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Here are complete answers to all General Physiology questions from your revision list:

GENERAL PHYSIOLOGY - COMPLETE ANSWERS

ESSAY QUESTIONS

1. Secondary Active Transport

Definition: Secondary active transport is the coupled transport of two or more solutes across the cell membrane where the movement of one solute (usually Na+) down its electrochemical gradient provides the energy for the movement of another solute against its electrochemical gradient. ATP is not used directly - it is used indirectly via the Na+ concentration gradient maintained by the Na+-K+-ATPase.

Energy Source:

The Na+-K+-ATPase (using ATP) pumps 3 Na+ out and 2 K+ in, creating a low intracellular Na+ concentration.
This Na+ gradient is the "driving force" for secondary active transport.
Hence it is called "secondary" - the energy is indirect.

Two Types:

Type	Also Called	Direction	Example
Cotransport	Symport	Both solutes move in the SAME direction	Na+-glucose (SGLT1), Na+-amino acid
Countertransport	Antiport/Exchange	Solutes move in OPPOSITE directions	Na+-H+ exchanger, Na+-Ca2+ exchanger

Key Examples:

Na+-Glucose cotransport (SGLT1) - in luminal membrane of small intestine and proximal renal tubule. Na+ enters down its gradient; glucose is co-transported into the cell against its gradient.
Na+-K+-2Cl- cotransport - in thick ascending limb of loop of Henle.
Na+-H+ exchanger - in proximal tubule (countertransport).

Effect of Na+-K+-ATPase inhibition: Inhibition by ouabain decreases the Na+ gradient → intracellular Na+ rises → driving force for secondary active transport diminishes → all secondary active transport processes are indirectly impaired.

(Costanzo Physiology 7th Ed., p. 14-16; Ganong's Review of Medical Physiology 26th Ed.)

2. Resting Membrane Potential (RMP) - Ionic Basis

Definition: The resting membrane potential (RMP) is the electrical potential difference across the membrane of an excitable cell (nerve or muscle) at rest, between action potentials. By convention, the intracellular potential is expressed relative to the extracellular potential.

Normal Value: -70 to -80 mV in most excitable cells (intracellular negative relative to extracellular).

Ionic Basis of RMP:

The RMP arises from diffusion potentials generated by unequal ion concentrations across the membrane.

Ion	Intracellular	Extracellular	Equilibrium Potential	Resting Permeability
K+	140 mEq/L	4 mEq/L	-94 mV	HIGH
Na+	14 mEq/L	140 mEq/L	+66 mV	LOW
Cl-	4 mEq/L	114 mEq/L	-90 mV	Moderate
Ca2+	0.0001 mEq/L	2.5 mEq/L	+132 mV	Very LOW

Key Principle: Each ion drives the membrane potential toward its own equilibrium potential. Ions with the highest permeability at rest contribute most to RMP.

At rest, permeability to K+ and Cl- is high → RMP is close to K+ and Cl- equilibrium potentials (~-70 to -90 mV)
Permeability to Na+ and Ca2+ is low at rest → minimal contribution to RMP

Chord Conductance Equation:

Em = (gK+/gT) × EK+ + (gNa+/gT) × ENa+ + (gCl-/gT) × ECl- + (gCa2+/gT) × ECa2+

Where g = conductance, gT = total conductance, E = equilibrium potential

Role of Na+-K+-ATPase in RMP:

Direct (electrogenic) contribution: Pumps 3 Na+ out for every 2 K+ in - creates a small negative charge inside.
Indirect (major) contribution: Maintains the K+ and Na+ concentration gradients, which are responsible for the diffusion potentials that establish RMP. Without the pump, the gradients would dissipate and RMP would collapse.

(Costanzo Physiology 7th Ed., p. 26-27)

3. Structure and Functions of Cell Junctions

Cell junctions are specialized structures between cells that provide mechanical linkage, regulation of permeability, and cell-to-cell communication.

Classification:

A. Tight Junction (Zonula Occludens)

Location: Surrounds apical margins of epithelial cells (intestinal mucosa, renal tubules, choroid plexus).
Structure: Ridges from two adjacent cells fuse - nearly obliterating the intercellular space. Made up of transmembrane proteins: occludin, claudins, and junctional adhesion molecules (JAMs). Cytosolic proteins also interact (e.g., ZO-1, ZO-2).
Functions:
- Seals the paracellular space - controls what passes between cells.
- Degree of "leakiness" varies by protein composition.
- Maintains cell polarity - prevents mixing of apical and basolateral membrane proteins.
- Allows some paracellular passage of ions and solutes (magnitude varies).

B. Adherens Junction (Zonula Adherens)

Location: Just basal to the tight junction in epithelial cells - forms a continuous belt.
Structure: Contains cadherins (Ca2+-dependent adhesion molecules). Major site of attachment for intracellular microfilaments (actin).
Function: Mechanical linkage between adjacent cells; important in maintaining tissue integrity during morphogenesis.

C. Desmosome (Macula Adherens)

Structure: Patchy thickenings of membranes of two adjacent cells. Intermediate filaments attach to the dense plaque on each side. Intercellular space contains cadherins and other transmembrane proteins.
Function: Strong mechanical linkage - resists shearing forces. Abundant in skin (epidermis) and cardiac muscle.

D. Hemidesmosome

Location: Basal surface of epithelial cells.
Structure: Resembles half a desmosome. Contains integrins (not cadherins). Connected intracellularly to intermediate filaments.
Function: Anchors cell to the underlying basal lamina.

E. Focal Adhesion

Structure: Labile structures associated with actin filaments intracellularly; connected to basal lamina via integrins.
Function: Cell-to-extracellular matrix attachment; involved in cell signaling and migration.

F. Gap Junction (Nexus)

Structure: Channels made of connexins (6 connexins form one connexon; two connexons from adjacent cells align to form a complete channel).
Function: Forms cytoplasmic "tunnels" for direct diffusion of small molecules (<1000 Da) - ions, second messengers, metabolites - between adjacent cells. Enables electrical and metabolic coupling. Critical in cardiac muscle (impulse propagation) and smooth muscle.

(Ganong's Review of Medical Physiology 26th Ed., p. 52-54)

4. Na+-K+-ATPase System

Overview: The Na+-K+-ATPase is a primary active transport pump found in all cell membranes. It uses energy from ATP hydrolysis directly to transport ions against their electrochemical gradients.

Mechanism:

Pumps 3 Na+ OUT of the cell
Pumps 2 K+ IN to the cell
Per molecule of ATP hydrolyzed
Coupling ratio = 3:2 (electrogenic pump - net movement of positive charge out → contributes to negative RMP)

Structure:

Heterodimer: α subunit (MW ~100,000) + β subunit (MW ~55,000)
Both span the cell membrane; separation eliminates activity
α subunit: Spans membrane ~10 times. Has:
- Intracellular Na+-binding site
- Intracellular ATP-binding site and phosphorylation site
- Extracellular K+-binding site
- Extracellular ouabain-binding site
β subunit: Glycoprotein with a single membrane-spanning domain; has 3 extracellular glycosylation sites

Inhibitors: Ouabain and related digitalis glycosides (used in heart failure treatment) bind the extracellular site of the α subunit and inhibit the pump.

Functions:

Maintains low intracellular Na+ and high intracellular K+.
Establishes the Na+ gradient used for secondary active transport (glucose, amino acids).
Contributes to RMP (electrogenic effect + maintains K+ gradient).
Regulates cell volume (by controlling intracellular osmolarity).
Maintains excitability of nerve and muscle cells.

(Ganong's Review of Medical Physiology 26th Ed., p. 62-64)

5. Simple Diffusion

Definition: Simple diffusion is the passive movement of a solute across a membrane from an area of high concentration to an area of low concentration, driven entirely by the concentration gradient (or electrochemical gradient for charged solutes). No carrier protein or energy (ATP) is required.

Mechanism: Results from random thermal motion of molecules. Net flux occurs from high to low concentration until equilibrium is reached.

Fick's Law (Net Diffusion Equation):

J = P × A × (CA - CB)

Where:

J = Net rate of diffusion (mmol/s)
P = Permeability (cm/s) - incorporates partition coefficient, diffusion coefficient, and membrane thickness
A = Surface area (cm²)
CA, CB = Concentrations on each side

Factors Affecting Rate of Simple Diffusion:

Factor	Effect on Diffusion
Concentration gradient (CA - CB)	↑ gradient → ↑ diffusion
Partition coefficient (K)	↑ lipid solubility → ↑ diffusion
Diffusion coefficient (D)	↑ in small molecules, low viscosity
Membrane thickness (Δx)	↑ thickness → ↓ diffusion
Surface area (A)	↑ area → ↑ diffusion

Partition coefficient: Solubility in oil / solubility in water. Nonpolar (lipid-soluble) molecules have high K → cross membrane easily (e.g., O2, CO2, steroids).
Diffusion coefficient (Stokes-Einstein equation): D = kT / (6πηr) - inversely related to molecular radius and viscosity.

Characteristics of Simple Diffusion:

No carrier protein
Not saturable
No stereospecificity (cannot distinguish D- and L-isomers)
No competition between similar molecules
Proceeds as long as concentration gradient exists

Examples: O2, CO2, urea, ethanol, steroid hormones, lipid-soluble vitamins

(Costanzo Physiology 7th Ed., p. 13-15)

6. Facilitated Diffusion

Definition: Facilitated diffusion is a form of passive transport (no energy required) in which a solute moves down its electrochemical gradient with the help of a specific membrane carrier protein (transporter).

Key Features - Carrier-Mediated Transport:

Feature	Explanation
Saturation	Rate increases with concentration but plateaus (Vmax) when all carriers are occupied - unlike simple diffusion which increases linearly
Stereospecificity	Carrier recognizes specific molecular shape (e.g., GLUT4 transports D-glucose but NOT L-glucose)
Competition	Structurally similar molecules compete for same carrier (e.g., D-galactose competes with D-glucose for the glucose transporter)
No energy required	Moves solute only DOWN electrochemical gradient

Comparison with Simple Diffusion:

Feature	Simple Diffusion	Facilitated Diffusion
Carrier protein	No	Yes
Energy (ATP)	No	No
Saturation	No	Yes (Vmax)
Stereospecificity	No	Yes
Competition	No	Yes
Rate at low concentration	Slower	Faster
Rate at high concentration	Continues to rise	Plateaus at Vmax

Classic Example:

GLUT4 transporter - transports D-glucose into skeletal muscle and adipose cells.
Glucose moves from high concentration (blood) to low concentration (inside cell) down the gradient.
Insulin increases insertion of GLUT4 into the membrane → increased glucose uptake.

