Molecular bases of life

A.Y. 2020/2021
Overall hours
BIO/10 BIO/11
Learning objectives
The course aims to:
a) explain molecular/cellular mechanisms related to human biological systems and to understand the genesis of pathological states;
b) explain the structure-function relationship of macromolecules;
c) Describe intra- and inter-cellular communication of tissues and systems with particular reference to muscle, nervous, respiratory, digestive, coagulative, skeletal, immune, hematological systems;
d) understand the biochemical processes from the point of view of physiological and pathological outcomes;
e) learn the molecular mechanisms involved in pathological processes, the development of innovative diagnostic strategies and their role in precision medicine.
Expected learning outcomes
a) know the molecular and biochemical mechanisms underlying the biological systems in health and their alterations in disease;
b) know the basics of molecular, translational and personalized medicine, as well as system biochemistry;
c) develop the ability to identify and deepen the topics covered in the course through the international scientific literature by compiling a mini-review in English.
Course syllabus and organization

Single session

In the first semester the lectures will take place as concurrent classroms:
·in the classroom with a limited number of students, who have previously booked using the "lezioniUnimi" app with the unimi e-mail account username and password; (…) and at the same time through the "Teams platform" for online students ;
· The student must wear a surgical mask for the entire duration of his/her stay in the classroom and to sit using every other free seat
· the lectures will be recorded and made available on the teacher's Ariel website for students with proven difficulties to connect during classes
· the lectures will take place at the San Paolo Hospital on the 3rd floor of Blocco C. Students must access classrooms via Blocco C and exit via the side blocks (students leaving Pauling and Fleming rooms towards Blocco B and students leaving Curie, Golgi and Pasteur rooms towards Blocco A).
Students must enter from the main hall (R floor) of the San Paolo hospital and undergo body temperature measurement by the infrared cameras. It is strongly recommended to use the stairs for classrooms entering and/or leaving.
NB for any further information check the website: (Home Studiare Frequentare un corso di laurea Seguire il percorso di studi Orari delle lezioni)
Prerequisites for admission
The student will use the information learned in the courses of Biology and Chemistry and Biochemistry to explain the mechanisms related to certain human biological systems and the origins of certain pathological states.
Assessment methods and Criteria
The course is divided into two modules, Human Systematic Biochemistry (6 CFU) and Molecular Medicine (3 CFU).
For the Human Systematic Biochemistry module, the verification consists in a computer test (multiple choice questions) in which 31 quizzes on the topics covered will be delivered, and the student must select the only correct answer from 5 proposals. The final vote will be the sum of the exact answers, taking into account that each incorrect answer will be penalized with -0.25 points.
For the Molecular Medicine module, the verification consists in the presentation of a minireview followed by a moment of discussion of the elaborate, followed by evaluation (max score 30/30).
The final vote of the Integrated Course will be the average obtained by weighing the two modules according to the CFU provided
Course syllabus
BLOOD COMPOSITION. Need for anticoagulants; Erythrocytes and hematocrit; Serum and plasma; Erythropoiesis.
Oxygen. A nod to physics.
MYGLOBIN AND HEMOGLOBIN IN THE TRANSPORT OF OXYGEN. Structure and function of the heme; Methemoglobin; Spectrophotometric differences between oxy- and deoxy-globins; Oxygen content.
HEMOGLOBIN STRUCTURE. Dissociation curve for oxygen and P50; Allosterism; Molecular mechanisms during the transition deossi-oxy hemoglobin; Allosteric effectors; Bohr effect; Carbon dioxide and 2.3-diphosphoglycerate ; Carbon monoxide and carbon dioxide; Forms in which CO2 appears in the blood.
GENETIC OF HEMOGLOBIN. Variants; Natural selection and conservation; Molecular pathology of hemoglobin; Hemoglobin S and malaria resistance; Fetal hemoglobin and 2.3-DPG; Thalassemias.
CLINICAL ASPECTS. Primary and derived blood parameters; glycated hemoglobin; Role of nitric oxide.
IRON METABOLISM. Absorption of iron; Transferrin and Ferritin; Management of the states of deficiency and iron overload.
HEME'S METABOLISM. Porphyrias; Fates of bilirubin and jaundice.

