Cells, Molecules and Genes 2

· Cellular membranes: molecular components, structure, organization, and roles
· Relationships between membrane structure, dynamics and functional properties
· Role of the specific lipid, protein and carbohydrate components in conferring peculiar functions to cellular membranes
· Mechanisms underlying lateral and trans-bilayer motions of membrane lipids, lateral membrane heterogeneity of membrane components, and role of microdomains as functional compartments
· Transport across a membrane: simple diffusion, passive and active transport, energy change factors that influence transport, and role of solute transport in homeostasis
· Main features of protein-mediated transport and mechanisms of passive and active transport
· Pores, channels, ionophores.
· Molecular mechanisms of active transport and their control
· Passive and active transmembrane transporters of ions, glucose , amino acids, and fatty acids
· Vesicular transport mechanisms and roles
· Hormones: definition, chemical structure, classification, and properties of hormonal classes
· Fundamental aspects of hormone biosynthesis, release, and mechanisms underlying hormonal control and cyclic hormonal systems
· Hormone receptors and properties, and action mechanism of lipophilic and hydrophilic hormones
· Enzymes: definition, structure, international classification, and functional properties
· Enzymes: catalytic mechanisms, factors affecting enzymatic activity, isoenzymes and properties
· Enzyme cofactors: types, properties and roles in enzyme catalysis
· Inhibition of enzyme action
· Enzyme properties and regulation mechanisms of enzyme activity, including the properties of allosteric enzymes
· Clinical significance of enzymes
· Metabolism: definition, aims, features, and energetic strategies
· Catabolic and anabolic pathways, their interconnections and control
· Molecular mechanisms underlying cell transformation of energetic nutrients into usable energy
· High-energy compounds, and role of ATP as energy transporter inside cells
· Role of biological oxidation in homeostasis, and involved enzymes and coenzymes
· Nutrients: definition, functional types, and essential nutrients
· Energetic nutrients: energy content and its evaluation, measure units of energy in foods
· Basal metabolic rate, factors influencing it, and measurement
· Total energetic requirement, its components and energetic needs for physical activity
· Energetic flux and transformation in cells, and differences between ATP formation by substrate-level phosphorylation and oxidative phosphorylation
· Metabolic origins and fates of acetyl-CoA
· The tricarboxylic acid cycle: location, substrates, products, cofactors, sites of energy recovery, and regulation
· The amphibolic role of tricarboxylic acid cycle, and the role of anaplerotic reactions.
· Mitochondrial respiratory chain: components, organization, properties, and control
· Energy release by the mitochondrial electron transport chain, and alterations in human diseases
· ATP synthase: structure, functional components, and coupling with the respiratory chain
· Inhibitors and uncouplers of oxidative phosphorylation
· The ATP/ADP cycle, and the concept of respiratory control
· The key role of oxygen in human cells, and its different uses as metabolic substrate
· Free radicals and ROS: definition, production, clearance and effects in physiological and physio-pathological conditions
· Nitric oxide metabolism, functions and toxicity
· Antioxidant defences and redox homeostasis
· Structural and functional features of the major carbohydrates in humans
· Digestion and absorption of carbohydrates
· Major metabolic origins and fates of glucose and their roles
· Glucose phosphorylation: enzymes, importance in metabolism, and medical application in PET
· The glycolytic pathway: stages, reactions, and mechanisms of energy recovery
· Regulation of key glycolytic enzymes by local and hormonal control
· Energy production from anaerobic and aerobic glycolysis
· Lactate: production from pyruvate, transmembrane transport and intercellular shuttles
· Pyruvate transport into mitochondria and metabolic fates by pyruvate dehydrogenase and pyruvate carboxylase in mitochondria and control of these enzymes
· Shuttle mechanisms for transfer of reducing equivalents from cytosol to mitochondria
· Role of glycolytic intermediates and pyruvate as precursors for biosynthesis
· Metabolism of fructose and galactose in human cells and connected metabolic diseases