Other Examples:

GLUT1, GLUT2 (erythrocytes, liver) - glucose transport
Urea transporters in renal medulla

(Costanzo Physiology 7th Ed., p. 15-16)

7. Apoptosis

Definition: Apoptosis (from Greek: "falling off") is programmed cell death - a highly regulated, caspase-dependent process by which the cell actively dismantles itself without inducing inflammation. It is distinct from necrosis (uncontrolled, pathological cell death).

Physiological Significance:

Eliminates defective, aged, or excess cells under normal conditions.
Essential for embryonic development, immune tolerance, and tissue homeostasis.
When proliferation exceeds apoptosis → hyperplasia/tumor; when excess apoptosis → atrophy.

Morphological Features of Apoptosis:

Cell shrinkage
Membrane blebbing
Chromatin condensation and nuclear fragmentation
Formation of apoptotic bodies (membrane-bound fragments)
Cell membrane integrity is maintained throughout - no spillage of contents
Apoptotic bodies are phagocytosed by neighboring cells or macrophages → NO inflammation

Molecular Mechanisms - Two Main Pathways:

A. Intrinsic (Mitochondrial) Pathway

Triggered by: DNA damage, oxidative stress, lack of growth factors, radiation
Key proteins: Bcl-2 family
- Proapoptotic members (BAX, BAK, BIM) increase mitochondrial membrane permeability
- Antiapoptotic members (Bcl-2, Bcl-XL) inhibit this
Mitochondria release cytochrome c and SMAC/DIABLO into the cytoplasm
Cytochrome c + Apaf-1 + procaspase-9 → form apoptosome
Apoptosome activates caspase-9 → activates executioner caspases (3, 6, 7)
Caspases dismantle the cell by digesting cytoplasmic proteins

B. Extrinsic (Death Receptor) Pathway

Triggered by: FasL binding to Fas (CD95), TNF binding to TNFR
Formation of DISC (Death-Inducing Signaling Complex)
Activates caspase-8 → executioner caspases

Types of Programmed Cell Death:

Type	Feature
Apoptosis	Caspase-dependent, membrane intact, no inflammation
Anoikis	Apoptosis triggered by lack of cell-to-ECM contact
Necroptosis	Programmed, caspase-independent, membrane rupture
Autophagy	Cell "self-eating" - degradation of own organelles
Pyroptosis	Inflammatory cell death (caspase-1 dependent)

Clinical Relevance:

Cancer: Mutations in p53 or Bcl-2 overexpression → apoptosis resistance → tumor survival
Neurodegeneration: Excessive apoptosis → Parkinson's, Alzheimer's
Autoimmune disease: Defective apoptosis of self-reactive lymphocytes (FAS defects → ALPS)

(Histology: A Text and Atlas, Correlated Cell and Molecular Biology; Costanzo Physiology 7th Ed.)

Summary Table - General Physiology Topics

Topic	Key Point
Secondary Active Transport	Uses Na+ gradient (maintained by Na-K-ATPase); Cotransport (symport) vs Countertransport (antiport)
RMP	-70 to -80 mV; driven by high K+ permeability; Na-K-ATPase maintains gradient
Cell Junctions	Tight (seal), Adherens (actin-based), Desmosome (intermediate filaments), Hemidesmosome (basal lamina), Gap (communication)
Na+-K+-ATPase	3Na+ out : 2K+ in per ATP; α+β subunits; inhibited by ouabain/digitalis
Simple Diffusion	Passive; no carrier; rate = P×A×(CA-CB); governed by partition & diffusion coefficients
Facilitated Diffusion	Passive with carrier; saturable, stereospecific, competitive; GLUT4 is classic example
Apoptosis	Programmed cell death; caspase-dependent; intrinsic (mitochondrial) or extrinsic (death receptor) pathway

Generate a summary PDF with diagrams and key equations

Reading File

Running Command

mkdir -p /home/daytona/workspace/gen-physiology-pdf && ls /home/daytona/workspac…

Writing File

~/gen-physiology-pdf/build_pdf.py

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, Rect, String, Line, Arrow, Circle, Polygon
from reportlab.graphics import renderPDF
from reportlab.graphics.shapes import Group
import math

# ── Output path ──────────────────────────────────────────────────────────────
OUTPUT = "/home/daytona/workspace/gen-physiology-pdf/General_Physiology_Summary.pdf"

# ── Colour palette ────────────────────────────────────────────────────────────
BLUE_DARK   = colors.HexColor("#1A3A5C")
BLUE_MID    = colors.HexColor("#2E6DA4")
BLUE_LIGHT  = colors.HexColor("#D6E8FA")
TEAL        = colors.HexColor("#0B7285")
TEAL_LIGHT  = colors.HexColor("#C8EEF2")
GREEN_DARK  = colors.HexColor("#1B5E20")
GREEN_LIGHT = colors.HexColor("#E8F5E9")
ORANGE_DARK = colors.HexColor("#E65100")
ORANGE_LIGHT= colors.HexColor("#FFF3E0")
RED_DARK    = colors.HexColor("#B71C1C")
RED_LIGHT   = colors.HexColor("#FFEBEE")
PURPLE_DARK = colors.HexColor("#4A148C")
PURPLE_LIGHT= colors.HexColor("#F3E5F5")
YELLOW      = colors.HexColor("#FFF9C4")
GRAY_LIGHT  = colors.HexColor("#F5F5F5")
GRAY_MID    = colors.HexColor("#BDBDBD")
WHITE       = colors.white
BLACK       = colors.black

# ── Styles ────────────────────────────────────────────────────────────────────
styles = getSampleStyleSheet()

def S(name, **kw):
    return ParagraphStyle(name, **kw)

COVER_TITLE = S("CoverTitle", fontSize=28, leading=36, textColor=WHITE,
                fontName="Helvetica-Bold", alignment=TA_CENTER)
COVER_SUB   = S("CoverSub",  fontSize=14, leading=20, textColor=BLUE_LIGHT,
                fontName="Helvetica", alignment=TA_CENTER)
H1  = S("H1",  fontSize=16, leading=22, textColor=WHITE,
         fontName="Helvetica-Bold", alignment=TA_CENTER, spaceAfter=6)
H2  = S("H2",  fontSize=13, leading=18, textColor=BLUE_DARK,
         fontName="Helvetica-Bold", spaceBefore=10, spaceAfter=4)
H3  = S("H3",  fontSize=11, leading=15, textColor=TEAL,
         fontName="Helvetica-Bold", spaceBefore=6, spaceAfter=3)
BODY = S("Body", fontSize=9, leading=13, textColor=BLACK,
          fontName="Helvetica", spaceAfter=4, alignment=TA_JUSTIFY)
BULLET = S("Bullet", fontSize=9, leading=13, textColor=BLACK,
            fontName="Helvetica", leftIndent=14, firstLineIndent=-10,
            spaceAfter=3)
EQUATION = S("Equation", fontSize=10, leading=16, textColor=BLUE_DARK,
              fontName="Helvetica-Bold", alignment=TA_CENTER,
              spaceBefore=4, spaceAfter=4,
              backColor=BLUE_LIGHT, borderPad=6)
KEY_BOX = S("KeyBox", fontSize=9, leading=13, textColor=GREEN_DARK,
             fontName="Helvetica-Bold", alignment=TA_CENTER,
             backColor=GREEN_LIGHT, borderPad=5)
NOTE = S("Note", fontSize=8, leading=12, textColor=ORANGE_DARK,
          fontName="Helvetica-Oblique", spaceAfter=3)

# ── Helper: Section header banner ─────────────────────────────────────────────
class ColorBanner(Flowable):
    def __init__(self, text, bg=BLUE_DARK, fg=WHITE, height=28, fontsize=13):
        super().__init__()
        self.text     = text
        self.bg       = bg
        self.fg       = fg
        self.height   = height
        self.fontsize = fontsize
        self.width    = 0  # set by wrap

    def wrap(self, availW, availH):
        self.width = availW
        return (availW, self.height)

    def draw(self):
        c = self.canv
        c.setFillColor(self.bg)
        c.roundRect(0, 0, self.width, self.height, 5, stroke=0, fill=1)
        c.setFillColor(self.fg)
        c.setFont("Helvetica-Bold", self.fontsize)
        c.drawCentredString(self.width / 2, (self.height - self.fontsize) / 2 + 2, self.text)

# ── Helper: Diagram flowable base ─────────────────────────────────────────────
class DiagramFlowable(Flowable):
    def __init__(self, width, height, draw_fn):
        super().__init__()
        self._w = width
        self._h = height
        self._draw_fn = draw_fn

    def wrap(self, availW, availH):
        return (self._w, self._h)

    def draw(self):
        self._draw_fn(self.canv, self._w, self._h)

# ─────────────────────────────────────────────────────────────────────────────
# DIAGRAM FUNCTIONS
# ─────────────────────────────────────────────────────────────────────────────

def draw_secondary_active_transport(c, W, H):
    """Diagram: Secondary active transport - cotransport and countertransport."""
    # Background
    c.setFillColor(BLUE_LIGHT)
    c.roundRect(0, 0, W, H, 8, stroke=0, fill=1)

    mid = W / 2
    # Cell membrane bar
    memb_y = H / 2
    c.setFillColor(colors.HexColor("#7B9ABF"))
    c.rect(20, memb_y - 8, W - 40, 16, stroke=0, fill=1)
    c.setFillColor(BLACK)
    c.setFont("Helvetica-Bold", 7)
    c.drawCentredString(mid, memb_y + 20, "CELL MEMBRANE")
    c.drawCentredString(mid * 0.5, memb_y + 28, "ECF (High Na+)")
    c.drawCentredString(mid * 0.5, memb_y - 28, "ICF (Low Na+)")

    # === LEFT SIDE: Cotransport (Symport) ===
    cx = mid * 0.48
    # Carrier box
    c.setFillColor(TEAL)
    c.roundRect(cx - 22, memb_y - 18, 44, 36, 4, stroke=0, fill=1)
    c.setFillColor(WHITE)
    c.setFont("Helvetica-Bold", 7)
    c.drawCentredString(cx, memb_y + 2, "SGLT1")
    c.drawCentredString(cx, memb_y - 8, "Cotransport")

    # Arrows pointing DOWN (into cell) for both Na+ and Glucose
    c.setStrokeColor(BLUE_DARK)
    c.setLineWidth(1.8)
    c.line(cx - 10, memb_y + 38, cx - 10, memb_y + 22)
    _arrowhead(c, cx - 10, memb_y + 22, "down", BLUE_DARK)
    c.setFillColor(BLUE_DARK)
    c.setFont("Helvetica-Bold", 8)
    c.drawString(cx - 26, memb_y + 42, "Na+")

    c.setStrokeColor(GREEN_DARK)
    c.line(cx + 10, memb_y + 38, cx + 10, memb_y + 22)
    _arrowhead(c, cx + 10, memb_y + 22, "down", GREEN_DARK)
    c.setFillColor(GREEN_DARK)
    c.drawString(cx + 12, memb_y + 42, "Gluc")

