United States Medical Licensing Examination (USMLE) Foundational Biomedical Sciences (Step 1 Core) Syllabus

What molecule shuttles fatty acids into the mitochondria for beta-oxidation, and what inhibits this shuttle?

Carnitine (via carnitine acyltransferase I/CPT-1). Malonyl-CoA inhibits CPT-1, preventing simultaneous fatty acid synthesis and oxidation.

Name the three ketone bodies and the conditions that promote ketogenesis.

Acetoacetate, beta-hydroxybutyrate, and acetone. Ketogenesis (in liver) increases in prolonged fasting/starvation, diabetic ketoacidosis, and alcoholism due to high acetyl-CoA and low oxaloacetate.

What is the rate-limiting enzyme of cholesterol synthesis and the drug class that inhibits it?

HMG-CoA reductase; inhibited by statins (HMG-CoA reductase inhibitors).

What are the two main mechanisms for disposing of ammonia, and where does the urea cycle's rate-limiting step occur?

Glutamine (via glutamine synthetase) transports ammonia, and the urea cycle in the liver excretes it. The rate-limiting enzyme is carbamoyl phosphate synthetase I (mitochondria), requiring N-acetylglutamate as activator.

Classify amino acids as glucogenic, ketogenic, or both — which two are purely ketogenic?

Leucine and lysine are purely ketogenic. Most amino acids are glucogenic; isoleucine, phenylalanine, threonine, tryptophan, and tyrosine are both glucogenic and ketogenic.

What is the enzyme defect and key management in phenylketonuria (PKU)?

Deficiency of phenylalanine hydroxylase (or BH4 cofactor), causing phenylalanine buildup. Management: low-phenylalanine diet, avoid aspartame, supplement tyrosine (becomes essential).

Match the vitamin to its deficiency disease: B1, B3, C, and D.

B1 (thiamine) = beriberi/Wernicke-Korsakoff; B3 (niacin) = pellagra (diarrhea, dermatitis, dementia); C (ascorbate) = scurvy; D = rickets/osteomalacia.

Which vitamins serve as cofactors for the pyruvate dehydrogenase complex?

The five cofactors: thiamine pyrophosphate (B1), lipoic acid, CoA (B5/pantothenate), FAD (B2), and NAD (B3).

In autosomal dominant inheritance, what is the recurrence risk for offspring of one affected heterozygous parent, and what are typical features?

50% of offspring affected; features include vertical transmission across generations, both sexes affected, often involve structural proteins, variable expressivity, and incomplete penetrance.

How does X-linked recessive inheritance present in terms of affected sex and transmission?

Predominantly affects males; no male-to-male transmission; sons of carrier mothers have 50% risk; daughters of affected fathers are obligate carriers.

State the Hardy-Weinberg equations and the assumptions required for equilibrium.

p + q = 1 and p^2 + 2pq + q^2 = 1 (p^2 = homozygous dominant, 2pq = heterozygotes/carriers, q^2 = homozygous recessive). Assumptions: no mutation, no migration, no selection, random mating, large population.

Compare the genetics and phenotype of Down syndrome, Edwards syndrome, and Patau syndrome.

Down = trisomy 21 (flat facies, simian crease, AV septal defect, increased Alzheimer/leukemia risk); Edwards = trisomy 18 (rocker-bottom feet, clenched hands, micrognathia); Patau = trisomy 13 (cleft lip/palate, polydactyly, holoprosencephaly). Severity/lethality: 13 ~ 18 > 21.

Contrast Turner syndrome and Klinefelter syndrome karyotypes and key features.

Turner = 45,XO (short stature, webbed neck, streak ovaries, coarctation, bicuspid aortic valve, primary amenorrhea). Klinefelter = 47,XXY (tall, testicular atrophy, gynecomastia, infertility, high FSH/LH).

Define genomic imprinting and contrast Prader-Willi with Angelman syndrome.

Imprinting: expression depends on parent of origin. Prader-Willi = loss of paternal chromosome 15q (hyperphagia, obesity, hypogonadism, hypotonia). Angelman = loss of maternal 15q (ataxia, seizures, inappropriate laughter, 'happy puppet').

Explain anticipation and give an example trinucleotide repeat disorder.

Anticipation = disease severity worsens and onset is earlier in successive generations as repeats expand. Example: Huntington disease (CAG repeats), fragile X (CGG), myotonic dystrophy (CTG).