· Nucleotide-activated sugars and their different fates
· The polyol pathway and its positive and negative effects
· The pentose phosphate pathway: mechanisms, regulation, and differences with glycolysis
· NADPH generation and roles in different cells
· Glutathione structure and role in cell structure and functions
· Glycogen: structural features, localization, functions, and advantages/disadvantages of glycogen as energy storage
· Local and systemic roles of glycogen as glucose store
· Glycogen metabolism, its enzymes and mechanisms of regulation.
· The medical importance of glycogen storage diseases.
· Glycocoproteins: structural features, localization, functions, and metabolism.
· Lipid types and functions
· Dietary lipids and fatty acids found in foods, including essential fatty acids and their roles
· Emulsification, enzymatic digestion and absorption of dietary lipids and differences between digestion, absorption and transport of short, medium- and long-chain fatty acids
· Chylomicrons: composition, metabolism and role in the inter-organ transport of dietary fatty acids
· Mechanisms of inter-organ transport of different lipids in blood and lipoproteins, including classification, composition, types, and roles
· Origins of fatty acids as metabolic fuel, and role of lipoprotein lipase and hormone-sensitive lipase
· Fatty acid β-oxidation, including fatty acid activation and transport into mitochondria, enzymes, coenzymes, and connections to the mitochondrial electron transport chain and
· Energetic yield and control mechanism of fatty acid catabolism
· Differences in oxidation of saturated, unsaturated, odd and even carbon fatty acids and differences between mitochondrial and peroxisomal oxidation of fatty acids
· Ketone bodies: structure, ketogenesis, catabolism, and clinical significance of ketosis.
· Fatty acid biosynthesis; location, substrates, multi-enzyme complex mechanism, coenzymes, and regulation. Fatty acid chain elongation and desaturation
· Triacylglycerols: structure, blood transport, localization and their advantages/disadvantages as energy store
· Biosynthesis and catabolism of triacylglycerols and its hormonal control.
· Major metabolic fates of fatty acids and their functional roles
· Structure, origins, and functions of cholesterol
· Dietary origin and absorption of cholesterol and phytosterols
· Biosynthesis of cholesterol, its requirements and regulation
· Inter-organ transport of cholesterol by blood lipoproteins and cellular uptake of cholesterol from them
· Cholesterol as precursor of steroid hormones and bile acids
· Regulation of blood cholesterol and its importance
· Metabolism of phospholipids, sphingolipids, and eicosanoids
· Origins of amino acids in humans
· Digestion of dietary proteins including localization, enzyme activation and catalytic roles of different digestive proteases; absorption mechanisms of amino acids and peptides by the human intestine
· Protein turnover, mechanism and control of protein catabolism.
· Major reactions involving amino acids: transamination, deamination and decarboxylation, including mechanisms, coenzymes and functional importance
· Biosynthesis of non essential amino acids: precursors, cofactors, and mechanisms.
· Normal and abnormal metabolism of phenylalanine.
· Role of amino acids as precursors of key nitrogen-containing compounds
· Energetic fates of amino acids, cofactor requirement, glucogenic and ketogenic amino acids
· Gluconeogenesis pathway, localization, substrates and energetic
· The glucose-lactate cycle and the alanine cycle and their role in homeostasis
· Regulation of gluconeogenesis and its coordinated control with glycolysis.
· Nitrogen balance and physio-pathological variations
· Formation, blood transport, and strategies for elimination of ammonia
· Urea cycle and its regulation, reactions that feed nitrogen into it, and its connections with the tricarboxylic acid cycle
· Nucleotide biosynthesis, including sources of the ring atoms of purines and pyrimidines, and role of amino acids and involved coenzymes in it
· Nucleotide catabolism, final products and medical significance of elevated uric acid production
· Prompt and long-lasting stores of energy (circulating and tissue stores)
· Endocrine control of glycemia and role of inter-tissue glucose sensing and communication
· Metabolic adaptations and regulation in the fed and fasting state and in stress conditions
· Metabolic cooperation among different cells as the key to healthy survival.