    # Both exit arrow downward from carrier
    c.setStrokeColor(BLUE_DARK)
    c.line(cx - 10, memb_y - 18, cx - 10, memb_y - 36)
    _arrowhead(c, cx - 10, memb_y - 36, "down", BLUE_DARK)
    c.setStrokeColor(GREEN_DARK)
    c.line(cx + 10, memb_y - 18, cx + 10, memb_y - 36)
    _arrowhead(c, cx + 10, memb_y - 36, "down", GREEN_DARK)

    # Label
    c.setFillColor(TEAL)
    c.setFont("Helvetica-Bold", 8)
    c.drawCentredString(cx, 14, "SYMPORT (same direction)")

    # === RIGHT SIDE: Countertransport (Antiport) ===
    cx2 = mid + mid * 0.52
    c.setFillColor(ORANGE_DARK)
    c.roundRect(cx2 - 22, memb_y - 18, 44, 36, 4, stroke=0, fill=1)
    c.setFillColor(WHITE)
    c.setFont("Helvetica-Bold", 7)
    c.drawCentredString(cx2, memb_y + 2, "NHE1")
    c.drawCentredString(cx2, memb_y - 8, "Antiport")

    # Na+ moves DOWN (in), H+ moves UP (out)
    c.setStrokeColor(BLUE_DARK)
    c.line(cx2 - 10, memb_y + 38, cx2 - 10, memb_y + 22)
    _arrowhead(c, cx2 - 10, memb_y + 22, "down", BLUE_DARK)
    c.setFillColor(BLUE_DARK)
    c.setFont("Helvetica-Bold", 8)
    c.drawString(cx2 - 26, memb_y + 42, "Na+")

    c.setStrokeColor(RED_DARK)
    c.line(cx2 + 10, memb_y - 18, cx2 + 10, memb_y - 36)
    _arrowhead(c, cx2 + 10, memb_y - 36, "up", RED_DARK)
    c.setFillColor(RED_DARK)
    c.drawString(cx2 + 12, memb_y - 40, "H+")

    c.line(cx2 - 10, memb_y - 18, cx2 - 10, memb_y - 36)
    _arrowhead(c, cx2 - 10, memb_y - 36, "down", BLUE_DARK)

    c.setStrokeColor(RED_DARK)
    c.line(cx2 + 10, memb_y + 38, cx2 + 10, memb_y + 22)
    _arrowhead(c, cx2 + 10, memb_y + 22, "up", RED_DARK)
    c.setFillColor(RED_DARK)
    c.drawString(cx2 + 12, memb_y + 42, "H+")

    c.setFillColor(ORANGE_DARK)
    c.setFont("Helvetica-Bold", 8)
    c.drawCentredString(cx2, 14, "ANTIPORT (opposite directions)")

    # Divider
    c.setStrokeColor(GRAY_MID)
    c.setLineWidth(1)
    c.line(mid, 10, mid, H - 10)


def _arrowhead(c, x, y, direction, color):
    c.setFillColor(color)
    size = 5
    if direction == "down":
        path = c.beginPath()
        path.moveTo(x, y)
        path.lineTo(x - size, y + size * 1.6)
        path.lineTo(x + size, y + size * 1.6)
        path.close()
        c.drawPath(path, fill=1, stroke=0)
    elif direction == "up":
        path = c.beginPath()
        path.moveTo(x, y)
        path.lineTo(x - size, y - size * 1.6)
        path.lineTo(x + size, y - size * 1.6)
        path.close()
        c.drawPath(path, fill=1, stroke=0)
    elif direction == "right":
        path = c.beginPath()
        path.moveTo(x, y)
        path.lineTo(x - size * 1.6, y + size)
        path.lineTo(x - size * 1.6, y - size)
        path.close()
        c.drawPath(path, fill=1, stroke=0)
    elif direction == "left":
        path = c.beginPath()
        path.moveTo(x, y)
        path.lineTo(x + size * 1.6, y + size)
        path.lineTo(x + size * 1.6, y - size)
        path.close()
        c.drawPath(path, fill=1, stroke=0)


def draw_rmp_diagram(c, W, H):
    """Ionic basis of RMP - bar chart of equilibrium potentials."""
    c.setFillColor(YELLOW)
    c.roundRect(0, 0, W, H, 8, stroke=0, fill=1)

    # Title
    c.setFillColor(BLUE_DARK)
    c.setFont("Helvetica-Bold", 9)
    c.drawCentredString(W / 2, H - 14, "IONIC BASIS OF RESTING MEMBRANE POTENTIAL")

    # Axes
    origin_x = 60
    origin_y = 35
    axis_w   = W - origin_x - 20
    axis_h   = H - 60

    # Zero line (0 mV)
    zero_y = origin_y + axis_h * 0.62   # ~60% up for 0 mV (range -100 to +140)
    range_mv = 240  # from -100 to +140
    scale = axis_h / range_mv

    def mv_to_y(mv):
        return origin_y + (mv + 100) * scale

    # Draw y-axis
    c.setStrokeColor(BLACK)
    c.setLineWidth(1.2)
    c.line(origin_x, origin_y, origin_x, origin_y + axis_h)

    # Y gridlines and labels
    c.setFont("Helvetica", 7)
    c.setFillColor(BLACK)
    for mv in [-100, -70, -50, 0, +50, +100, +132]:
        y = mv_to_y(mv)
        c.setStrokeColor(GRAY_MID)
        c.setLineWidth(0.5)
        c.line(origin_x, y, origin_x + axis_w, y)
        c.setFillColor(BLACK)
        c.drawRightString(origin_x - 3, y - 3, f"{mv:+d}")

    # Zero mV label
    c.setFillColor(RED_DARK)
    c.setFont("Helvetica-Bold", 7)
    c.drawRightString(origin_x - 3, mv_to_y(0) - 3, " 0")

    # Bars
    bar_data = [
        ("K+",   -94,  BLUE_MID,    "HIGH perm."),
        ("Na+",  +66,  RED_DARK,    "LOW perm."),
        ("Cl-",  -90,  TEAL,        "HIGH perm."),
        ("Ca2+", +132, ORANGE_DARK, "LOW perm."),
    ]
    bar_w  = axis_w / (len(bar_data) * 2.2)
    spacing = axis_w / len(bar_data)

    for i, (ion, eq_pot, col, perm) in enumerate(bar_data):
        bx = origin_x + i * spacing + spacing * 0.2
        by_zero = mv_to_y(0)
        by_eq   = mv_to_y(eq_pot)
        bh = by_eq - by_zero

        c.setFillColor(col)
        c.setStrokeColor(col)
        if bh >= 0:
            c.rect(bx, by_zero, bar_w, bh, stroke=0, fill=1)
        else:
            c.rect(bx, by_zero + bh, bar_w, -bh, stroke=0, fill=1)

        # Ion label
        c.setFillColor(col)
        c.setFont("Helvetica-Bold", 8)
        c.drawCentredString(bx + bar_w / 2, origin_y - 18, ion)
        c.setFont("Helvetica", 6)
        c.setFillColor(BLACK)
        c.drawCentredString(bx + bar_w / 2, origin_y - 28, perm)

        # Value label on bar
        c.setFillColor(WHITE)
        c.setFont("Helvetica-Bold", 7)
        label_y = by_eq + (5 if eq_pot < 0 else -12)
        c.drawCentredString(bx + bar_w / 2, label_y, f"{eq_pot:+d}mV")

    # RMP line
    rmp_y = mv_to_y(-75)
    c.setStrokeColor(BLUE_DARK)
    c.setLineWidth(2)
    c.setDash([4, 3])
    c.line(origin_x + 5, rmp_y, origin_x + axis_w, rmp_y)
    c.setDash()
    c.setFillColor(BLUE_DARK)
    c.setFont("Helvetica-Bold", 8)
    c.drawString(origin_x + axis_w + 2, rmp_y - 3, "RMP\n-75mV")

    # Y-axis label
    c.saveState()
    c.setFillColor(BLACK)
    c.setFont("Helvetica-Bold", 8)
    c.translate(12, origin_y + axis_h / 2)
    c.rotate(90)
    c.drawCentredString(0, 0, "Equilibrium Potential (mV)")
    c.restoreState()


def draw_nak_atpase(c, W, H):
    """Na-K-ATPase pump diagram."""
    c.setFillColor(PURPLE_LIGHT)
    c.roundRect(0, 0, W, H, 8, stroke=0, fill=1)

    # Title
    c.setFillColor(PURPLE_DARK)
    c.setFont("Helvetica-Bold", 10)
    c.drawCentredString(W / 2, H - 14, "Na⁺-K⁺-ATPase PUMP")

    # Cell membrane
    mid_y = H / 2 + 5
    c.setFillColor(colors.HexColor("#9E9E9E"))
    c.rect(30, mid_y - 10, W - 60, 20, stroke=0, fill=1)

    # Labels
    c.setFillColor(BLUE_DARK)
    c.setFont("Helvetica-Bold", 9)
    c.drawString(35, mid_y + 18, "ECF")
    c.drawString(35, mid_y - 28, "ICF")

    # Pump protein
    pump_cx = W / 2
    c.setFillColor(PURPLE_DARK)
    c.roundRect(pump_cx - 28, mid_y - 28, 56, 56, 8, stroke=0, fill=1)
    c.setFillColor(WHITE)
    c.setFont("Helvetica-Bold", 8)
    c.drawCentredString(pump_cx, mid_y + 10, "α subunit")
    c.drawCentredString(pump_cx, mid_y - 2, "Na⁺-K⁺")
    c.drawCentredString(pump_cx, mid_y - 14, "ATPase")

    # 3 Na+ arrows going OUT (up, ECF side)
    for i, dx in enumerate([-18, 0, 18]):
        x = pump_cx + dx
        c.setStrokeColor(RED_DARK)
        c.setLineWidth(1.8)
        c.line(x, mid_y + 28, x, mid_y + 52)
        _arrowhead(c, x, mid_y + 52, "up", RED_DARK)
    c.setFillColor(RED_DARK)
    c.setFont("Helvetica-Bold", 9)
    c.drawCentredString(pump_cx, mid_y + 60, "3 Na⁺  OUT")

