Genes And Proteins Flashcards
Clinical use of bio markers
Diagnosis, prediction of drug response, treatment response, disease progression, prognosis.
Translational research
Applying basic research to a clinical setting, e.g., many labs around the globe are currently researching SARS-COV2, selective targeting of cancer cells (antibody-drug conjugate therapy, TNF and IL-1 inhibitors)
TNF
Tumour necrosis factors: 1. Cytokine involved in inflammation 2. Primarily generated in macrophages 3. Binds to the cell surface receptors TNFR1 and TNRR2 4. This molecular pathway initiates inflammation Mutations in the TNFRSF1A gene can lead to unprovoked inflammation. TNFR1-associated periodic (TRAPS). Use of anti-TNF therapy. Anti-TNF biological therapies are used for rheumatoid arthritis, anklyosing spondylitis, psoriasis, Crohn’s disease, and ulcerative colitis.
IL-1
Interleukin-1 1. Cytokine involved in inflammation. 2. Primary generated in macrophages but also endothelial and epithelial cells. 3. Binds to the cell surface receptor IL-1 receptor type 1 (IL-1RI). 4. This molecular pathways initiates inflammation. Common diseases: Still’s disease Schnitzler syndrome, hidradenitis suppurative, gout, T2DM. Treatment options: use of IL-1 blockade 1. Anti IL1R1 2. Recombinant IL-1 receptors antagonist
Stratified medicine
We identify subgroups of a population with exhibit distinct characteristics of disease (or a treatment response). All Breast Cancers: 1. PR+, ER+, 65-75% 2. HER2+, 15-20% 3. Triple Negative 15%
Personalised medicine
Cancer patients-> tumour -> sequencing -> analysis, modelling -> different personalised drugs for each individual patient A tailor made clinical model whereby therapy is delivered on an individualised basis. Broadly interchangeable with stratified medicine but can be taken to a greater depth.
Gene therapy
Replace a defective gene with a functional one. Enhancements include the use of retro viral elements. Alternates include the use of protocols such as CRISPR.
Homeostasis
The regulation of the state of cells and of the body. Normally about maintaining something at a particular desired level or set point.
Positive feedback (homeostasis)
Increased uterine excitability ->uterine contraction -> foetus presses on cervix -> Oxytocin secreted -> uterine contractions -> foetus presses on cervix -> oxytocin secreted -> goes in a loop.
Negative feedback (homeostasis)
Body temperature set point controlled by the hypothalamus: positive feedback: hypothalamus detected high core temperature,vasoconstriction, piloerection, shivering. Negative feedback: vasodilation, sweating, thirst, hypothalamus detects low core temperature. Blood glucose levels controlled by the pancreas :positive feedback: promotes glucose production and release and pancreatic B cells detect this and secrete insulin. Negative feedback: promotes glucose uptake in responsive cells, pancreatic alpha cells detect this and secrete glucagon.
Fluid in the body Total body fluid percent and volume Intracellular and extracellular body fluid percent and volume.
- Water is the critical biological solvent. 2. Solutes are what is dissolved in the body Total body fluid = 42L Intracellular = 28L 66.7% of body fluid Extracellular = 14L 33.3% of body fluid
Examples of ions in the body
Cations such as 1. sodium (12mM in the cytosol and 145mM in the blood 2. Potassium (139mM in the cytosol and 4mM in the blood) 3. Calcium (<0.0002mM in the cytosol and 1.8mM in the blood) Anions such as 1. Hydroxide 2. Chloride (4mM in the cytosol and 116mM in the blood 3. Bicarbonate (12mM in the cytosol and 29mM in the blood) Non-ionic solutes e.g., glucose, H2O and most proteins Amino Acids: 138mM in the cytosol and 9mM in the blood
How do ions drive cell function
- Ions directly result in changes to cellular function. 2. E.g., free calcium activates enzymes 3. Normally present at very low levels in the cytoskeleton 4. Many enzymes or proteins that are activated by increased intracellular calcium 5. Can drive dramatic changes in the cell
Channel transport proteins
Open and close and let a specific ion flow down a concentration gradient
Transporter proteins
Couples the transport of to different molecules with at least one going down a concentration gradient.
Exchanger proteins
Two molecules move in opposite directions
Facilitated diffusion
Works with the gradient, No energy required, Requires a membrane protein, Specific
What are results of an imbalance in ion function
Cardiac Arrhythmias, nervous tics, seizures, oedema,bone deformities.
pH in the body
The concentration of protons (H+)
Carbonic anhydride
Catalysed the reversible reaction that creates carbonic acid: H2O + CO2 H2CO3 Reaction goes forward where CO2 is high (e.g., active muscle) Reaction goes backward where CO2 is low (e.g., lungs)
Voltage in the body
- Voltage is the difference in potential energy between 2 points in an electrical field. 2. Biologically relevant voltages and currents are a consequence of membrane properties and ion concentrations. 3. Cell membranes not normally permeable to charged ions. 4. Ions moved by various active and passive processes. 5. K+ forms the majority of cations inside the cell and Na+ forms the majority outside the cell.
Electrical vs chemical force
The chemical force (diffusion also force) • Is based upon the difference in concentration ACROSS the membrane. The electrical force: • This is based on Vm, where a few positive charges are not paired with negative charges on the same side of the membrane.