What is heteroplasmy in mitochondrial inheritance, and how is the trait transmitted?

Heteroplasmy = a mix of mutant and wild-type mitochondrial DNA within cells, causing variable expression. Mitochondrial DNA is transmitted exclusively from the mother; all offspring of an affected female may be affected.

Compare PCR, Southern blot, and Northern blot in what they detect.

PCR amplifies a specific DNA segment. Southern blot detects DNA; Northern blot detects RNA; Western blot detects protein. (Mnemonic SNoW DRoP.)

What is the principle of CRISPR/Cas9 gene editing?

A guide RNA directs the Cas9 endonuclease to a complementary DNA sequence, creating a double-strand break; the cell then repairs it (NHEJ for knockout or homology-directed repair for precise edits).

Differentiate the cell wall and Gram-stain result of Gram-positive versus Gram-negative bacteria.

Gram-positive: thick peptidoglycan, retains crystal violet (purple), has teichoic acid. Gram-negative: thin peptidoglycan with outer membrane containing LPS/endotoxin, stains pink (safranin).

Which bacterial structure is responsible for endotoxin activity, and what is its key component and effect?

The outer membrane lipopolysaccharide (LPS) of Gram-negatives; its lipid A component triggers macrophage release of IL-1, TNF, and IL-6, causing fever, hypotension, and septic shock (DIC).

Contrast exotoxins and endotoxins in source, chemistry, and antigenicity.

Exotoxins: secreted proteins from Gram-positive and Gram-negative bacteria, highly antigenic (induce antitoxins/vaccines as toxoids), often very potent and specific. Endotoxin: LPS (lipid A), from Gram-negative outer membrane, poorly antigenic, released on lysis.

Classify viruses by genome: give one key feature distinguishing DNA from RNA viruses.

Most DNA viruses are double-stranded, replicate in the nucleus, and are enveloped or naked (all DNA viruses are dsDNA except parvovirus). Most RNA viruses are single-stranded and replicate in the cytoplasm (except influenza and retroviruses).

What enzyme allows retroviruses like HIV to replicate, and what does it do?

Reverse transcriptase, an RNA-dependent DNA polymerase, transcribes the viral RNA genome into DNA, which integrates into the host genome (via integrase) as a provirus.

Compare the staining/identification of the major fungi: Cryptococcus, Pneumocystis, and Aspergillus.

Cryptococcus: India ink/mucicarmine, narrow-based budding with capsule. Pneumocystis jirovecii: silver stain (GMS) showing disc/cup-shaped cysts. Aspergillus: septate hyphae branching at acute (45-degree) angles.

Distinguish Plasmodium falciparum malaria from other species in periodicity and severity.

P. falciparum causes irregular/continuous fever, parasitizes RBCs of all ages causing high parasitemia and severe disease (cerebral malaria), and lacks a dormant liver stage. P. vivax/ovale have 48-hr fevers and dormant hypnozoites; P. malariae has 72-hr fevers.

List the major components of innate immunity and how it differs from adaptive immunity.

Innate: physical barriers, neutrophils, macrophages, NK cells, complement, dendritic cells; nonspecific, fast, no memory, recognizes PAMPs via PRRs (e.g., Toll-like receptors). Adaptive is specific, slower, and has memory (B and T cells).

What is the function of NK cells and how do they recognize targets?

NK cells kill virus-infected and tumor cells via perforin/granzymes and antibody-dependent cellular cytotoxicity. They are activated by absence of MHC I ('missing self') and stress signals; enhanced by IL-12, IL-15, IFN.

Contrast MHC class I and class II: which cells express them and which T cells they engage.

MHC I: on all nucleated cells, presents endogenous (intracellular) peptides to CD8+ cytotoxic T cells. MHC II: on antigen-presenting cells (macrophages, B cells, dendritic cells), presents exogenous peptides to CD4+ helper T cells.

Compare the cytokines and functions of Th1 versus Th2 helper T-cell subsets.

Th1: secretes IFN-gamma and IL-2, activates macrophages and cytotoxic T cells (cell-mediated/intracellular pathogens); induced by IL-12. Th2: secretes IL-4, IL-5, IL-13, helps B cells/IgE and eosinophils (parasites, allergy); induced by IL-4.

List the four types of hypersensitivity reactions with a mechanism and example for each.

