
            c.setFillColor(colors.white)
            c.setFont("Helvetica-Bold", 10)
            c.drawCentredString(20, self.height / 2 - 4, str(self.num))
        # Text
        c.setFillColor(colors.white)
        c.setFont("Helvetica-Bold", 13)
        tx = 36 if self.num else 14
        c.drawString(tx, self.height / 2 - 5, self.text)


class InfoBox(Flowable):
    """Coloured info box."""
    def __init__(self, lines, col=LIGHT_BLUE, border_col=MID_BLUE, w=480):
        Flowable.__init__(self)
        self.lines = lines
        self.col = col
        self.border_col = border_col
        self.width = w
        self.height = 14 * len(lines) + 16

    def draw(self):
        c = self.canv
        c.setFillColor(self.col)
        c.setStrokeColor(self.border_col)
        c.setLineWidth(1.2)
        c.roundRect(0, 0, self.width, self.height, 5, stroke=1, fill=1)
        # Left stripe
        c.setFillColor(self.border_col)
        c.roundRect(0, 0, 5, self.height, 4, stroke=0, fill=1)
        c.setFillColor(TEXT_DARK)
        c.setFont("Helvetica", 9)
        for i, line in enumerate(self.lines):
            y = self.height - 14 * (i + 1) - 2
            c.drawString(12, y, line)


# ── Build Document ────────────────────────────────────────────────────────────

def build_pdf(path):
    W, H = A4
    doc = SimpleDocTemplate(
        path, pagesize=A4,
        leftMargin=2.2*cm, rightMargin=2.2*cm,
        topMargin=2*cm, bottomMargin=2*cm,
        title="The Cell Cycle", author="Orris Medical AI"
    )

    styles = make_styles()
    S = styles
    story = []

    # ── COVER ────────────────────────────────────────────────────────────────
    story.append(CoverPage(W, H))
    story.append(PageBreak())

    # ── PAGE 2 – OVERVIEW ────────────────────────────────────────────────────
    story.append(SectionHeader("1.  Overview of the Cell Cycle", num=1))
    story.append(Spacer(1, 8))
    story.append(Paragraph(
        "The cell cycle is a self-regulated sequence of events that controls cell growth and "
        "cell division. Its ultimate goal is to produce two genetically identical daughter cells, "
        "each with the same chromosome number and DNA content as the parent cell. The cycle "
        "incorporates two principal phases: <b>interphase</b> (continuous growth) and the "
        "<b>M phase</b> (mitosis or meiosis, where the genome is partitioned).",
        S['body']))
    story.append(Paragraph(
        "Most human cells complete the cell cycle in approximately <b>24 hours</b>. "
        "The duration of each phase is: G1 ~9-12 h, S ~10 h, G2 ~5 h, M ~30-60 min. "
        "Cells that stop dividing exit into the <b>G0 (resting/quiescent)</b> phase.",
        S['body']))
    story.append(Spacer(1, 10))
    story.append(CellCycleWheel(260))
    story.append(Spacer(1, 6))
    story.append(CheckpointDiagram(480, 72))
    story.append(Spacer(1, 10))

    # Quick-reference box
    story.append(InfoBox([
        "KEY FACT:  Rapidly renewing human cells complete the full cycle in ~24 hours.",
        "G0 cells can re-enter the cycle when stimulated by growth factors or steroid hormones.",
        "Terminally differentiated cells (neurons, RBCs, cardiac muscle) CANNOT re-enter the cycle.",
    ], col=LIGHT_BLUE, border_col=MID_BLUE))
    story.append(PageBreak())