During the module:
· Case studies

Difference between genotype and phenotype, locus and allele.
· The Modification of Dominance Relationships (Complete dominance, Incomplete dominance Codominance)
· The concept of Multiple-allele Series, and list the ABO, the MN and Rh blood groups
· The Lethal alleles, and list examples of lethal alleles in humans
· The relationships between gene expression and environment (Penetrance, Expressivity Pleotropy)
· Definition of the hereditary trait
· Classification of the genetic disorders (Single gene disorders, Chromosomal disorders, Complex disorders)
· The importance of family history
· The goals of pedigree analysis, the construction of a pedigree (symbols and rules) and the key information helpful for drawing a genetic family history
· The basic Mendelian patterns: Autosomal recessive, Autosomal dominant X-linked recessive, X-linked dominant, Y-linked and the characteristics of single gene inheritance
· Description of some traits in humans due to autosomal dominant and recessive alleles
· Explanation of the occurrence of X-linked recessive traits
· The factors affecting pedigree patterns: Pseudo Dominance, Reduced Penetrance, Variable expression, Age of onset, De novo mutation and germline mosaicism, Genetic heterogeneity (allelic heterogeneity, locus heterogeneity and phenotypic heterogeneity), Complementation, Digenic inheritance
· The multiple explanations for reduced penetrance and variable expressivity of single gene disorders
· The Non mendelian Inheritance: Mitochondrial Inheritance. A brief review of mitochondrial function and the molecular mechanisms of mitochondrial diseases caused by nuclear and mitochondrial genome mutations.
· The difference between mutation and polymorphism of DNA
· Definition of the mutation rate, the incidence and the prevalence of mutation
· The parameters to classify the mutation: Phenotypic effect (lethal or sub vital, conditional, neutral and pleiotropic); Age of onset (early onset, late onset).
· The types of DNA mutation including substitution (missense, nonsense), insertion/deletion (in-frame, frameshift), splice-site, amplification of repeated sequences, genomic instability.
· The potential consequences (on gene expression) of the different types of mutation (gain of functions, loss of function)
· The mutation nomenclature
· Examples of human diseases associated with a loss-of-function effect (Cystic Fibrosis and Haemoglobin disorders) and a gain of function effect (Achondroplasia)
The classification of tandemly repeated sequences
· Definition of the microsatellites and the mechanisms underlying to trinucleotide instability
· The concept of triplet repeat diseases and the correlation between earlier manifestations of clinical symptoms ('anticipation') and molecular pattern
· The common features of triplet repeat expansion diseases (germline instability, anticipation, parental origin of disease allele)
· The classification of diseases due to unstable repeat expansions (class 1, 2 and 3)
· The Polyglutamine diseases: Huntington's Disease (clinical features, and molecular pathogenesis)
· The Fragile X Syndrome (Clinical Features, Sherman Paradox, molecular pathogenesis)
· The FXTAS and the RNA gain-of-function model
· The Myotonic dystrophy (DM) (clinical features and molecular pathogenesis)

Population genetics: definition of population, gene pool, allele frequencies and genotype frequencies
· The Hardy-Weinberg law (HWL) of allelic and genotypic frequencies and the Hardy-Weinberg equilibrium (HWE)
· Calculation of the allele and/or genotypic frequencies of genes of interest in human genetics, by applying the HWL
· The factors (inbreeding, genetic drift, mutation, migration, selection) affecting the HWE and alter allele frequencies
· The multifactorial inheritance
· The Polygenic Traits and Variation in Phenotype
· The Additive Model for Polygenic Inheritance
· The Complex disorders and the threshold model
· The concept of Heritability to measure the genetic contribution to phenotypic variation
· The models to study the complex disorders
· The genetic mapping of Monogenic Traits: Linkage analysis, Genetic markers and Recombination
· The Two-point Mapping, Multipoint Mapping: the LOD scores, Linkage Disequilibrium and Haplotype Analysis
· The Mapping of Complex Traits by Non-Parametric Linkage Analysis and Association Studies.