PLASMA PROTEIN. General information.
ONCOTIC PRESSURE. Osmotic and oncotic or colloidal pressure; Regulation of the distribution of liquids and genesis of tissue edema.
CLINICAL SIGNIFICANCE OF PLASMA PROTEINS. Albumin; Albumin/globulin ratio; Metal ion transport proteins; a1-antItripsin; haptoglobin and the destiny of the erythrocytes; Acute phase proteins; Protein electrophoresis; Isoenzymes; Meaning of their alterations.
IMMUNOLOGICAL SYSTEM. Molecular and cellular components of the immune system and mechanisms of immune responses; Theory of clonal selection, versatility, specificity and memory of immune responses; Structure of immunoglobulins and structure-function relationships; Classes of immunoglobulins; Generation of immunoglobulin diversity; Using Ig as diagnostic tools.
COAGULATION. Principles of hemostasis and Virchow triad; Platelets; Key features of the intrinsic and extrinsic Systems of X-factor activation; Mechanisms of activation of thrombin and role of vitamin K; Activating the fibrin; Control of clotting and platelet aggregation; Hemophylias.

FUNCTIONS AND STRUCTURE. N- and O-glycoprotein; Sequon; Types of N-glycosylated Glycoproteins; Biosynthesis of Glycoproteins and secretory pathway; Polysaccarides; Processing and degradation of glycoproteins; Diseases and metabolic dysfunctions attributable to glycoproteins; ABO system.
PROTEOGLYCANS. Classes of glucosylaminoglicans; Structure of proteoglycans; Main types of proteoglycans; Functions and pathophysiology of proteoglycans; Differences between glycoproteins and proteoglycans.
COLLAGEN. Ultrastructure of fibrils; Molecular structure of collagen types; Intra- and inter-molecular links; Composition in amino acids; Post-translational modifications of some amino acids; Carbohydrates; Biosynthesis of collagen; Key pathologies of collagen.
NON-COLLAGEN PROTEIN OF EXTRACELLULAR MATRIX. Elastin and major pathologies; Fibronectin, the role of isoforms; Laminin.

SIGNAL TRANSDUCTION. General mechanisms and interaction with receptors; G protein and adrenergic beta receptors; cAMP; Phosphate inositol diphosphate; Phospholipase A2; Prostaglandins and leukotrienes; Signaling for steroid and thyroid hormones.
HORMONES. Functional classification of hormones; Hormone-receptor interactions; Agonists and antagonists; Hormonal cascade from neuro-sensory stimuli; Pituitary and hypothalamic hormones; Hypothalamus-pituitary-thyroid axis; Hypothalamus-adrenal pituitary axis and adrenal cortex hormones; Glucocorticoids, mineralocorticoids and androgens; Biosynthesis and secretion of steroid hormones; Hypothalamus-pituitary-gonadal axis; Axis of growth hormone; Axis of prolactin; Catecholamines; Pancreatic hormones.

Distribution in the body, requirements and flows of calcium and phosphate; parathyroid hormone, calcitonin and vitamin D; Osteoporosis, osteomalacia and rickets; Bone remodeling; Osteoblasts and bone growth; Osteoclasts and demineralization; The calcium in the bones and teeth; Cariogenicity; Fluoride.