    # ── PAGE 3 – PHASES ──────────────────────────────────────────────────────
    story.append(SectionHeader("2.  Phases of the Cell Cycle", num=2))
    story.append(Spacer(1, 8))

    phase_data = [
        [Paragraph("<b>Phase</b>", S['table_hdr']),
         Paragraph("<b>Key Events</b>", S['table_hdr']),
         Paragraph("<b>Duration</b>", S['table_hdr'])],
        [Paragraph("<b>G0</b>\n(Resting)", S['table_cell']),
         Paragraph("Quiescent; cell has exited the cycle. Re-entry triggered by mitogens.", S['table_cell']),
         Paragraph("Variable\n(days–lifetime)", S['table_cell'])],
        [Paragraph("<b>G1</b>\n(Gap 1)", S['table_cell']),
         Paragraph(
             "• Cell increases in size\n"
             "• Synthesises RNA and proteins needed for DNA replication\n"
             "• Contains the Restriction Checkpoint (point of no return)\n"
             "• p53 monitors DNA damage; if irreparable → apoptosis",
             S['table_cell']),
         Paragraph("9-12 h\n(longest phase)", S['table_cell'])],
        [Paragraph("<b>S Phase</b>\n(Synthesis)", S['table_cell']),
         Paragraph(
             "• DNA is replicated (genome doubles from 2N → 4N)\n"
             "• Each chromosome duplicated into two sister chromatids\n"
             "• S-phase DNA-damage checkpoint monitors replication fidelity",
             S['table_cell']),
         Paragraph("~10 h", S['table_cell'])],
        [Paragraph("<b>G2</b>\n(Gap 2)", S['table_cell']),
         Paragraph(
             "• Cell continues to grow and prepares for division\n"
             "• Checks quality of newly synthesised DNA\n"
             "• G2 DNA-damage checkpoint & unreplicated DNA checkpoint active",
             S['table_cell']),
         Paragraph("~5 h", S['table_cell'])],
        [Paragraph("<b>M Phase</b>\n(Mitosis)", S['table_cell']),
         Paragraph(
             "• Chromosome segregation and nuclear division\n"
             "• 4 sub-phases: Prophase → Metaphase → Anaphase → Telophase\n"
             "• Ends with Cytokinesis (cytoplasm division)\n"
             "• Produces 2 genetically identical daughter cells",
             S['table_cell']),
         Paragraph("30-60 min", S['table_cell'])],
    ]
    phase_table = Table(phase_data, colWidths=[80, 310, 90])
    phase_table.setStyle(TableStyle([
        ('BACKGROUND', (0, 0), (-1, 0), DEEP_BLUE),
        ('BACKGROUND', (0, 1), (-1, 1), PHASE_G0),
        ('BACKGROUND', (0, 2), (-1, 2), colors.HexColor("#D6EAF8")),
        ('BACKGROUND', (0, 3), (-1, 3), colors.HexColor("#FADBD8")),
        ('BACKGROUND', (0, 4), (-1, 4), colors.HexColor("#E8DAEF")),
        ('BACKGROUND', (0, 5), (-1, 5), colors.HexColor("#D5F5E3")),
        ('TEXTCOLOR', (0, 1), (-1, 1), colors.white),
        ('ROWBACKGROUNDS', (0, 0), (-1, 0), [DEEP_BLUE]),
        ('ALIGN', (0, 0), (-1, 0), 'CENTER'),
        ('VALIGN', (0, 0), (-1, -1), 'TOP'),
        ('GRID', (0, 0), (-1, -1), 0.5, colors.white),
        ('TOPPADDING', (0, 0), (-1, -1), 6),
        ('BOTTOMPADDING', (0, 0), (-1, -1), 6),
        ('LEFTPADDING', (0, 0), (-1, -1), 8),
        ('RIGHTPADDING', (0, 0), (-1, -1), 8),
        ('ROWBACKGROUNDS', (0, 1), (-1, -1), [
            PHASE_G0,
            colors.HexColor("#D6EAF8"),
            colors.HexColor("#FADBD8"),
            colors.HexColor("#E8DAEF"),
            colors.HexColor("#D5F5E3"),
        ]),
    ]))
    story.append(phase_table)
    story.append(Spacer(1, 12))
    story.append(PageBreak())