    # 2 K+ arrows coming IN (down, from ECF)
    for dx in [-10, 10]:
        x = pump_cx + dx + 50
        c.setStrokeColor(BLUE_MID)
        c.setLineWidth(1.8)
        c.line(x, mid_y + 52, x, mid_y + 28)
        _arrowhead(c, x, mid_y + 28, "down", BLUE_MID)
    c.setFillColor(BLUE_MID)
    c.setFont("Helvetica-Bold", 9)
    c.drawCentredString(pump_cx + 50, mid_y + 60, "2 K⁺  IN")

    # ATP → ADP at bottom
    c.setFillColor(ORANGE_DARK)
    c.setFont("Helvetica-Bold", 9)
    c.drawCentredString(pump_cx, mid_y - 42, "ATP  →  ADP + Pi")

    # Ouabain binding label
    c.setFillColor(RED_DARK)
    c.setFont("Helvetica", 7)
    c.drawCentredString(pump_cx, 14, "Inhibited by: Ouabain / Digitalis glycosides")

    # Stoichiometry box
    c.setFillColor(ORANGE_LIGHT)
    c.roundRect(W - 100, H - 55, 90, 40, 4, stroke=1, fill=1)
    c.setStrokeColor(ORANGE_DARK)
    c.setLineWidth(0.8)
    c.roundRect(W - 100, H - 55, 90, 40, 4, stroke=1, fill=0)
    c.setFillColor(ORANGE_DARK)
    c.setFont("Helvetica-Bold", 8)
    c.drawCentredString(W - 55, H - 32, "Coupling Ratio")
    c.drawCentredString(W - 55, H - 46, "3 Na⁺ : 2 K⁺ : 1 ATP")


def draw_diffusion_comparison(c, W, H):
    """Simple vs Facilitated Diffusion side-by-side."""
    c.setFillColor(GREEN_LIGHT)
    c.roundRect(0, 0, W, H, 8, stroke=0, fill=1)

    c.setFillColor(GREEN_DARK)
    c.setFont("Helvetica-Bold", 9)
    c.drawCentredString(W / 2, H - 14, "SIMPLE vs FACILITATED DIFFUSION")

    mid = W / 2

    # Divider
    c.setStrokeColor(GRAY_MID)
    c.setLineWidth(1)
    c.line(mid, 10, mid, H - 25)

    # ── LEFT: Simple Diffusion ──
    lx = mid * 0.5
    c.setFillColor(BLUE_DARK)
    c.setFont("Helvetica-Bold", 9)
    c.drawCentredString(lx, H - 30, "SIMPLE DIFFUSION")

    # Membrane
    memb_y = H * 0.55
    c.setFillColor(colors.HexColor("#7B9ABF"))
    c.rect(20, memb_y - 5, mid - 30, 10, stroke=0, fill=1)

    # Molecules (circles) high side
    c.setFillColor(BLUE_MID)
    for i, (x, y) in enumerate([(35, memb_y + 25), (55, memb_y + 40), (75, memb_y + 20),
                                  (45, memb_y + 55), (65, memb_y + 50)]):
        c.circle(x, y, 7, stroke=0, fill=1)
    c.setFont("Helvetica", 7)
    c.setFillColor(BLACK)
    c.drawCentredString(lx, H - 45, "High [conc] side")

    # Molecules (fewer) low side
    c.setFillColor(BLUE_LIGHT)
    for x, y in [(40, memb_y - 30), (70, memb_y - 25)]:
        c.circle(x, y, 7, stroke=0, fill=1)
    c.drawCentredString(lx, memb_y - 55, "Low [conc] side")
    c.setFillColor(BLACK)

    # Net flux arrow
    c.setStrokeColor(BLUE_DARK)
    c.setLineWidth(2)
    c.line(lx, memb_y + 15, lx, memb_y - 15)
    _arrowhead(c, lx, memb_y - 15, "down", BLUE_DARK)
    c.setFillColor(BLUE_DARK)
    c.setFont("Helvetica-Bold", 7)
    c.drawCentredString(lx, memb_y - 60, "No carrier needed")

    # Features
    feats = ["✓ No carrier protein", "✓ Not saturable", "✓ No stereospecificity",
             "✓ Linear rate ∝ gradient"]
    c.setFont("Helvetica", 7)
    c.setFillColor(GREEN_DARK)
    for i, f in enumerate(feats):
        c.drawString(22, 75 - i * 12, f)

    # ── RIGHT: Facilitated Diffusion ──
    rx = mid + mid * 0.5
    c.setFillColor(TEAL)
    c.setFont("Helvetica-Bold", 9)
    c.drawCentredString(rx, H - 30, "FACILITATED DIFFUSION")

    c.setFillColor(colors.HexColor("#7B9ABF"))
    c.rect(mid + 10, memb_y - 5, mid - 30, 10, stroke=0, fill=1)

    # Carrier protein in membrane
    c.setFillColor(TEAL)
    c.roundRect(rx - 15, memb_y - 20, 30, 40, 5, stroke=0, fill=1)
    c.setFillColor(WHITE)
    c.setFont("Helvetica-Bold", 7)
    c.drawCentredString(rx, memb_y + 5, "GLUT4")
    c.drawCentredString(rx, memb_y - 7, "Carrier")

    # Molecules high side
    c.setFillColor(GREEN_DARK)
    for i, (x, y) in enumerate([(mid + 25, memb_y + 30), (mid + 45, memb_y + 45),
                                  (mid + 65, memb_y + 25), (mid + 55, memb_y + 55)]):
        c.circle(x, y, 7, stroke=0, fill=1)
    c.setFillColor(BLACK)
    c.setFont("Helvetica", 7)
    c.drawCentredString(rx, H - 45, "High [conc] side (D-glucose)")

    # Arrow through carrier
    c.setStrokeColor(TEAL)
    c.setLineWidth(2)
    c.line(rx, memb_y + 18, rx, memb_y - 18)
    _arrowhead(c, rx, memb_y - 18, "down", TEAL)

    c.setFillColor(GREEN_DARK)
    c.setFont("Helvetica-BoldOblique", 7)
    c.drawCentredString(rx, memb_y - 55, "Requires specific carrier")

    feats2 = ["✓ Carrier protein (GLUT4)", "✓ Saturable (Vmax)", "✓ Stereospecific",
              "✓ Competition between solutes"]
    c.setFont("Helvetica", 7)
    c.setFillColor(TEAL)
    for i, f in enumerate(feats2):
        c.drawString(mid + 18, 75 - i * 12, f)


def draw_apoptosis_pathway(c, W, H):
    """Apoptosis pathways diagram."""
    c.setFillColor(RED_LIGHT)
    c.roundRect(0, 0, W, H, 8, stroke=0, fill=1)

    c.setFillColor(RED_DARK)
    c.setFont("Helvetica-Bold", 10)
    c.drawCentredString(W / 2, H - 14, "APOPTOSIS PATHWAYS")

    mid = W / 2

    def box(cx, y, w, h, label, sublabel, bg, fg=WHITE, fontsize=8):
        c.setFillColor(bg)
        c.roundRect(cx - w/2, y - h/2, w, h, 5, stroke=0, fill=1)
        c.setFillColor(fg)
        c.setFont("Helvetica-Bold", fontsize)
        c.drawCentredString(cx, y + h/4 - 2, label)
        if sublabel:
            c.setFont("Helvetica", fontsize - 1)
            c.drawCentredString(cx, y - h/4, sublabel)

    def arrow_down(cx, y_top, y_bot, col=BLACK):
        c.setStrokeColor(col)
        c.setLineWidth(1.5)
        c.line(cx, y_top, cx, y_bot + 8)
        _arrowhead(c, cx, y_bot + 8, "down", col)

    def arrow_right(x_l, x_r, y, col=BLACK):
        c.setStrokeColor(col)
        c.setLineWidth(1.5)
        c.line(x_l, y, x_r - 8, y)
        _arrowhead(c, x_r - 8, y, "right", col)

    # Intrinsic pathway (left column)
    lx = mid * 0.38
    # Trigger
    box(lx, H - 38, 100, 22, "DNA Damage /", "Oxidative Stress", BLUE_DARK)
    arrow_down(lx, H - 49, H - 65, BLUE_DARK)
    box(lx, H - 78, 100, 22, "Proapoptotic", "BAX, BAK, BIM↑", RED_DARK)
    arrow_down(lx, H - 89, H - 105, RED_DARK)
    box(lx, H - 118, 100, 22, "Mitochondria", "Cytochrome c release", ORANGE_DARK)
    arrow_down(lx, H - 129, H - 145, ORANGE_DARK)
    box(lx, H - 158, 100, 22, "Apoptosome", "Cyt c + Apaf-1", PURPLE_DARK)
    arrow_down(lx, H - 169, H - 185, PURPLE_DARK)
    box(lx, H - 198, 100, 22, "Caspase-9", "(Initiator)", PURPLE_DARK)

    c.setFillColor(BLUE_DARK)
    c.setFont("Helvetica-Bold", 8)
    c.drawCentredString(lx, H - 25, "INTRINSIC PATHWAY")

    # Extrinsic pathway (right column)
    rx = mid + mid * 0.62
    box(rx, H - 38, 100, 22, "Death Receptor", "Fas / TNFR", BLUE_DARK)
    arrow_down(rx, H - 49, H - 65, BLUE_DARK)
    box(rx, H - 78, 100, 22, "FasL binding", "DISC formation", RED_DARK)
    arrow_down(rx, H - 89, H - 145, RED_DARK)
    box(rx, H - 158, 100, 22, "Caspase-8", "(Initiator)", TEAL)

    c.setFillColor(RED_DARK)
    c.setFont("Helvetica-Bold", 8)
    c.drawCentredString(rx, H - 25, "EXTRINSIC PATHWAY")

    # Both converge → Caspase 3/6/7
    exec_y = H - 235
    # Arrows from caspase 9 and 8 converging
    arrow_down(lx, H - 209, exec_y + 12, PURPLE_DARK)
    arrow_down(rx, H - 169, exec_y + 12, TEAL)
    # Lines from both columns to center
    conv_y = exec_y + 16
    c.setStrokeColor(GRAY_MID)
    c.setLineWidth(1)
    c.line(lx, conv_y, mid, conv_y)
    c.line(rx, conv_y, mid, conv_y)
    c.line(mid, conv_y, mid, exec_y + 12)

    box(mid, exec_y, 130, 24, "EXECUTIONER CASPASES", "3, 6, 7", RED_DARK, WHITE, 9)
    arrow_down(mid, exec_y - 12, exec_y - 35, RED_DARK)
    box(mid, exec_y - 48, 140, 22, "CELL DISMANTLING", "Protein degradation → Apoptotic bodies", colors.HexColor("#880E4F"), WHITE, 7)