Action potential
When at rest, Vm = Vrest=RMP Vm is based on the balance between positive and negative charged across the membrane. Significant changes in VM can be produced by the movement of only a tiny number of ions.
Excitable and non-excitable cells
Excitable cells can produce or respond to electrical signals, can also propagate action potentials.e.g., neurons, skeletal muscle cells, smooth muscle cells, cardiac myocytes. Non-excitable: everything else.
Differences between prokaryotes and eukaryotes
- Size Pro: 2mcm Euk: 10-100mcm 2. Amount of DNA: Pro: 1.36mm Euk: 990mm 3. No of genes: Pro:4377 Euk: 30-38000 4. DNA organisation: Pro:1 circular chromosome in nucleoid Euk: 2 or more chromosomes in membrane bound nucleus. 4. Organelles: none in Pro, Extensive and specialised in Euk.
The plasma membrane
A phospholipid bilayer. Hydrophilic phosphate head groups orientate toward the aqueous internal/external environments. Hydrophobic lipid tails orientate towards each other. One of the most common lipids in the PM is phosphatidylcholine. Cholesterol alters the fluidity of the plasma membrane. Selective permeability of the plasma membrane: gases and ethanol are permeable and some uncharged polar molecules is slightly permeable. Large uncharged polar molecules, ions, charged polar molecules are impermeable.
Endoplasmic reticulum
Rough: studded with ribosome (rough appearance) Smooth ER: site of fatty acid and phospholipid synthesis
Golgi apparatus
Golgi sorts proteins and lipids so that they end up at their correct cellular destinations by recognising tags encoded within the protein. Golgi has 3 defined regions: -cis (same) -medial (middle) -trans (away) Site of post-translational modifications
The lysosome
Contains a battery of degradative enzymes.Acidic=pH5 Help to break down to complex molecules into their component parts.
Peroxisome
Contain enzymes that break down fatty acids and amino acids and as a by product generate hydrogen peroxide (H2O2). This potentially damaging chemical is neutralised by large amounts of catalase within the peroxisome. Many peroxisomes contain a crystalline array of catalase.
The mitochondrian
Completes the aerobic degradation of glucose. Most eukaryotic cells contain many mitochrondria. Contains a double membrane: Inner- impermeable and has a large number of folding called cristae. Outer- permeable due to presence of poring (proteins that allow the passage of small molecules.
Cytoskeleton
-involved in processes such as mitosis -acts as a highway for intracellular vesicles -provides support to the plasma membrane -enables cellular locomotion -controls the shape of the cell
Actin
A dynamic filament that assembles at the minus and plus ends. Interaction with myosin generates muscle contraction. Cellular motion utilises actin
Intermediate filaments
Keratin, vimentin, lamins (nucleus), neurofilament proteins.
Microtubules
-long tube-like structures composed of alpha and beta tubulin -utilised as a transport medium, for structural motility, and cell division -they are dynamic structures that are regulated by numerous binding partners.
Stem cells
-they can divide indefinitely -are not terminally differentiated -daughters have a choice:differentiate or remain a stem cell
DNA structure
DNA is a nucleotide polymer made of four different nucleotides with sugar phosphate group based on covalent bonds and pentose sugar. The nitrogenous bases include thymine or uracil, cytosine, guanine and adenine Replication can proceed in the 5’ to 3’ direction.
DNA packaging
• Chromatin (DNA and associated proteins) is mostly compact, with euchromatin about compacted c.1000 fold and heterochromatin (and metaphase chromosomes) compacted c.10000 fold • Fundamental subunit is the nucleoside, comprising 8 histories wrapped with c.200bp of DNA • Nucleosomes form a ‘bead-on-a-string’ fibre ~10nm in diameter. These are further coiled into fibres and loops.
DNA replication
- The ds DNA starts to unwind and open. 2. Small, single stranded, pieces of RNA bind to the unwound DNA. 3. 5’ to 3’ DNA synthesis starts on both of the DNA strands. 4. DNA synthesis on the other strand requires further primer binding and is therefore discontinuous.
Cell cycle checkpoints
G1: unfavourable environment, DNA damaged M-> G1: chromosomes not attached to mitosis spindle G2, S: DNA damaged or incompletely replicated Controlled by cyclins and protein kinases Chemotherapy targets S and M phases.
Mitosis
One parents nucleus gives rise to two daughter nuclei, genetically identical to each other and to parent nucleus. 1. Prophase: chromosomes start to condense, mitotic spindle begins to form, the nucleolus disintegrates 2. Metaphase: spindle captures chromosomes, all the chromosomes align at the metaphase plate, two kinetichores of each chromosome should be attached to microtubules from opposite spindle poles. 3. Anaphase: the sister chromatids separate and pulled towards opposite end of the cells, microtubules not attached to the chromosomes elongate and push apart separating the poles and making the cell longer. 4. Telophase: the mitotic spindle is broken own into building blocks, two new nuclei form, chromosomes decondense.
Channel proteins
Open and close and let a specific ion flow down a concentration gradient
Prokaryotes vs Eukaryotes
Different kinds of RNA Polymerase
Points of control in gene expression