    # ── PAGE 4 – CHECKPOINTS ─────────────────────────────────────────────────
    story.append(SectionHeader("3.  Cell Cycle Checkpoints", num=3))
    story.append(Spacer(1, 8))
    story.append(Paragraph(
        "Checkpoints are biochemical surveillance pathways that monitor the integrity and "
        "completion of each stage before permitting progression to the next. They act as "
        "quality-control gates throughout the cycle.", S['body']))
    story.append(Spacer(1, 8))

    cp_data = [
        [Paragraph("<b>Checkpoint</b>", S['table_hdr']),
         Paragraph("<b>Location</b>", S['table_hdr']),
         Paragraph("<b>What It Monitors</b>", S['table_hdr']),
         Paragraph("<b>Key Molecules</b>", S['table_hdr'])],
        [Paragraph("Restriction Point (R)", S['table_cell']),
         Paragraph("Late G1", S['table_cell']),
         Paragraph("Cell size, nutrient availability, extracellular signals", S['table_cell']),
         Paragraph("Rb, E2F, Cyclin D/CDK4,6", S['table_cell'])],
        [Paragraph("G1 DNA-Damage", S['table_cell']),
         Paragraph("G1", S['table_cell']),
         Paragraph("Integrity of DNA before replication", S['table_cell']),
         Paragraph("p53, p21, ATM/ATR kinases", S['table_cell'])],
        [Paragraph("S-Phase DNA-Damage", S['table_cell']),
         Paragraph("S phase", S['table_cell']),
         Paragraph("Replication fork stalling; DNA strand breaks", S['table_cell']),
         Paragraph("CHK1, CHK2, ATR", S['table_cell'])],
        [Paragraph("G2/M DNA-Damage", S['table_cell']),
         Paragraph("Late G2", S['table_cell']),
         Paragraph("Completeness and accuracy of DNA replication", S['table_cell']),
         Paragraph("Cyclin B/CDK1, CDC25C, p53", S['table_cell'])],
        [Paragraph("Spindle-Assembly (SAC)", S['table_cell']),
         Paragraph("M phase", S['table_cell']),
         Paragraph("Attachment of all chromosomes to spindle microtubules", S['table_cell']),
         Paragraph("MAD1, MAD2, BUB1, BUBR1", S['table_cell'])],
    ]
    cp_table = Table(cp_data, colWidths=[100, 60, 160, 140])
    cp_table.setStyle(TableStyle([
        ('BACKGROUND', (0, 0), (-1, 0), DEEP_BLUE),
        ('ALIGN', (0, 0), (-1, 0), 'CENTER'),
        ('VALIGN', (0, 0), (-1, -1), 'TOP'),
        ('GRID', (0, 0), (-1, -1), 0.4, colors.HexColor("#BDC3C7")),
        ('ROWBACKGROUNDS', (0, 1), (-1, -1), [
            colors.HexColor("#EBF5FB"), colors.white,
            colors.HexColor("#EBF5FB"), colors.white,
            colors.HexColor("#EBF5FB"),
        ]),
        ('TOPPADDING', (0, 0), (-1, -1), 5),
        ('BOTTOMPADDING', (0, 0), (-1, -1), 5),
        ('LEFTPADDING', (0, 0), (-1, -1), 7),
        ('RIGHTPADDING', (0, 0), (-1, -1), 7),
    ]))
    story.append(cp_table)
    story.append(Spacer(1, 10))
    story.append(InfoBox([
        "CLINICAL PEARL:  When the G1 DNA-damage checkpoint detects irreparable DNA damage,",
        "p53 accumulates and triggers APOPTOSIS, preventing propagation of mutant cells.",
        "Mutations in TP53 (p53 gene) are found in >50% of all human cancers.",
    ], col=colors.HexColor("#FEF9E7"), border_col=GOLD))
    story.append(PageBreak())