Type I: IgE-mediated mast cell degranulation (anaphylaxis, allergy). Type II: antibody (IgG/IgM) against cell-surface antigens (autoimmune hemolytic anemia, Goodpasture). Type III: immune complex deposition (SLE, serum sickness). Type IV: T-cell mediated/delayed (TB skin test, contact dermatitis).

Differentiate the immune defect in DiGeorge syndrome from chronic granulomatous disease.

DiGeorge: 22q11 deletion, failed development of 3rd/4th pharyngeal pouches, thymic aplasia causing T-cell deficiency (plus hypocalcemia, cardiac defects). Chronic granulomatous disease: NADPH oxidase defect, phagocytes cannot make reactive oxygen species, recurrent catalase-positive infections; diagnosed by abnormal dihydrorhodamine test.

List the order of histologic changes in reversible versus irreversible cell injury.

Reversible: cellular/mitochondrial swelling, decreased ATP, ribosomal detachment, membrane blebbing. Irreversible: mitochondrial damage with Ca2+ influx, membrane rupture, lysosomal enzyme release, and nuclear changes (pyknosis, karyorrhexis, karyolysis).

Match the type of necrosis to its classic setting: coagulative, liquefactive, caseous, fat, fibrinoid, gangrenous.

Coagulative = ischemic infarct of solid organs (not brain); liquefactive = brain infarct/abscess; caseous = TB and fungal granulomas; fat = pancreatitis/breast trauma; fibrinoid = vessel wall in vasculitis/malignant hypertension; gangrenous = ischemic limb (dry/wet).

Name the five cardinal signs of acute inflammation and the predominant cell type.

Rubor (redness), calor (heat), tumor (swelling), dolor (pain), functio laesa (loss of function); the predominant cell is the neutrophil.

Outline the steps of neutrophil extravasation (leukocyte adhesion cascade).

Margination, rolling (selectins/sialyl-Lewis X), activation, tight adhesion (integrins-ICAM), transmigration/diapedesis (PECAM-1), and chemotaxis (C5a, LTB4, IL-8, bacterial products) toward the injury.

Compare labile, stable, and permanent tissue types in regenerative capacity.

Labile: continuously dividing, regenerate well (gut/skin epithelium, bone marrow). Stable: quiescent (G0) but can divide if stimulated (hepatocytes, renal tubules). Permanent: cannot regenerate, heal by scar (neurons, cardiac and skeletal muscle).

Distinguish healing by primary versus secondary intention.

Primary intention: clean wound with apposed edges (sutured), minimal scar. Secondary intention: large gaping wound healing from the bottom up with granulation tissue, wound contraction (myofibroblasts), and a larger scar.

State Virchow's triad and its clinical significance.

The three factors promoting thrombosis: endothelial injury, stasis (abnormal blood flow), and hypercoagulability. It explains predisposition to venous thromboembolism (e.g., DVT/PE).

Differentiate transudate from exudate in an effusion.

Transudate: low protein, low specific gravity, due to increased hydrostatic or decreased oncotic pressure (CHF, cirrhosis, nephrotic syndrome). Exudate: high protein, high specific gravity, cellular, due to inflammation/increased vascular permeability (infection, malignancy).

Define the steps/hallmarks of neoplastic progression and contrast benign vs malignant tumors.

Hallmarks include self-sufficient growth signals, evasion of apoptosis, limitless replication, angiogenesis, invasion/metastasis. Benign: well-differentiated, slow, encapsulated, no metastasis. Malignant: poorly differentiated/anaplastic, rapid, invasive, metastasizes.

Differentiate oncogenes from tumor suppressor genes with one example of each.

Oncogenes: gain-of-function mutations (one allele) promoting cancer (e.g., RAS, MYC, HER2). Tumor suppressors: loss-of-function requiring both alleles inactivated/two-hit hypothesis (e.g., TP53, RB, APC, BRCA).

Define bioavailability (F) and volume of distribution (Vd), including their formulas.

Bioavailability F = fraction of drug reaching systemic circulation (100% for IV). Vd = amount of drug in body / plasma drug concentration; high Vd suggests tissue/lipophilic distribution, low Vd suggests confinement to plasma.

Give the formulas for clearance, half-life, and loading dose.

Clearance CL = rate of elimination / plasma concentration = Vd x ke. Half-life t1/2 = 0.7 x Vd / CL. Loading dose = (Css x Vd)/F; maintenance dose = (Css x CL)/F.

