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Question 1

1. Describe the four phases of the mitotic cell cycle and the steps involved leading to replication and cytokinesis.

Answer 1

The four phases of the mitotic cell cycle are:
a. G1 Phase: Cell growth occurs, and the cell prepares for DNA replication.
b. S Phase: DNA replication takes place, resulting in the duplication of genetic material.
c. G2 Phase: Further cell growth and preparation for mitosis occur.
d. M Phase: Mitosis occurs, including prophase, metaphase, anaphase, and telophase, leading to the division of the cell into two daughter cells through cytokinesis.

Question 2

Describe the key kinases, cyclins, and mitogens that are involved with these steps and at which stages of the cell cycle.

Answer 2

Key kinases, cyclins, and mitogens involved in the cell cycle:
a. Kinases: CDK (Cyclin-Dependent Kinases) are activated by cyclins at specific stages. For example, CDK4 and CDK6 in G1 phase, CDK2 in S phase, and CDK1 in G2 and M phases.
b. Cyclins: Cyclin proteins bind to CDKs, activating them at specific points in the cell cycle. Examples include Cyclin D in G1 phase, Cyclin E in G1/S transition, Cyclin A in S and G2 phases, and Cyclin B in G2 and M phases.
c. Mitogens: External signals such as growth factors stimulate cell division. Examples include growth factors like EGF (Epidermal Growth Factor) and PDGF (Platelet-Derived Growth Factor).

Question 3

Outline the components responsible for degrading cyclins and inhibiting cyclin-dependent kinases.

Answer 3

Components responsible for cyclin degradation and CDK inhibition:
a. APC/C (Anaphase-Promoting Complex/Cyclosome): Degrades cyclins at the end of metaphase and during anaphase.
b. CKIs (Cyclin-Dependent Kinase Inhibitors): Proteins like p21 and p27 inhibit CDK activity, regulating the cell cycle progression.

Question 4

Identify one example of where defective cell cycle can cause stress or disease

Answer 4

Example of defective cell cycle causing stress or disease:
Defects in cell cycle regulation can lead to uncontrolled cell proliferation, resulting in cancer. For instance, mutations in genes encoding for cyclins, CDKs, or their regulators can disrupt the balance of cell cycle control, leading to abnormal cell growth and tumor formation.

Question 5

Outline examples of internal and external stressors that can cause DNA damage.

Answer 5

Internal stressors causing DNA damage:

Reactive oxygen species (ROS) generated during normal cellular metabolism.
Errors during DNA replication.
Spontaneous chemical reactions within cells.
External stressors causing DNA damage:

UV radiation from the sun.
Ionizing radiation from sources like X-rays and radioactive materials.
Environmental toxins such as pollutants and carcinogens.

Question 6

Compare the differences between DNA damage and DNA mutation.

Answer 6

DNA damage vs. DNA mutation:

DNA damage refers to alterations in the structure of DNA, such as strand breaks or chemical modifications, that can interfere with normal cellular processes.
DNA mutation, on the other hand, involves changes in the nucleotide sequence of DNA, which can result from DNA damage or errors during DNA replication.

Question 7

Describe the key features of the different DNA repair mechanisms and global responses to DNA damage (checkpoints) and the procedural steps.

Answer 7

Key features of DNA repair mechanisms and checkpoints:

DNA repair mechanisms include:
Base Excision Repair (BER): Corrects single base lesions.
Nucleotide Excision Repair (NER): Fixes bulky lesions like those caused by UV radiation.
Mismatch Repair (MMR): Corrects errors made during DNA replication.
Homologous Recombination (HR) and Non-Homologous End Joining (NHEJ): Repair double-strand breaks.
Checkpoints: Control points in the cell cycle that monitor DNA integrity before progression to the next phase.
G1/S Checkpoint: Checks DNA integrity before DNA replication.
G2/M Checkpoint: Ensures DNA is undamaged before mitosis.
Spindle Assembly Checkpoint: Monitors chromosome attachment to spindle fibers during mitosis.

Question 8

Describe the DNA damage response in disease (eg in cancer).