    # ── PAGE 5 – MITOSIS + MEIOSIS ───────────────────────────────────────────
    story.append(SectionHeader("4.  Mitosis", num=4))
    story.append(Spacer(1, 6))
    story.append(Paragraph(
        "Mitosis is the process of chromosome segregation, nuclear division, and cell division "
        "that produces two genetically identical daughter cells. It follows the S phase and "
        "consists of four continuous phases plus cytokinesis.", S['body']))
    story.append(Spacer(1, 8))
    story.append(MitosisSteps(480, 88))
    story.append(Spacer(1, 8))

    mitosis_data = [
        [Paragraph("<b>Stage</b>", S['table_hdr']),
         Paragraph("<b>Key Events</b>", S['table_hdr'])],
        [Paragraph("Prophase", S['table_cell']),
         Paragraph("Chromosomes condense and become visible; nuclear envelope disassembles; "
                   "mitotic spindle forms from microtubules originating at centrosomes.", S['table_cell'])],
        [Paragraph("Metaphase", S['table_cell']),
         Paragraph("Chromosomes align at the cell equator (metaphase plate); "
                   "spindle-assembly checkpoint verifies kinetochore attachment.", S['table_cell'])],
        [Paragraph("Anaphase", S['table_cell']),
         Paragraph("Sister chromatids separate and are pulled to opposite poles "
                   "by shortening spindle fibres.", S['table_cell'])],
        [Paragraph("Telophase", S['table_cell']),
         Paragraph("Nuclear envelope reconstructs around each set of chromosomes; "
                   "chromosomes decondense; two nuclei form.", S['table_cell'])],
        [Paragraph("Cytokinesis", S['table_cell']),
         Paragraph("Cytoplasm divides via the contractile ring (actin/myosin), "
                   "producing two complete daughter cells.", S['table_cell'])],
    ]
    mit_table = Table(mitosis_data, colWidths=[90, 380])
    mit_table.setStyle(TableStyle([
        ('BACKGROUND', (0, 0), (-1, 0), PHASE_M),
        ('ALIGN', (0, 0), (-1, 0), 'CENTER'),
        ('VALIGN', (0, 0), (-1, -1), 'TOP'),
        ('GRID', (0, 0), (-1, -1), 0.4, colors.HexColor("#BDC3C7")),
        ('ROWBACKGROUNDS', (0, 1), (-1, -1), [
            colors.HexColor("#EAFAF1"), colors.white,
            colors.HexColor("#EAFAF1"), colors.white,
            colors.HexColor("#EAFAF1"),
        ]),
        ('TOPPADDING', (0, 0), (-1, -1), 5),
        ('BOTTOMPADDING', (0, 0), (-1, -1), 5),
        ('LEFTPADDING', (0, 0), (-1, -1), 7),
        ('RIGHTPADDING', (0, 0), (-1, -1), 7),
    ]))
    story.append(mit_table)
    story.append(Spacer(1, 12))

    story.append(SectionHeader("5.  Meiosis (vs Mitosis)", num=5))
    story.append(Spacer(1, 6))

    meiosis_data = [
        [Paragraph("<b>Feature</b>", S['table_hdr']),
         Paragraph("<b>Mitosis</b>", S['table_hdr']),
         Paragraph("<b>Meiosis</b>", S['table_hdr'])],
        ["Purpose", "Growth & tissue repair", "Gamete production"],
        ["Divisions", "1", "2 (Meiosis I + II)"],
        ["Daughter cells", "2 diploid (2N)", "4 haploid (N)"],
        ["Genetic identity", "Identical to parent", "Genetically unique"],
        ["Crossing-over", "Does not occur", "Occurs in Prophase I"],
        ["Occurs in", "All somatic cells", "Gonads only"],
    ]
    mei_table = Table(meiosis_data, colWidths=[130, 170, 170])
    mei_table.setStyle(TableStyle([
        ('BACKGROUND', (0, 0), (-1, 0), colors.HexColor("#8E44AD")),
        ('ALIGN', (0, 0), (-1, 0), 'CENTER'),
        ('VALIGN', (0, 0), (-1, -1), 'MIDDLE'),
        ('GRID', (0, 0), (-1, -1), 0.4, colors.HexColor("#BDC3C7")),
        ('ROWBACKGROUNDS', (0, 1), (-1, -1), [
            colors.HexColor("#F5EEF8"), colors.white,
            colors.HexColor("#F5EEF8"), colors.white,
            colors.HexColor("#F5EEF8"), colors.white,
        ]),
        ('FONTNAME', (0, 1), (0, -1), 'Helvetica-Bold'),
        ('FONTSIZE', (0, 0), (-1, -1), 8.5),
        ('TOPPADDING', (0, 0), (-1, -1), 5),
        ('BOTTOMPADDING', (0, 0), (-1, -1), 5),
        ('LEFTPADDING', (0, 0), (-1, -1), 8),
    ]))
    story.append(mei_table)
    story.append(PageBreak())