    # Features box
    c.setFillColor(YELLOW)
    c.roundRect(4, 4, W - 8, 36, 4, stroke=0, fill=1)
    c.setFillColor(BLUE_DARK)
    c.setFont("Helvetica-Bold", 7)
    c.drawString(10, 30, "Key features: Caspase-dependent  |  Cell membrane INTACT  |  No inflammation  |  Apoptotic bodies phagocytosed")


def draw_cell_junctions(c, W, H):
    """Cell junctions diagram."""
    c.setFillColor(TEAL_LIGHT)
    c.roundRect(0, 0, W, H, 8, stroke=0, fill=1)

    c.setFillColor(TEAL)
    c.setFont("Helvetica-Bold", 10)
    c.drawCentredString(W / 2, H - 14, "TYPES OF CELL JUNCTIONS")

    # Two cell columns
    cell_w = 50
    gap    = 20
    lx     = W / 2 - gap / 2 - cell_w
    rx     = W / 2 + gap / 2
    cell_h = H - 70

    c.setFillColor(colors.HexColor("#BBDEFB"))
    c.rect(lx, 30, cell_w, cell_h, stroke=1, fill=1)
    c.setFillColor(colors.HexColor("#C8E6C9"))
    c.rect(rx, 30, cell_w, cell_h, stroke=1, fill=1)

    c.setFillColor(BLACK)
    c.setFont("Helvetica-Bold", 7)
    c.drawCentredString(lx + cell_w / 2, 22, "Cell A")
    c.drawCentredString(rx + cell_w / 2, 22, "Cell B")

    # Junction data: (y_fraction, name, color, description)
    junctions = [
        (0.85, "Tight Jn\n(Zonula Occludens)", BLUE_DARK,    "Occludin, Claudins\nSeals paracellular space"),
        (0.70, "Adherens Jn\n(Zonula Adherens)", GREEN_DARK,  "Cadherins + Actin\nMechanical link"),
        (0.55, "Desmosome\n(Macula Adherens)",   ORANGE_DARK, "Cadherins + Intermediate\nfilaments - resists shear"),
        (0.38, "Gap Junction\n(Nexus)",           PURPLE_DARK, "Connexins (<1000 Da)\nElectric coupling"),
        (0.22, "Hemidesmosome",                   TEAL,        "Integrins\nAnchor to basal lamina"),
    ]

    for frac, name, col, desc in junctions:
        jy = 30 + cell_h * frac

        # Junction block between cells
        c.setFillColor(col)
        c.rect(lx + cell_w - 5, jy - 8, gap + 10, 16, stroke=0, fill=1)

        # Labels on left
        c.setFillColor(col)
        c.setFont("Helvetica-Bold", 7)
        lines = name.split("\n")
        for k, line in enumerate(lines):
            c.drawRightString(lx - 5, jy + 5 - k * 10, line)

        # Description on right
        c.setFillColor(BLACK)
        c.setFont("Helvetica", 6)
        desc_lines = desc.split("\n")
        for k, dl in enumerate(desc_lines):
            c.drawString(rx + cell_w + 5, jy + 4 - k * 9, dl)


# ─────────────────────────────────────────────────────────────────────────────
# BUILD DOCUMENT
# ─────────────────────────────────────────────────────────────────────────────

def build():
    doc = SimpleDocTemplate(
        OUTPUT, pagesize=A4,
        leftMargin=1.8*cm, rightMargin=1.8*cm,
        topMargin=1.5*cm, bottomMargin=1.5*cm
    )

    W = A4[0] - 3.6*cm  # usable width
    story = []

    # ── COVER PAGE ─────────────────────────────────────────────────────────────
    class CoverBg(Flowable):
        def wrap(self, aw, ah): return (aw, 280)
        def draw(self):
            c = self.canv
            cw, _ = self.wrap(0, 0)
            # gradient-ish block
            c.setFillColor(BLUE_DARK)
            c.roundRect(0, 0, cw, 280, 10, stroke=0, fill=1)
            c.setFillColor(BLUE_MID)
            c.roundRect(0, 0, cw, 200, 10, stroke=0, fill=1)
            c.setFillColor(BLUE_DARK)
            c.roundRect(0, 0, cw, 60, 0, stroke=0, fill=1)

            c.setFillColor(WHITE)
            c.setFont("Helvetica-Bold", 26)
            c.drawCentredString(cw / 2, 200, "GENERAL PHYSIOLOGY")
            c.setFont("Helvetica-Bold", 16)
            c.drawCentredString(cw / 2, 168, "Summary with Diagrams & Key Equations")
            c.setFillColor(BLUE_LIGHT)
            c.setFont("Helvetica", 11)
            c.drawCentredString(cw / 2, 140, "SRM Medical College — Must Know Revision")
            c.drawCentredString(cw / 2, 122, "Topics: Secondary Active Transport  |  RMP  |  Cell Junctions")
            c.drawCentredString(cw / 2, 106, "Na⁺-K⁺-ATPase  |  Simple Diffusion  |  Facilitated Diffusion  |  Apoptosis")
            c.setFillColor(YELLOW)
            c.setFont("Helvetica-BoldOblique", 9)
            c.drawCentredString(cw / 2, 72, "Based on: Costanzo Physiology 7e  |  Ganong's Review 26e  |  Guyton & Hall")
            # decorative line
            c.setStrokeColor(YELLOW)
            c.setLineWidth(2)
            c.line(cw * 0.15, 88, cw * 0.85, 88)

    story.append(CoverBg())
    story.append(Spacer(1, 0.5*cm))

    # Table of contents box
    toc_data = [
        ["#", "Topic", "Type"],
        ["1", "Secondary Active Transport", "Essay"],
        ["2", "Resting Membrane Potential (RMP)", "Essay"],
        ["3", "Structure & Functions of Cell Junctions", "Essay"],
        ["4", "Na⁺-K⁺-ATPase System", "Essay"],
        ["5", "Simple Diffusion", "Essay"],
        ["6", "Facilitated Diffusion", "Essay"],
        ["7", "Apoptosis", "Essay"],
    ]
    toc_style = TableStyle([
        ("BACKGROUND",   (0,0), (-1,0),  BLUE_DARK),
        ("TEXTCOLOR",    (0,0), (-1,0),  WHITE),
        ("FONTNAME",     (0,0), (-1,0),  "Helvetica-Bold"),
        ("FONTSIZE",     (0,0), (-1,0),  10),
        ("BACKGROUND",   (0,1), (-1,-1), BLUE_LIGHT),
        ("ROWBACKGROUNDS",(0,1),(-1,-1), [WHITE, BLUE_LIGHT]),
        ("FONTNAME",     (0,1), (-1,-1), "Helvetica"),
        ("FONTSIZE",     (0,1), (-1,-1), 9),
        ("ALIGN",        (0,0), (-1,-1), "CENTER"),
        ("VALIGN",       (0,0), (-1,-1), "MIDDLE"),
        ("GRID",         (0,0), (-1,-1), 0.5, GRAY_MID),
        ("TOPPADDING",   (0,0), (-1,-1), 5),
        ("BOTTOMPADDING",(0,0), (-1,-1), 5),
        ("ROUNDEDCORNERS", (0,0), (-1,-1), [4, 4, 4, 4]),
    ])
    toc_table = Table(toc_data, colWidths=[W*0.08, W*0.65, W*0.2])
    toc_table.setStyle(toc_style)
    story.append(toc_table)
    story.append(PageBreak())

    # ═══════════════════════════════════════════════════════════════════════════
    # 1. SECONDARY ACTIVE TRANSPORT
    # ═══════════════════════════════════════════════════════════════════════════
    story.append(ColorBanner("1. SECONDARY ACTIVE TRANSPORT", bg=TEAL))
    story.append(Spacer(1, 4))

    story.append(Paragraph(
        "<b>Definition:</b> Transport of two or more solutes where one solute (Na⁺) moves "
        "<i>down</i> its electrochemical gradient, providing energy for the other solute to move "
        "<i>against</i> its gradient. ATP is <b>not used directly</b> - energy comes indirectly from the Na⁺ gradient maintained by Na⁺-K⁺-ATPase.",
        BODY))

    # Key equation box
    story.append(Paragraph("Energy Source:  Na⁺ gradient  (maintained by Na⁺-K⁺-ATPase using ATP)", EQUATION))
    story.append(Spacer(1, 4))

    story.append(Paragraph("<b>Two Types:</b>", H3))
    type_data = [
        ["Type", "Synonym", "Solute Direction", "Classic Example"],
        ["Cotransport", "Symport",  "Both in SAME direction",     "Na⁺-Glucose (SGLT1)\nNa⁺-Amino Acid"],
        ["Countertransport", "Antiport", "OPPOSITE directions",   "Na⁺-H⁺ exchanger (NHE)\nNa⁺-Ca²⁺ exchanger"],
    ]
    ts = TableStyle([
        ("BACKGROUND",   (0,0),(-1,0), TEAL),
        ("TEXTCOLOR",    (0,0),(-1,0), WHITE),
        ("FONTNAME",     (0,0),(-1,0), "Helvetica-Bold"),
        ("FONTSIZE",     (0,0),(-1,-1), 8),
        ("ROWBACKGROUNDS",(0,1),(-1,-1),[TEAL_LIGHT, WHITE]),
        ("GRID",         (0,0),(-1,-1), 0.5, GRAY_MID),
        ("VALIGN",       (0,0),(-1,-1), "MIDDLE"),
        ("ALIGN",        (0,0),(-1,-1), "CENTER"),
        ("TOPPADDING",   (0,0),(-1,-1), 5),
        ("BOTTOMPADDING",(0,0),(-1,-1), 5),
    ])
    t = Table(type_data, colWidths=[W*0.22, W*0.18, W*0.3, W*0.28])
    t.setStyle(ts)
    story.append(t)
    story.append(Spacer(1, 6))