WATER DISTRIBUTION, CATIONS AND ANIONS. Distribution of water in the body; Anion Gap; Water balance.
ACID-BASE ADJUSTMENT SYSTEMS. Buffer systems; The body's defenses against CO2 and acid. Blood buffer systems; CO2-bicarbonate system; CO2 hydration reaction; Henderson-Hasselbalch equation.
ACID-BASE DISORDERS. PH-bicarbonate diagram; Measures that give information about the base state in the fetus; Genesis of the main acid/base pathologies; Compensation mechanisms for acid-base, kidney and respiratory diseases; Renal control and secretion of H; Buffers in urines and other fluids.
KIDNEY BIOCHEMISTRY. Main functions of the kidney; The nephron, functional unit of the kidney; Structure of the kidney gland; Glomerular filtration mechanism; Composition and tone of the filtered glomerular; water, proteins, glucose, creatinine, amino acids and other ions; Mechanism of the reabsorption of Na and other components; Measurement of clearance; Potassium; Aquaporins.

STRUCTURE AND ULTRASTRUCTURE. Morphological differences between skeletal, heart and smooth muscles; Non-mechanical muscle functions; Sliding filament model; Relationship between developed tension and cross-bridges; Protein of thin and thick filaments; Myosin; Actin; Titin and nebulin; Dystrophin; Actin and treadmilling polymerization; Tropomyosin and troponin; Actin-myosin interaction; Troponin conformation.
ROLE OF Ca. Ca's entry mechanisms; Sarcoplasmic reticulum; Receptors sensitive to dihydrohydroridine and rianodine; Ca-antagonists and blocking of the Na channels.
VARIOUS TYPES OF MUSCLE. Principles of bioenergetics, ATP and phosphocreatine; Red and white fibers; Metabolic responses to exercise and use of substrates; Skeletal and cardiac muscle; Role of phosphocreatine and adenylate kinase; Cardiac Ischemia: Smooth muscle contraction.
NON-MUSCULAR CONTRACTILE UNITS. Other roles of the actin; Alpha-actinin.

CHEMISTRY AND PROPAGATION MECHANISM. Oxygen and Reactive Oxygen Species; Role of mitochondria and peroxisomes; Other biological reactions that generate free radicals; Free radicals centered on C; Markers of damage from free radicals; Free radicals centered on metals; Nitric oxide.
SCAVENGERS. Scavenging systems; Antioxidants and oxidative stress control systems.
AGING. Age-related fragility; Hayflick's limit; Telomeres and telomerases; Theories of aging.

RESPIRATORY FUNCTION. Alveolus, Gas Exchange and Transport of O2 and CO2, Oxygen Sensing; Nitric oxide, carbon monoxide.
ENDOTHELIUM. Role of NO and hypoxic pulmonary vasoconstriction, Elastin, basal membrane.
Epithelium. Alveolar cells, Mucus, Cystic Fibrosis and CFTR; Pulmonary edema and pulmonary adjustments to high altitude. Defense against infection.

THE NERVE TISSUE. Metabolic principles and morphology; Blood brain barrier; Key characteristics of neurons; Neuronal transport systems; Electrical and chemical synapses; ATPase; Ion channels, membrane depolarization and action potential.
CHEMICAL NEUROTRANSMITTERS. Synaptic vesicles; Mode of neuronal transmission; Glutamate and GABA; Catecholamines, adrenaline and norepinephrine; Dopamine; Serotonin or hydroxytriptamine; Acetylcholine and other neurotransmitters.
VISION MECHANISM. Retina morphology, cones and rods; Rhodopsin; Vitamin A or retinal; Modulation of Na and hyperpolarization; Color vision and cones; Color blindness. Retina metabolisms; Crystallin and protein homeostasis; Senile and diabetic cataract.
SENSES. Sensory transduction; Smell; Hearing; Taste.
Teaching methods
The programme will be carried out exclusively through face-to-face lessons with the help of educational materials (slide projections and/or films), with possible interventions by qualified external teachers.
Teaching Resources
· J.W.Baynes, M.H.Dominiczak, Biochimica per le discipline biomediche, 2° edizione, Casa Editrice Ambrosiana.
· T.M.Devlin, Biochimica, Seconda Edizione Italiana sulla Terza Edizione Americana, Gnocchi.
· P.Champe, R.A.Harvey, D.R.Ferrier, Le basi della biochimica, Zanichelli.
· D.L.Nelson, M.M.Cox, I principi di biochimica, 4° edizione, Zanichelli
Molecular biology
Course syllabus
The concept of "Precision Medicine" is introduced following the growing knowledge in genetics and molecular biology associated with the availability of clinical data that project the opportunity to personalize the care and clinical management of the patient.