    # ── PAGE 6 – CYCLINS & CDKs ──────────────────────────────────────────────
    story.append(SectionHeader("6.  Cyclins and Cyclin-Dependent Kinases (CDKs)", num=6))
    story.append(Spacer(1, 6))
    story.append(Paragraph(
        "Progression through the cell cycle is driven by a two-protein complex: "
        "<b>cyclin</b> (regulatory subunit) and <b>cyclin-dependent kinase (CDK)</b> "
        "(catalytic subunit). Cyclins are synthesised and degraded at regular intervals, "
        "providing oscillatory control of CDK activity.", S['body']))
    story.append(Spacer(1, 8))
    story.append(CyclinCDKBar(480, 90))
    story.append(Spacer(1, 8))

    cdk_data = [
        [Paragraph("<b>Cyclin-CDK Complex</b>", S['table_hdr']),
         Paragraph("<b>Phase Active</b>", S['table_hdr']),
         Paragraph("<b>Main Function</b>", S['table_hdr'])],
        ["Cyclin D / CDK4,6", "G1", "Phosphorylates Rb → releases E2F → drives G1 progression"],
        ["Cyclin E / CDK2",   "G1→S", "Triggers entry into S phase; initiates DNA replication"],
        ["Cyclin A / CDK2",   "S→G2", "Sustains DNA replication; promotes G2 entry"],
        ["Cyclin A / CDK1",   "G2",   "Promotes mitotic entry"],
        ["Cyclin B / CDK1",   "M phase", "MPF (Maturation-Promoting Factor); drives mitosis; degraded at end of M"],
    ]
    cdk_table = Table(cdk_data, colWidths=[140, 80, 250])
    cdk_table.setStyle(TableStyle([
        ('BACKGROUND', (0, 0), (-1, 0), DEEP_BLUE),
        ('ALIGN', (0, 0), (-1, 0), 'CENTER'),
        ('VALIGN', (0, 0), (-1, -1), 'TOP'),
        ('GRID', (0, 0), (-1, -1), 0.4, colors.HexColor("#BDC3C7")),
        ('ROWBACKGROUNDS', (0, 1), (-1, -1), [
            colors.HexColor("#D6EAF8"), colors.white,
            colors.HexColor("#D6EAF8"), colors.white,
            colors.HexColor("#D6EAF8"),
        ]),
        ('FONTNAME', (0, 1), (0, -1), 'Helvetica-Bold'),
        ('FONTSIZE', (0, 0), (-1, -1), 8.5),
        ('TOPPADDING', (0, 0), (-1, -1), 5),
        ('BOTTOMPADDING', (0, 0), (-1, -1), 5),
        ('LEFTPADDING', (0, 0), (-1, -1), 7),
    ]))
    story.append(cdk_table)
    story.append(Spacer(1, 10))
    story.append(InfoBox([
        "CDK INHIBITORS (CKIs): Proteins like p21, p27, p57 (CIP/KIP family) and p16, p15 (INK4 family)",
        "bind to cyclin-CDK complexes and INHIBIT their activity, halting cell cycle progression.",
        "CDK4/6 inhibitors (palbociclib, ribociclib) are FDA-approved cancer drugs.",
    ], col=colors.HexColor("#EBF5FB"), border_col=MID_BLUE))
    story.append(PageBreak())