    # Diagram
    story.append(DiagramFlowable(W, 155, draw_secondary_active_transport))
    story.append(Spacer(1, 6))

    story.append(Paragraph(
        "<b>Effect of Ouabain (Na⁺-K⁺-ATPase inhibitor):</b> "
        "Intracellular Na⁺ rises → Na⁺ gradient decreases → ALL secondary active transport is impaired indirectly.",
        NOTE))

    story.append(Paragraph("<b>Key Examples:</b>", H3))
    examples = [
        ("SGLT1", "Na⁺-Glucose cotransport", "Luminal membrane — small intestine & proximal renal tubule"),
        ("NKCC2", "Na⁺-K⁺-2Cl⁻ cotransport", "Thick ascending limb of loop of Henle"),
        ("NHE1",  "Na⁺-H⁺ exchanger",         "Proximal tubule — Na⁺ in, H⁺ out"),
        ("NCX",   "Na⁺-Ca²⁺ exchanger",        "Cardiac & smooth muscle — Ca²⁺ homeostasis"),
    ]
    ex_data = [["Transporter", "Process", "Location"]] + [[e[0], e[1], e[2]] for e in examples]
    ex_t = Table(ex_data, colWidths=[W*0.12, W*0.38, W*0.48])
    ex_t.setStyle(TableStyle([
        ("BACKGROUND",  (0,0),(-1,0), TEAL),
        ("TEXTCOLOR",   (0,0),(-1,0), WHITE),
        ("FONTNAME",    (0,0),(-1,0), "Helvetica-Bold"),
        ("FONTSIZE",    (0,0),(-1,-1), 8),
        ("ROWBACKGROUNDS",(0,1),(-1,-1),[TEAL_LIGHT, WHITE]),
        ("GRID",        (0,0),(-1,-1), 0.5, GRAY_MID),
        ("TOPPADDING",  (0,0),(-1,-1), 4),
        ("BOTTOMPADDING",(0,0),(-1,-1), 4),
    ]))
    story.append(ex_t)
    story.append(PageBreak())

    # ═══════════════════════════════════════════════════════════════════════════
    # 2. RESTING MEMBRANE POTENTIAL
    # ═══════════════════════════════════════════════════════════════════════════
    story.append(ColorBanner("2. RESTING MEMBRANE POTENTIAL (RMP)", bg=BLUE_DARK))
    story.append(Spacer(1, 4))

    story.append(Paragraph(
        "<b>Definition:</b> The electrical potential difference across the membrane of excitable cells "
        "(nerve, muscle) at rest. Expressed as intracellular potential relative to extracellular potential.",
        BODY))

    story.append(Paragraph("RMP  =  −70  to  −80 mV  (intracellular negative)", EQUATION))

    story.append(Paragraph("<b>Ionic Concentrations & Equilibrium Potentials (Nernst Equation):</b>", H3))
    ion_data = [
        ["Ion", "Intracellular", "Extracellular", "Equilibrium Pot.", "Resting Perm.", "Contribution"],
        ["K⁺",   "140 mEq/L",  "4 mEq/L",   "−94 mV",  "HIGH ✓",     "MAJOR"],
        ["Na⁺",  "14 mEq/L",  "140 mEq/L",  "+66 mV",  "LOW",         "Minor"],
        ["Cl⁻",  "4 mEq/L",  "114 mEq/L",  "−90 mV",  "Moderate ✓", "Moderate"],
        ["Ca²⁺", "0.0001",    "2.5 mEq/L",  "+132 mV", "Very LOW",    "Negligible"],
    ]
    ion_ts = TableStyle([
        ("BACKGROUND",  (0,0),(-1,0), BLUE_DARK),
        ("TEXTCOLOR",   (0,0),(-1,0), WHITE),
        ("FONTNAME",    (0,0),(-1,0), "Helvetica-Bold"),
        ("FONTSIZE",    (0,0),(-1,-1), 8),
        ("ROWBACKGROUNDS",(0,1),(-1,-1),[BLUE_LIGHT, WHITE]),
        ("BACKGROUND",  (0,1),(-1,1), colors.HexColor("#BBDEFB")),
        ("BACKGROUND",  (0,3),(-1,3), colors.HexColor("#E0F7FA")),
        ("GRID",        (0,0),(-1,-1), 0.5, GRAY_MID),
        ("ALIGN",       (0,0),(-1,-1), "CENTER"),
        ("TOPPADDING",  (0,0),(-1,-1), 4),
        ("BOTTOMPADDING",(0,0),(-1,-1), 4),
    ])
    ion_t = Table(ion_data, colWidths=[W*0.08, W*0.18, W*0.18, W*0.17, W*0.18, W*0.18])
    ion_t.setStyle(ion_ts)
    story.append(ion_t)
    story.append(Spacer(1, 6))

    story.append(Paragraph("<b>Key Equations:</b>", H3))
    story.append(Paragraph(
        "Nernst Equation:   E_ion = (RT/zF) × ln([ion]_out / [ion]_in)   =   61/z × log([ion]_out / [ion]_in)",
        EQUATION))
    story.append(Paragraph(
        "Chord Conductance:   Em = (gK/gT)·EK  +  (gNa/gT)·ENa  +  (gCl/gT)·ECl  +  (gCa/gT)·ECa",
        EQUATION))

    story.append(DiagramFlowable(W, 200, draw_rmp_diagram))
    story.append(Spacer(1, 4))

    story.append(Paragraph("<b>Role of Na⁺-K⁺-ATPase in RMP:</b>", H3))
    role_data = [
        ["Contribution", "Mechanism", "Importance"],
        ["Direct (electrogenic)", "Pumps 3 Na⁺ out : 2 K⁺ in → net negative charge inside", "Small"],
        ["Indirect (major)",      "Maintains K⁺ gradient → K⁺ diffusion potential → RMP",   "LARGE"],
    ]
    role_t = Table(role_data, colWidths=[W*0.28, W*0.48, W*0.2])
    role_t.setStyle(TableStyle([
        ("BACKGROUND",  (0,0),(-1,0), BLUE_DARK),
        ("TEXTCOLOR",   (0,0),(-1,0), WHITE),
        ("FONTNAME",    (0,0),(-1,0), "Helvetica-Bold"),
        ("FONTSIZE",    (0,0),(-1,-1), 8),
        ("ROWBACKGROUNDS",(0,1),(-1,-1),[BLUE_LIGHT, WHITE]),
        ("GRID",        (0,0),(-1,-1), 0.5, GRAY_MID),
        ("TOPPADDING",  (0,0),(-1,-1), 4),
        ("BOTTOMPADDING",(0,0),(-1,-1), 4),
    ]))
    story.append(role_t)
    story.append(PageBreak())

    # ═══════════════════════════════════════════════════════════════════════════
    # 3. CELL JUNCTIONS
    # ═══════════════════════════════════════════════════════════════════════════
    story.append(ColorBanner("3. STRUCTURE & FUNCTIONS OF CELL JUNCTIONS", bg=TEAL))
    story.append(Spacer(1, 4))

    story.append(Paragraph(
        "Cell junctions are specialised membrane structures that <b>mechanically link cells</b>, "
        "<b>regulate paracellular permeability</b>, and enable <b>direct cell-to-cell communication</b>.",
        BODY))
    story.append(Spacer(1, 4))

    jn_data = [
        ["Junction", "Also Called", "Proteins", "Location", "Function"],
        ["Tight Junction",    "Zonula Occludens",  "Occludin, Claudins, JAMs",        "Apical epithelium",             "Seals paracellular space; cell polarity"],
        ["Adherens Junction", "Zonula Adherens",   "Cadherins + Actin",               "Just basal to TJ",              "Mechanical link; morphogenesis"],
        ["Desmosome",         "Macula Adherens",   "Cadherins + Intermediate filaments","Skin, cardiac muscle",          "Resists shearing forces"],
        ["Hemidesmosome",     "—",                 "Integrins + Intermediate filaments","Basal epithelium",              "Anchors cell to basal lamina"],
        ["Focal Adhesion",    "—",                 "Integrins + Actin",               "Basal surface",                 "ECM attachment; cell signaling"],
        ["Gap Junction",      "Nexus",             "Connexins (connexons)",            "Heart, smooth muscle, glia",    "Ion/molecule transfer <1000 Da; electrical coupling"],
    ]
    jn_ts = TableStyle([
        ("BACKGROUND",  (0,0),(-1,0), TEAL),
        ("TEXTCOLOR",   (0,0),(-1,0), WHITE),
        ("FONTNAME",    (0,0),(-1,0), "Helvetica-Bold"),
        ("FONTSIZE",    (0,0),(-1,-1), 7.5),
        ("ROWBACKGROUNDS",(0,1),(-1,-1),[TEAL_LIGHT, WHITE]),
        ("GRID",        (0,0),(-1,-1), 0.5, GRAY_MID),
        ("VALIGN",      (0,0),(-1,-1), "MIDDLE"),
        ("TOPPADDING",  (0,0),(-1,-1), 4),
        ("BOTTOMPADDING",(0,0),(-1,-1), 4),
    ])
    jn_t = Table(jn_data, colWidths=[W*0.16, W*0.16, W*0.22, W*0.2, W*0.26])
    jn_t.setStyle(jn_ts)
    story.append(jn_t)
    story.append(Spacer(1, 6))

    story.append(DiagramFlowable(W, 210, draw_cell_junctions))
    story.append(Spacer(1, 4))

    story.append(Paragraph(
        "<b>Note:</b> Desmosomes and hemidesmosomes use <b>intermediate filaments</b>; "
        "adherens junctions and focal adhesions use <b>actin filaments</b>. "
        "Tight junctions are the most apical; the junctional complex (zonula occludens + adherens + desmosome) forms the <i>terminal bar</i>.",
        NOTE))
    story.append(PageBreak())

    # ═══════════════════════════════════════════════════════════════════════════
    # 4. Na+-K+-ATPase
    # ═══════════════════════════════════════════════════════════════════════════
    story.append(ColorBanner("4. Na⁺-K⁺-ATPase SYSTEM", bg=PURPLE_DARK))
    story.append(Spacer(1, 4))

    story.append(Paragraph(
        "The Na⁺-K⁺-ATPase is a <b>primary active transport</b> pump present in ALL cell membranes. "
        "It directly uses ATP to transport ions against their electrochemical gradients.",
        BODY))

    story.append(Paragraph("3 Na⁺ OUT  :  2 K⁺ IN  :  1 ATP hydrolysed     →     Coupling ratio  3:2", EQUATION))

    story.append(Paragraph("<b>Structural Components:</b>", H3))
    struct_data = [
        ["Subunit", "MW", "Membrane Spans", "Key Binding Sites"],
        ["α subunit", "~100,000 Da", "~10 transmembrane domains",
         "Intracellular: Na⁺ site, ATP site, phosphorylation site\nExtracellular: K⁺ site, ouabain site"],
        ["β subunit (glycoprotein)", "~55,000 Da", "1 transmembrane domain",
         "3 extracellular glycosylation sites (1/3 of MW is carbohydrate)\nRequired for activity — separation destroys function"],
    ]
    struct_ts = TableStyle([
        ("BACKGROUND",  (0,0),(-1,0), PURPLE_DARK),
        ("TEXTCOLOR",   (0,0),(-1,0), WHITE),
        ("FONTNAME",    (0,0),(-1,0), "Helvetica-Bold"),
        ("FONTSIZE",    (0,0),(-1,-1), 8),
        ("ROWBACKGROUNDS",(0,1),(-1,-1),[PURPLE_LIGHT, WHITE]),
        ("GRID",        (0,0),(-1,-1), 0.5, GRAY_MID),
        ("VALIGN",      (0,0),(-1,-1), "MIDDLE"),
        ("TOPPADDING",  (0,0),(-1,-1), 5),
        ("BOTTOMPADDING",(0,0),(-1,-1), 5),
    ])
    struct_t = Table(struct_data, colWidths=[W*0.22, W*0.15, W*0.25, W*0.38])
    struct_t.setStyle(struct_ts)
    story.append(struct_t)
    story.append(Spacer(1, 6))