Compare zero-order and first-order elimination kinetics with examples.

Zero-order: constant amount eliminated per unit time (rate independent of concentration) — phenytoin, ethanol, aspirin (high dose). First-order: constant fraction eliminated per unit time (rate proportional to concentration) — most drugs.

Define potency versus efficacy and how they appear on a dose-response curve.

Potency: amount of drug needed for a given effect (related to EC50; left-shifted curve = more potent). Efficacy: maximal achievable effect (Emax; higher plateau = more efficacious).

Contrast competitive and noncompetitive antagonists in their effects on agonist potency and efficacy.

Competitive antagonist: surmountable, shifts dose-response curve right (decreases potency/increases EC50), Emax unchanged. Noncompetitive (irreversible/allosteric): insurmountable, decreases Emax (efficacy), potency may be unchanged.

Define therapeutic index and write its formula.

Therapeutic index (TI) = TD50 / ED50 (or LD50/ED50 in animals); the median toxic (or lethal) dose divided by the median effective dose. A higher TI means a safer drug.

Compare Phase I and Phase II drug metabolism reactions.

Phase I: oxidation, reduction, hydrolysis (often via cytochrome P450) yielding slightly polar, sometimes active metabolites. Phase II: conjugation (glucuronidation, acetylation, sulfation) producing polar, usually inactive, water-soluble metabolites for excretion.

What is the difference between cytochrome P450 inducers and inhibitors for drug interactions?

Inducers (e.g., rifampin, phenytoin, carbamazepine, barbiturates, St. John's wort, chronic alcohol) increase metabolism and lower drug levels. Inhibitors (e.g., azoles, macrolides, grapefruit juice, ritonavir, cimetidine) decrease metabolism and raise drug levels/toxicity.

Contrast the receptors and overall effects of the sympathetic versus parasympathetic autonomic nervous systems.

Sympathetic ('fight or flight'): mostly adrenergic (alpha/beta) via norepinephrine, increases heart rate, dilates pupils/bronchi, decreases GI activity. Parasympathetic ('rest and digest'): cholinergic (muscarinic) via acetylcholine, decreases heart rate, constricts pupils, increases GI/secretions. Both ganglia and adrenal medulla use nicotinic ACh receptors.

Match adrenergic receptor subtypes to their primary actions: alpha-1, alpha-2, beta-1, beta-2.

Alpha-1: vasoconstriction, mydriasis, increased sphincter tone (Gq). Alpha-2: decreased sympathetic outflow, decreased insulin/NE release (Gi). Beta-1: increased heart rate, contractility, renin (Gs). Beta-2: bronchodilation, vasodilation, uterine relaxation (Gs).

What are the signs of cholinergic (muscarinic) excess, and what is the antidote for organophosphate poisoning?

Cholinergic toxicity (DUMBBELSS): Diarrhea, Urination, Miosis, Bronchospasm, Bradycardia, Excitation of muscle, Lacrimation, Sweating, Salivation. Antidote: atropine (muscarinic blocker) plus pralidoxime (regenerates acetylcholinesterase).

Match the toxin/overdose to its specific antidote: acetaminophen, opioids, benzodiazepines, warfarin, heparin.

Acetaminophen = N-acetylcysteine; opioids = naloxone; benzodiazepines = flumazenil; warfarin = vitamin K and fresh frozen plasma; heparin = protamine sulfate.

What are the antidotes for methanol/ethylene glycol, iron, lead, and digoxin toxicity?

Methanol/ethylene glycol = fomepizole (and ethanol); iron = deferoxamine/deferasirox; lead = EDTA, dimercaprol, succimer; digoxin = digoxin-specific Fab antibodies (Digibind).

What is the universal direct acceptor of high-energy electrons that yields the most ATP, and how many ATP does NADH versus FADH2 generate?

NADH and FADH2 donate electrons to the electron transport chain. NADH yields ~2.5 ATP and FADH2 yields ~1.5 ATP per molecule (entering at Complex I vs Complex II, respectively).

Compare primary, secondary, and tertiary protein structure.

Primary: linear amino acid sequence (peptide bonds). Secondary: local folding into alpha-helices and beta-sheets (hydrogen bonds). Tertiary: overall 3D shape of a polypeptide (disulfide, hydrophobic, ionic interactions). Quaternary: assembly of multiple subunits.