    # ── PAGE 7 – CELL CYCLE REGULATION & CANCER ──────────────────────────────
    story.append(SectionHeader("7.  Regulation of the Cell Cycle", num=7))
    story.append(Spacer(1, 6))
    story.append(Paragraph(
        "Cell cycle progression is tightly regulated by a balance of positive (pro-proliferative) "
        "and negative (anti-proliferative) signals. Disruption of this balance leads to uncontrolled "
        "proliferation (cancer) or failure to divide.", S['body']))
    story.append(Spacer(1, 6))

    reg_data = [
        [Paragraph("<b>Regulator</b>", S['table_hdr']),
         Paragraph("<b>Type</b>", S['table_hdr']),
         Paragraph("<b>Role</b>", S['table_hdr'])],
        ["Rb (Retinoblastoma protein)", "Tumour suppressor",
         "Binds and inhibits E2F; when phosphorylated by Cyclin D/CDK4,6 → releases E2F → S phase entry"],
        ["p53 (TP53 gene)", "Tumour suppressor",
         "Senses DNA damage; induces p21 (CDK inhibitor) → G1 arrest; triggers apoptosis if damage irreparable"],
        ["E2F transcription factors", "Pro-proliferative",
         "When released from Rb, activates genes needed for S phase (thymidine kinase, DNA polymerase)"],
        ["Growth factors (EGF, PDGF)", "Mitogen",
         "Bind surface receptors → activate RAS/MAPK → induce Cyclin D → drive G1 progression"],
        ["CDK inhibitors (p21, p27, p16)", "Negative regulators",
         "Bind and inhibit cyclin-CDK complexes; key targets of p53 signalling"],
        ["Proto-oncogenes (RAS, MYC)", "Positive regulators",
         "When mutated become oncogenes; drive uncontrolled proliferation"],
    ]
    reg_table = Table(reg_data, colWidths=[130, 100, 240])
    reg_table.setStyle(TableStyle([
        ('BACKGROUND', (0, 0), (-1, 0), DEEP_BLUE),
        ('ALIGN', (0, 0), (-1, 0), 'CENTER'),
        ('VALIGN', (0, 0), (-1, -1), 'TOP'),
        ('GRID', (0, 0), (-1, -1), 0.4, colors.HexColor("#BDC3C7")),
        ('ROWBACKGROUNDS', (0, 1), (-1, -1), [
            colors.HexColor("#FDEDEC"), colors.white,
            colors.HexColor("#FDEDEC"), colors.white,
            colors.HexColor("#FDEDEC"), colors.white,
        ]),
        ('FONTNAME', (0, 1), (0, -1), 'Helvetica-Bold'),
        ('FONTSIZE', (0, 0), (-1, -1), 8.5),
        ('TOPPADDING', (0, 0), (-1, -1), 5),
        ('BOTTOMPADDING', (0, 0), (-1, -1), 5),
        ('LEFTPADDING', (0, 0), (-1, -1), 7),
    ]))
    story.append(reg_table)
    story.append(Spacer(1, 10))
    story.append(PageBreak())

    # ── PAGE 8 – CLINICAL RELEVANCE ──────────────────────────────────────────
    story.append(SectionHeader("8.  Clinical Relevance", num=8))
    story.append(Spacer(1, 6))

    story.append(Paragraph("<b>A. Cell Cycle Deregulation in Cancer</b>", S['sub_head']))
    story.append(Paragraph(
        "Cancer fundamentally results from deregulation of the cell cycle. Cells acquire "
        "hallmark mutations that override checkpoints, disable tumour suppressors, or "
        "constitutively activate pro-proliferative signals:", S['body']))

    cancer_bullets = [
        "Loss of Rb function → unchecked E2F activity → continuous G1→S transition",
        "TP53 mutation (>50% of cancers) → no G1 arrest or apoptosis after DNA damage",
        "Cyclin D/CDK4 amplification → accelerated passage through Restriction Point",
        "Oncogenic RAS/MYC → bypass of growth factor requirements",
        "Chromosomal instability from defective spindle-assembly checkpoint",
    ]
    for b in cancer_bullets:
        story.append(Paragraph(f"• {b}", S['bullet']))
    story.append(Spacer(1, 8))