    story.append(DiagramFlowable(W, 180, draw_nak_atpase))
    story.append(Spacer(1, 6))

    story.append(Paragraph("<b>Functions of Na⁺-K⁺-ATPase:</b>", H3))
    funcs = [
        "Maintains low intracellular Na⁺ and high intracellular K⁺.",
        "Creates the Na⁺ gradient used for ALL secondary active transport (glucose, amino acids, H⁺).",
        "Contributes to RMP: electrogenic effect (direct) + maintains K⁺ gradient (indirect, major).",
        "Regulates cell volume — controls intracellular osmolarity.",
        "Maintains excitability of nerve and muscle cells.",
    ]
    for f in funcs:
        story.append(Paragraph(f"• {f}", BULLET))

    story.append(Paragraph(
        "<b>Inhibitors:</b> Ouabain and digitalis glycosides (digoxin) bind the extracellular α subunit site → "
        "↑ intracellular Na⁺ → ↑ intracellular Ca²⁺ (via NCX) → ↑ cardiac contractility. "
        "Used clinically in heart failure.",
        NOTE))
    story.append(PageBreak())

    # ═══════════════════════════════════════════════════════════════════════════
    # 5. SIMPLE DIFFUSION
    # ═══════════════════════════════════════════════════════════════════════════
    story.append(ColorBanner("5. SIMPLE DIFFUSION", bg=GREEN_DARK))
    story.append(Spacer(1, 4))

    story.append(Paragraph(
        "Simple diffusion is the <b>passive movement</b> of a solute across a membrane from high to low "
        "concentration, driven by the concentration (or electrochemical) gradient. "
        "<b>No carrier protein or ATP is required.</b>",
        BODY))

    story.append(Paragraph("Fick's Law:   J  =  P  ×  A  ×  (C_A  −  C_B)", EQUATION))
    story.append(Spacer(1, 2))

    story.append(Paragraph("Diffusion Coefficient (Stokes-Einstein):   D  =  kT / (6πηr)", EQUATION))
    story.append(Spacer(1, 2))

    story.append(Paragraph("Permeability:   P  =  K × D / Δx     (K = partition coefficient, Δx = membrane thickness)", EQUATION))
    story.append(Spacer(1, 4))

    story.append(Paragraph("<b>Factors Affecting Rate of Simple Diffusion:</b>", H3))
    factor_data = [
        ["Factor", "Symbol", "Relationship", "Reason"],
        ["Concentration gradient", "C_A − C_B", "↑ gradient → ↑ diffusion", "Driving force"],
        ["Partition coefficient", "K",         "↑ K → ↑ diffusion",       "Lipid solubility → membrane penetration"],
        ["Diffusion coefficient",  "D",         "↑ D → ↑ diffusion",       "Smaller molecule, lower viscosity"],
        ["Membrane thickness",     "Δx",        "↑ Δx → ↓ diffusion",      "Greater distance to traverse"],
        ["Surface area",           "A",         "↑ A → ↑ diffusion",       "More membrane available"],
    ]
    fd_ts = TableStyle([
        ("BACKGROUND",   (0,0),(-1,0), GREEN_DARK),
        ("TEXTCOLOR",    (0,0),(-1,0), WHITE),
        ("FONTNAME",     (0,0),(-1,0), "Helvetica-Bold"),
        ("FONTSIZE",     (0,0),(-1,-1), 8),
        ("ROWBACKGROUNDS",(0,1),(-1,-1),[GREEN_LIGHT, WHITE]),
        ("GRID",         (0,0),(-1,-1), 0.5, GRAY_MID),
        ("ALIGN",        (0,0),(-1,-1), "CENTER"),
        ("TOPPADDING",   (0,0),(-1,-1), 4),
        ("BOTTOMPADDING",(0,0),(-1,-1), 4),
    ])
    fd_t = Table(factor_data, colWidths=[W*0.25, W*0.12, W*0.28, W*0.32])
    fd_t.setStyle(fd_ts)
    story.append(fd_t)
    story.append(Spacer(1, 6))

    story.append(Paragraph("<b>Characteristics vs Carrier-Mediated Transport:</b>", H3))
    char_data = [
        ["Characteristic", "Simple Diffusion", "Carrier-Mediated"],
        ["Carrier protein",   "NOT needed",     "Required"],
        ["Energy (ATP)",      "Not required",   "Not required (facilitated)\nRequired (active)"],
        ["Saturation",        "No — linear",    "Yes — plateaus at Vmax"],
        ["Stereospecificity", "None",           "Yes (D vs L isomers)"],
        ["Competition",       "None",           "Yes (structurally similar solutes)"],
        ["Examples",          "O₂, CO₂, urea,\nethanol, steroids", "Glucose (GLUT4),\nNa⁺-Glucose (SGLT1)"],
    ]
    char_ts = TableStyle([
        ("BACKGROUND",   (0,0),(-1,0), GREEN_DARK),
        ("TEXTCOLOR",    (0,0),(-1,0), WHITE),
        ("FONTNAME",     (0,0),(-1,0), "Helvetica-Bold"),
        ("FONTSIZE",     (0,0),(-1,-1), 8),
        ("ROWBACKGROUNDS",(0,1),(-1,-1),[GREEN_LIGHT, WHITE]),
        ("GRID",         (0,0),(-1,-1), 0.5, GRAY_MID),
        ("VALIGN",       (0,0),(-1,-1), "MIDDLE"),
        ("TOPPADDING",   (0,0),(-1,-1), 4),
        ("BOTTOMPADDING",(0,0),(-1,-1), 4),
    ])
    char_t = Table(char_data, colWidths=[W*0.3, W*0.35, W*0.33])
    char_t.setStyle(char_ts)
    story.append(char_t)
    story.append(PageBreak())

    # ═══════════════════════════════════════════════════════════════════════════
    # 6. FACILITATED DIFFUSION
    # ═══════════════════════════════════════════════════════════════════════════
    story.append(ColorBanner("6. FACILITATED DIFFUSION", bg=TEAL))
    story.append(Spacer(1, 4))

    story.append(Paragraph(
        "Facilitated diffusion is <b>passive transport</b> (no ATP) that uses a <b>specific membrane carrier protein</b>. "
        "The solute still moves DOWN its electrochemical gradient but is aided by the carrier. "
        "It exhibits all hallmarks of carrier-mediated transport.",
        BODY))

    story.append(Paragraph(
        "Rate  ∝  [Solute]  at low concentration  (faster than simple diffusion)",
        EQUATION))
    story.append(Paragraph(
        "Rate  →  Vmax  at high concentration  (saturation — unlike simple diffusion)",
        EQUATION))
    story.append(Spacer(1, 4))

    story.append(DiagramFlowable(W, 155, draw_diffusion_comparison))
    story.append(Spacer(1, 6))

    story.append(Paragraph("<b>Properties of Carrier-Mediated Transport:</b>", H3))
    prop_data = [
        ["Property", "Explanation", "Clinical Relevance"],
        ["Saturation (Vmax)", "At high [solute], all carriers are occupied → rate plateaus",
         "Tubular maximum (Tm) for glucose reabsorption in kidney"],
        ["Stereospecificity", "Carrier recognises D-glucose but NOT L-glucose",
         "Only natural isomers are transported"],
        ["Competition", "D-galactose competes with D-glucose for same GLUT transporter",
         "Galactosaemia — galactose competes, disrupting glucose transport"],
        ["Insulin regulation", "Insulin triggers GLUT4 insertion into muscle/adipose membrane",
         "Type 2 diabetes — GLUT4 insufficiency → hyperglycaemia"],
    ]
    prop_ts = TableStyle([
        ("BACKGROUND",   (0,0),(-1,0), TEAL),
        ("TEXTCOLOR",    (0,0),(-1,0), WHITE),
        ("FONTNAME",     (0,0),(-1,0), "Helvetica-Bold"),
        ("FONTSIZE",     (0,0),(-1,-1), 8),
        ("ROWBACKGROUNDS",(0,1),(-1,-1),[TEAL_LIGHT, WHITE]),
        ("GRID",         (0,0),(-1,-1), 0.5, GRAY_MID),
        ("VALIGN",       (0,0),(-1,-1), "MIDDLE"),
        ("TOPPADDING",   (0,0),(-1,-1), 4),
        ("BOTTOMPADDING",(0,0),(-1,-1), 4),
    ])
    prop_t = Table(prop_data, colWidths=[W*0.22, W*0.42, W*0.34])
    prop_t.setStyle(prop_ts)
    story.append(prop_t)
    story.append(Spacer(1, 6))

    story.append(Paragraph("<b>GLUT Transporter Family:</b>", H3))
    glut_data = [
        ["Transporter", "Location", "Regulation", "Notes"],
        ["GLUT1", "RBCs, brain, endothelium", "Constitutive",       "High affinity, low Km"],
        ["GLUT2", "Liver, β-cells, intestine", "Constitutive",      "Low affinity, high Km — glucose sensor"],
        ["GLUT4", "Skeletal muscle, adipose",  "Insulin-stimulated","Major route for post-meal glucose uptake"],
        ["GLUT5", "Small intestine",           "Constitutive",      "Fructose transport"],
    ]
    glut_ts = TableStyle([
        ("BACKGROUND",   (0,0),(-1,0), TEAL),
        ("TEXTCOLOR",    (0,0),(-1,0), WHITE),
        ("FONTNAME",     (0,0),(-1,0), "Helvetica-Bold"),
        ("FONTSIZE",     (0,0),(-1,-1), 8),
        ("ROWBACKGROUNDS",(0,1),(-1,-1),[TEAL_LIGHT, WHITE]),
        ("GRID",         (0,0),(-1,-1), 0.5, GRAY_MID),
        ("TOPPADDING",   (0,0),(-1,-1), 4),
        ("BOTTOMPADDING",(0,0),(-1,-1), 4),
    ])
    glut_t = Table(glut_data, colWidths=[W*0.14, W*0.28, W*0.22, W*0.34])
    glut_t.setStyle(glut_ts)
    story.append(glut_t)
    story.append(PageBreak())