During the module:
· Small groups activities:to help students to understand the genetic basis of various disorders and to participate in the complexities of choosing among the alternatives pattern of inheritance and to determine the probability of an affected offspring for a given cross
· 2 PBLs: The clinical manifestations of a common mendelian diseases: investigations of family

The cell cycle, the stages of mitosis and meiosis, and the significance of each.
· The difference between genome inheritance in somatic cells (Mitosis) and gametes (Meiosis).
· The haploid and diploid chromosome content during meiosis and mitosis.
· The importance the recombination and crossing-over events.
· The basic structure and function of chromosomes, the karyotype and how they relate to medicine.
· The methods for the chromosome identification: the chromosomal banding
· Chromosomal polymorphism
· Numerical chromosomal abnormalities: polyploidies and the causative mechanisms
· Numerical chromosomal abnormalities: aneuploidy involving autosomes and sex chromosomes, the causative mechanisms in a context of a constitutional and mosaic condition.
· Chromosomal abnormalities as cause of pregnancy loss
· Clinical cytogenetics: Down syndrome, Edwards syndrome, Patau syndrome; the origin of aneuploidy, maternal age, risk of occurrence and recurrence
· Clinical cytogenetics: Turner syndrome and Klinefelter syndrome
· Structural chromosomal anomalies: the effect of a balanced (translocations, inversions, insertions) and an unbalanced condition (deletions, duplications, isochromosomes ring chromosomes)
· Clinical indications for chromosome analysis in postnatal age.
· Genomic disorders: segmental duplications and recurrent rearrangements
· Comparison between the different techniques able to detect chromosomal abnormalities: classical karyotyping, FISH -Fluorescence in Situ Hybridization- and aCGH -Comparative Genomic Hybridization arrays. From "phenotype-first" to "genotype-first diagnosis
· Prenatal tests: methods for prenatal screening and prenatal diagnosis: invasive and non invasive testing. Indications for prenatal diagnosis by invasive testing.
· The recurrence risks in pregnancy for the principal types of cytogenetic abnormality (trisomies and translocations).
· The genetics of sex determination: the importance of the SRY gene in male sex differentiation, the male and female specific programmes
· Disorders of sex development related to genetic defects: Swyer syndrome, the androgen insensitivity syndromes (AIS), Adrenogenital syndrome
· Chromosome X versus chromosome Y
· How male and female compensate X-linked gene dosage and when it occurs
· The X inactivation control (XIC) region identification
· The mechanism leading to X-linked gene silencing related to XIST
· The difference between random and preferential inactivation.
· The concept that a number of X-linked genes escape X inactivation process and the relationship with Turner syndrome.
· X-chromosome inactivation and phenotype in carriers of X-linked disorders
· The imprinted genes and meaning of imprinting in mammals
· The evidences of genome imprinting
· The imprinting establishment: differential methylation of the parental allele, the imprinted gene clusters and the epigenetic mechanisms leading to silencing of the imprinted allele
· The chromosomal mechanisms leading to UPD and the phenotypic effect in humans
· Defects of genomic imprinting, Uniparental disomies (UPD) and imprinting diseases: PraderWilli/Angelman syndromes and Silver Russell/Beckwith-Weidemann syndromes
· The main classes of gene testing and methods to perform them.
· The importance of genetic counselling in genetic testing procedures
· The main applications of gene testing: carrier screening, pre-symptomatic testing for predicting adult-onset disorders such as Huntington's disease, diagnosis confirmation of a symptomatic individual.
· Gene testing: direct analysis and gene tracking


During the module, within asynchronous learning:

· The teaching staff will provide material for karyotyping: metaphases images from individuals carrying chromosomal abnormalities that will be karyotyped by separating individual chromosomes and arranging them systematically for examination.