    story.append(Paragraph("<b>B. Cell Cycle-Targeted Therapeutics</b>", S['sub_head']))
    drug_data = [
        [Paragraph("<b>Drug Class / Agent</b>", S['table_hdr']),
         Paragraph("<b>Target Phase</b>", S['table_hdr']),
         Paragraph("<b>Mechanism</b>", S['table_hdr'])],
        ["Alkylating agents\n(cyclophosphamide)", "Any phase (most effective S/G2)",
         "Cross-link DNA strands → strand breaks → apoptosis"],
        ["Antimetabolites\n(methotrexate, 5-FU)", "S phase",
         "Inhibit DNA/RNA synthesis; folate antagonism → arrest"],
        ["Taxanes\n(paclitaxel, docetaxel)", "M phase",
         "Stabilise microtubules → prevent spindle disassembly → M arrest"],
        ["Vinca alkaloids\n(vincristine)", "M phase",
         "Inhibit tubulin polymerisation → disrupt spindle formation"],
        ["CDK4/6 inhibitors\n(palbociclib, ribociclib)", "G1 phase",
         "Block Rb phosphorylation → prevent G1→S transition"],
        ["Topoisomerase inhibitors\n(etoposide, irinotecan)", "S/G2 phase",
         "Induce DNA double-strand breaks → S and G2 arrest"],
        ["PARP inhibitors\n(olaparib)", "S phase",
         "Block DNA repair → synthetic lethality in BRCA-mutant cancers"],
    ]
    drug_table = Table(drug_data, colWidths=[130, 100, 240])
    drug_table.setStyle(TableStyle([
        ('BACKGROUND', (0, 0), (-1, 0), colors.HexColor("#C0392B")),
        ('ALIGN', (0, 0), (-1, 0), 'CENTER'),
        ('VALIGN', (0, 0), (-1, -1), 'TOP'),
        ('GRID', (0, 0), (-1, -1), 0.4, colors.HexColor("#BDC3C7")),
        ('ROWBACKGROUNDS', (0, 1), (-1, -1), [
            colors.HexColor("#FDEDEC"), colors.white,
            colors.HexColor("#FDEDEC"), colors.white,
            colors.HexColor("#FDEDEC"), colors.white,
            colors.HexColor("#FDEDEC"),
        ]),
        ('FONTNAME', (0, 1), (0, -1), 'Helvetica-Bold'),
        ('FONTSIZE', (0, 0), (-1, -1), 8.5),
        ('TOPPADDING', (0, 0), (-1, -1), 5),
        ('BOTTOMPADDING', (0, 0), (-1, -1), 5),
        ('LEFTPADDING', (0, 0), (-1, -1), 7),
    ]))
    story.append(drug_table)
    story.append(Spacer(1, 10))
    story.append(PageBreak())

    # ── PAGE 9 – APOPTOSIS & KEY SUMMARY ─────────────────────────────────────
    story.append(SectionHeader("9.  Apoptosis and Cell Death", num=9))
    story.append(Spacer(1, 6))
    story.append(Paragraph(
        "Apoptosis (programmed cell death) is a normal physiologic process that balances "
        "cell proliferation in tissues. It is activated when checkpoint-repair mechanisms "
        "fail, ensuring that damaged cells do not propagate.", S['body']))
    story.append(Spacer(1, 4))

    apop_data = [
        [Paragraph("<b>Type</b>", S['table_hdr']),
         Paragraph("<b>Trigger</b>", S['table_hdr']),
         Paragraph("<b>Features</b>", S['table_hdr'])],
        ["Intrinsic pathway", "DNA damage, hypoxia, oxidative stress",
         "Mitochondria release cytochrome c → activates caspase-9 → caspase-3"],
        ["Extrinsic pathway", "Death receptor ligands (FasL, TNF-α)",
         "Fas/TNFR activation → caspase-8 → caspase-3 → apoptosis"],
        ["Necrosis (non-programmed)", "Severe injury, toxins",
         "Cell swelling → membrane rupture → inflammation; no caspase involvement"],
        ["Anoikis", "Loss of ECM attachment",
         "Cells deprived of substrate → apoptosis; prevents metastasis"],
    ]
    apop_table = Table(apop_data, colWidths=[120, 160, 190])
    apop_table.setStyle(TableStyle([
        ('BACKGROUND', (0, 0), (-1, 0), colors.HexColor("#922B21")),
        ('ALIGN', (0, 0), (-1, 0), 'CENTER'),
        ('VALIGN', (0, 0), (-1, -1), 'TOP'),
        ('GRID', (0, 0), (-1, -1), 0.4, colors.HexColor("#BDC3C7")),
        ('ROWBACKGROUNDS', (0, 1), (-1, -1), [
            colors.HexColor("#FDEDEC"), colors.white,
            colors.HexColor("#FDEDEC"), colors.white,
        ]),
        ('FONTNAME', (0, 1), (0, -1), 'Helvetica-Bold'),
        ('FONTSIZE', (0, 0), (-1, -1), 8.5),
        ('TOPPADDING', (0, 0), (-1, -1), 5),
        ('BOTTOMPADDING', (0, 0), (-1, -1), 5),
        ('LEFTPADDING', (0, 0), (-1, -1), 7),
    ]))
    story.append(apop_table)
    story.append(Spacer(1, 12))