    # ═══════════════════════════════════════════════════════════════════════════
    # 7. APOPTOSIS
    # ═══════════════════════════════════════════════════════════════════════════
    story.append(ColorBanner("7. APOPTOSIS", bg=RED_DARK))
    story.append(Spacer(1, 4))

    story.append(Paragraph(
        "<b>Definition:</b> Apoptosis (Greek: 'falling off') is <b>programmed cell death</b> — a "
        "highly regulated, <b>caspase-dependent</b> process in which a cell actively dismantles itself "
        "<b>without triggering inflammation</b>. Essential for normal development, immune tolerance, and tissue homeostasis.",
        BODY))

    story.append(Paragraph("<b>Apoptosis vs Necrosis:</b>", H3))
    diff_data = [
        ["Feature", "APOPTOSIS", "NECROSIS"],
        ["Cause",           "Physiological or programmed",     "Pathological (ischaemia, toxins)"],
        ["Cell membrane",   "INTACT throughout",               "Ruptures early"],
        ["Cell size",       "Shrinks",                         "Swells"],
        ["Inflammation",    "ABSENT (no spillage)",            "Present (cytoplasmic release)"],
        ["Caspases",        "Required (central)",              "Not involved"],
        ["DNA",             "Internucleosomal laddering",      "Random degradation"],
        ["End product",     "Apoptotic bodies (phagocytosed)", "Cell debris, inflammation"],
    ]
    diff_ts = TableStyle([
        ("BACKGROUND",   (0,0),(-1,0), RED_DARK),
        ("TEXTCOLOR",    (0,0),(-1,0), WHITE),
        ("FONTNAME",     (0,0),(-1,0), "Helvetica-Bold"),
        ("FONTSIZE",     (0,0),(-1,-1), 8),
        ("ROWBACKGROUNDS",(0,1),(-1,-1),[RED_LIGHT, WHITE]),
        ("BACKGROUND",   (0,2),(0,-1), colors.HexColor("#FFCDD2")),
        ("FONTNAME",     (0,1),(0,-1), "Helvetica-Bold"),
        ("GRID",         (0,0),(-1,-1), 0.5, GRAY_MID),
        ("ALIGN",        (0,0),(-1,-1), "CENTER"),
        ("TOPPADDING",   (0,0),(-1,-1), 4),
        ("BOTTOMPADDING",(0,0),(-1,-1), 4),
    ])
    diff_t = Table(diff_data, colWidths=[W*0.22, W*0.39, W*0.39])
    diff_t.setStyle(diff_ts)
    story.append(diff_t)
    story.append(Spacer(1, 6))

    story.append(DiagramFlowable(W, 260, draw_apoptosis_pathway))
    story.append(Spacer(1, 6))

    story.append(Paragraph("<b>Molecular Players:</b>", H3))
    mol_data = [
        ["Molecule", "Role"],
        ["Bcl-2, Bcl-XL",         "Anti-apoptotic — stabilise mitochondrial membrane"],
        ["BAX, BAK, BIM",          "Pro-apoptotic Bcl-2 family — ↑ mitochondrial permeability"],
        ["Cytochrome c",           "Released from mitochondria → activates apoptosome"],
        ["SMAC/DIABLO",            "Released with cytochrome c → inhibits IAPs → enables caspases"],
        ["Apaf-1",                 "Binds cytochrome c → forms apoptosome scaffold"],
        ["Caspase-9",              "Initiator caspase (intrinsic pathway)"],
        ["Caspase-8",              "Initiator caspase (extrinsic / death receptor pathway)"],
        ["Caspases 3, 6, 7",       "Executioner caspases — digest cytoplasmic proteins"],
        ["p53 (tumour suppressor)", "Triggers intrinsic pathway on DNA damage"],
    ]
    mol_ts = TableStyle([
        ("BACKGROUND",   (0,0),(-1,0), RED_DARK),
        ("TEXTCOLOR",    (0,0),(-1,0), WHITE),
        ("FONTNAME",     (0,0),(-1,0), "Helvetica-Bold"),
        ("FONTSIZE",     (0,0),(-1,-1), 8),
        ("ROWBACKGROUNDS",(0,1),(-1,-1),[RED_LIGHT, WHITE]),
        ("GRID",         (0,0),(-1,-1), 0.5, GRAY_MID),
        ("TOPPADDING",   (0,0),(-1,-1), 4),
        ("BOTTOMPADDING",(0,0),(-1,-1), 4),
    ])
    mol_t = Table(mol_data, colWidths=[W*0.32, W*0.66])
    mol_t.setStyle(mol_ts)
    story.append(mol_t)
    story.append(Spacer(1, 6))

    story.append(Paragraph("<b>Clinical Relevance:</b>", H3))
    clin = [
        "Cancer: p53 mutation / Bcl-2 overexpression → apoptosis resistance → tumour survival",
        "Leukaemia: t(14;18) translocation → Bcl-2 overexpression",
        "Neurodegeneration (Parkinson's, Alzheimer's): excessive apoptosis of neurons",
        "Autoimmune disease: defective FAS-mediated apoptosis → failure to delete self-reactive T cells (ALPS syndrome)",
        "HIV: CD4+ T cell depletion via apoptosis",
        "Anoikis: apoptosis triggered by loss of cell-ECM contact — important in cancer metastasis",
    ]
    for item in clin:
        story.append(Paragraph(f"• {item}", BULLET))

    story.append(PageBreak())

    # ═══════════════════════════════════════════════════════════════════════════
    # QUICK REVISION SUMMARY TABLE
    # ═══════════════════════════════════════════════════════════════════════════
    story.append(ColorBanner("QUICK REVISION SUMMARY", bg=BLUE_DARK))
    story.append(Spacer(1, 6))

    summary_data = [
        ["Topic", "Key Equation / Formula", "Must Remember"],
        ["Secondary Active\nTransport",
         "Energy = Na⁺ gradient\n(maintained by Na-K-ATPase)",
         "Symport: same direction\nAntiport: opposite\nInhibit NaKATPase → stops all SAT"],
        ["Resting Membrane\nPotential",
         "Em = Σ(gi/gT)·Ei\nNernst: E = 61/z · log([out]/[in])",
         "−70 to −80 mV\nK⁺ + Cl⁻ = main determinants\nNa-K-ATPase role = indirect (major)"],
        ["Cell Junctions",
         "No formula",
         "TJ: Occludin/Claudin (seal)\nAJ: Cadherin+Actin (link)\nDSM: Cadherin+IF (shear)\nGJ: Connexin <1000Da (comms)"],
        ["Na⁺-K⁺-ATPase",
         "3 Na⁺ out : 2 K⁺ in : 1 ATP\nCoupling = 3:2 (electrogenic)",
         "α subunit = functional core\nβ subunit = glycoprotein\nInhibited by Ouabain/Digitalis"],
        ["Simple Diffusion",
         "J = P × A × (CA − CB)\nP = KD/Δx",
         "No carrier, no saturation\nDriven by conc gradient\nLipid-soluble substances"],
        ["Facilitated\nDiffusion",
         "Vmax (saturable)\nKm = concentration at ½Vmax",
         "Carrier needed, no ATP\nStereospecific, competitive\nGLUT4 (insulin-stimulated)"],
        ["Apoptosis",
         "No formula\nCaspase cascade",
         "Intrinsic: Bcl-2/Cyt c/Casp-9\nExtrinsic: Fas/DISC/Casp-8\nExecutioner: Casp 3,6,7\nNO inflammation"],
    ]
    sum_ts = TableStyle([
        ("BACKGROUND",   (0,0),(-1,0), BLUE_DARK),
        ("TEXTCOLOR",    (0,0),(-1,0), WHITE),
        ("FONTNAME",     (0,0),(-1,0), "Helvetica-Bold"),
        ("FONTSIZE",     (0,0),(-1,-1), 8),
        ("ROWBACKGROUNDS",(0,1),(-1,-1),[BLUE_LIGHT, WHITE]),
        ("GRID",         (0,0),(-1,-1), 0.5, GRAY_MID),
        ("VALIGN",       (0,0),(-1,-1), "MIDDLE"),
        ("TOPPADDING",   (0,0),(-1,-1), 5),
        ("BOTTOMPADDING",(0,0),(-1,-1), 5),
    ])
    sum_t = Table(summary_data, colWidths=[W*0.22, W*0.35, W*0.41])
    sum_t.setStyle(sum_ts)
    story.append(sum_t)
    story.append(Spacer(1, 10))

    # Footer note
    story.append(HRFlowable(width=W, thickness=1, color=BLUE_DARK))
    story.append(Spacer(1, 4))
    story.append(Paragraph(
        "Sources: Costanzo Physiology 7e  |  Ganong's Review of Medical Physiology 26e  |  "
        "Guyton & Hall Textbook of Medical Physiology  |  Histology: A Text and Atlas (Ross & Pawlina)",
        S("Footer", fontSize=7, textColor=GRAY_MID, alignment=TA_CENTER)))

    doc.build(story)
    print(f"PDF generated: {OUTPUT}")

if __name__ == "__main__":
    build()

Running Command

cd /home/daytona/workspace/gen-physiology-pdf && python3 build_pdf.py 2>&1

Editing File

~/gen-physiology-pdf/build_pdf.py

Successfully replaced 1 instance(s) of the string in '/home/daytona/workspace/gen-physiology-pdf/build_pdf.py'

Running Command

cd /home/daytona/workspace/gen-physiology-pdf && python3 build_pdf.py 2>&1

Running Command

ls -lh /home/daytona/workspace/gen-physiology-pdf/General_Physiology_Summary.pdf

Your summary PDF is ready:

General Physiology Summary

PDF Document · PDF

What's inside the PDF (8 pages, A4):

Page	Content
1	Cover page + Table of Contents
2	Secondary Active Transport - diagram (symport vs antiport), transporter table
3	Resting Membrane Potential - ion table, Nernst & chord conductance equations, bar chart diagram
4	Cell Junctions - full comparison table + illustrated diagram of all 6 junction types
5	Na⁺-K⁺-ATPase - structure table, pump diagram with stoichiometry
6	Simple Diffusion - Fick's Law, Stokes-Einstein equation, factors table, comparison with carrier transport
7	Facilitated Diffusion - GLUT family table, saturation kinetics, diagram
8	Apoptosis - vs Necrosis table, intrinsic/extrinsic pathway diagram, molecular players, clinical correlations
Final	Quick Revision Summary Table - all 7 topics with key equations + must-remember points

All diagrams are drawn programmatically with colour-coded sections (teal for transport, blue for RMP, red for apoptosis, etc.) and sourced from Costanzo, Ganong's, and Guyton & Hall.

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