The characteristics of genotypic/phenotypic heterogeneity in some monogenic syndromic contexts, the diagnostic criticalities and the methodologies used to detect molecular anomalies are introduced.
· Sex chromosome disorders: pancake 'Turner'. The molecular side of sex chromosome abnormalities. Turner's syndrome; a simple model of complex alterations.
· Genomic Imprinting twilight: a parents affair. Parental balances in the control of gene dosage and the Angelman and Prader-Willi specular syndromes

MEN2 syndromes are discussed as molecular model of 'Receptor Tyrosine Kinase' alteration, representing an example of clinical/molecular management in endocrinology.

The concepts of genetic/chromosomal instability are discussed with an overview of some proposed models for understanding the phenomenon that acts as a motor in neoplastic transformation.
· Li Fraumeni syndrome fatal 'gain' of p53 missense. Paradigm of the mechanisms by which neoplastic progression acquires functions, p53 is the "tumor suppressor" molecule par excellence, the related syndrome guides us in the dynamics of its action mechanism.
· RecQ the genome unwinder. RecQ helicases represent the guardians of the genome, a model of genetic stability control, a syndromic paradigm the loss of their function.

We will explore the biological causes of aging analysing in details the molecular mechanisms that are involved, discussing the implications of aging in the development of diseases

We will analyse the role of epigenetic mechanisms and their contribution to the development of diseases. We will further analyse how the concept of epigenetic is strictly linked with the role that the environment plays in the development of diseases discussing its molecular implications.

We will explore the major molecular pathways involved in the development of different types of human cancer analysing their role in normal cellular function and homeostasis as well as their oncogenic properties. We will also discuss how new technological approaches allows to uncover molecular vulnerabilities opening towards effective personalized medicine approaches.

· The hidden molecular landscape of the AML Acute myeloid leukemias are neoplasms with low genetic instability, what emerges from the new generation genomic and molecular profiles?
· Core binding factor leukemia: a neverending story. "Core Binding Factor" leukemia: a multi-step progression model that harmonizes genetics and epigenetics in a molecular continuum capable of addressing new therapeutic approaches.
· A-to-I RNA editing: the "ADAR" side of cancer. One of the most relevant post-transcriptional modifications among genome plasticity functions is discussed; a two-sided medal in neoplastic transformation.
· Myeloproliferative disease in tris 21 a dosage enigma. The susceptibility to leukemia in Down subjects, a little-known aspect represents an interpretative challenge involving the mechanisms of gene dosage control.

We will analyse the molecular basis that allows to manipulate the identity of cells as well as their genetic content discussing technological strategies and potential therapeutic approaches.
Teaching methods
The programme will be carried out exclusively through face-to-face lessons with the help of educational materials (slide projections and/or films), with possible interventions by qualified external teachers.
Teaching Resources
· F.Amaldi, P.Benedetti, G.Pesole, P.Plevani. Biologia Molecolare terza ed. Editrice Ambrosiana.
· V.T. DeVita, T.S. Lawrance, S.A. Rosenberg. Cancer: Principles & Practice of Oncology. Primer of the Molecular Biology of Cancer. Lippincott Williams & Wilkins
BIO/10 - BIOCHEMISTRY - University credits: 6
Lessons: 72 hours
Molecular biology
BIO/11 - MOLECULAR BIOLOGY - University credits: 3
Lessons: 36 hours