    story.append(SectionHeader("10.  Key Summary Points", num=10))
    story.append(Spacer(1, 6))
    summary_pts = [
        "The cell cycle = G1 → S → G2 → M, with G0 as a quiescent state.",
        "Full cycle takes ~24 h; G1 is the longest and most variable phase.",
        "Checkpoints prevent propagation of DNA errors; p53 is the master guardian.",
        "Cyclins rise and fall rhythmically; CDKs are constitutive but need cyclin binding.",
        "The Restriction Point in G1 is the point of no return; Rb/E2F axis controls it.",
        "Mitosis produces 2 identical 2N daughter cells; meiosis produces 4 unique N cells.",
        "Cancer = deregulated cell cycle; most oncogenes/tumour suppressors map to checkpoint pathways.",
        "Many anticancer drugs exploit phase-specific vulnerabilities (S phase, M phase).",
        "CDK4/6 inhibitors (palbociclib etc.) are a clinical success story of checkpoint targeting.",
        "Apoptosis and the cell cycle are coupled: irreparable DNA damage → apoptosis, not division.",
    ]
    for i, pt in enumerate(summary_pts, 1):
        story.append(Paragraph(f"<b>{i}.</b>  {pt}", S['bullet']))

    story.append(Spacer(1, 10))
    story.append(InfoBox([
        "Sources: Histology – A Text and Atlas with Correlated Cell and Molecular Biology (Wolters Kluwer)",
        "         Berek & Novak's Gynecology, 16th ed. | Scott-Brown's Otorhinolaryngology Head & Neck Surgery",
    ], col=BG_LIGHT, border_col=DEEP_BLUE))

    # ── BUILD ────────────────────────────────────────────────────────────────
    def on_page(canvas, doc):
        # Header/Footer on all pages except cover
        if doc.page > 1:
            canvas.saveState()
            canvas.setFillColor(DEEP_BLUE)
            canvas.setFont("Helvetica-Bold", 8)
            canvas.drawString(2.2*cm, H - 1.4*cm, "THE CELL CYCLE")
            canvas.setFont("Helvetica", 8)
            canvas.drawRightString(W - 2.2*cm, H - 1.4*cm, "Orris Medical AI")
            canvas.setStrokeColor(ACCENT)
            canvas.setLineWidth(0.8)
            canvas.line(2.2*cm, H - 1.6*cm, W - 2.2*cm, H - 1.6*cm)
            # Footer
            canvas.setFont("Helvetica", 7.5)
            canvas.setFillColor(colors.HexColor("#7F8C8D"))
            canvas.drawCentredString(W/2, 1.2*cm, f"Page {doc.page - 1}")
            canvas.setStrokeColor(colors.HexColor("#BDC3C7"))
            canvas.setLineWidth(0.5)
            canvas.line(2.2*cm, 1.6*cm, W - 2.2*cm, 1.6*cm)
            canvas.restoreState()

    doc.build(story, onFirstPage=on_page, onLaterPages=on_page)
    print(f"PDF saved to: {path}")


if __name__ == "__main__":
    out = "/tmp/workspace/cell-cycle-pdf/Cell_Cycle.pdf"
    build_pdf(out)