Answer 8

DNA damage response in disease, such as cancer:

In cancer, defects in DNA repair mechanisms can lead to genomic instability and accumulation of mutations, contributing to tumor development.
Dysregulation of cell cycle checkpoints allows damaged cells to continue dividing, promoting tumor growth.
Cancer cells may exploit DNA repair pathways for survival and resistance to therapy, making them resistant to treatments like chemotherapy and radiation.

Question 9

Examine the roles of key signalling pathways in cell growth, differentiation and survival

Answer 9

Key signaling pathways in cell growth, differentiation, and survival:

MAPK (Mitogen-Activated Protein Kinase) pathway: Regulates cell proliferation and survival in response to external signals.
PI3K/Akt/mTOR pathway: Controls cell growth, metabolism, and survival.
Wnt signaling pathway: Involved in cell fate determination and tissue development.
Notch signaling pathway: Regulates cell differentiation and development.
JAK/STAT pathway: Mediates responses to cytokines and growth factors, influencing cell proliferation and differentiation.

Question 10

Appraise the effects of signalling pathway deregulation in cancer

Answer 10

Deregulation of signaling pathways can lead to uncontrolled cell growth and proliferation, characteristic of cancer.
Mutations or aberrant activation of oncogenes within these pathways can drive tumorigenesis.
Inactivation of tumor suppressor genes that normally inhibit these pathways can also contribute to cancer development.
Dysregulated signaling pathways can confer resistance to apoptosis (programmed cell death) and promote metastasis.

Question 11

Describe the phenomenon of oncogene addiction and rationale as a therapeutic target

Answer 11

Oncogene addiction refers to cancer cells’ dependence on the continuous activity of specific oncogenes for survival and proliferation.
Targeting these oncogenes with therapeutic agents can selectively kill cancer cells while sparing normal cells, minimizing side effects.
Examples include targeted therapies that inhibit specific kinases or molecules within aberrantly activated signaling pathways.
Rationale: By targeting the specific molecular drivers of cancer, oncogene-targeted therapies can be highly effective and less toxic than traditional chemotherapy.

Question 12

Assess the efficacy of current therapies targeting oncogenic signalling pathways

Answer 12

Targeted therapies have shown significant efficacy in certain cancers with specific molecular alterations.
Examples include inhibitors of EGFR (Epidermal Growth Factor Receptor) in lung cancer and BRAF inhibitors in melanoma.
However, resistance to targeted therapies often develops due to secondary mutations or activation of alternative pathways.
Combination therapies targeting multiple pathways or resistance mechanisms are being developed to overcome this challenge and improve treatment outcomes.

Question 13

Compare and contrast between types of cell death.

Answer 13

Apoptosis: Programmed cell death that occurs in a controlled manner, involving cellular shrinkage, chromatin condensation, and DNA fragmentation.
Necrosis: Uncontrolled cell death typically due to external factors like injury or infection, leading to cellular swelling, organelle damage, and inflammation.
Autophagy: Cellular self-degradation process where damaged organelles and proteins are engulfed by autophagosomes and degraded in lysosomes.

Question 14

Understandthepurposeofapoptosis.

Answer 14

Apoptosis serves as a mechanism to remove unwanted or damaged cells from the body in a controlled manner.
It plays crucial roles in tissue development, homeostasis, and the elimination of potentially harmful cells, such as those with DNA damage or infections.

Question 15

Explaintheintrinsicandextrinsicpathwaysofapoptosis,andtheir converging pathways.

Answer 15

Intrinsic pathway: Triggered by internal cellular stressors like DNA damage or cellular damage. It involves the release of cytochrome c from mitochondria, activating caspases and leading to apoptosis.
Extrinsic pathway: Initiated by external signals such as cytokines binding to death receptors on the cell surface. This activates caspases directly, leading to apoptosis.
Converging pathways: Both pathways ultimately activate caspases, which execute the apoptotic process by cleaving various cellular substrates.

Question 16

Understandtheroleofkeymoleculeswithintheapoptosispathways.

Answer 16

Bcl-2 family proteins: Regulate mitochondrial outer membrane permeabilization (MOMP) and control the intrinsic pathway. Anti-apoptotic proteins like Bcl-2 inhibit apoptosis, while pro-apoptotic proteins like Bax promote it.
Caspases: Proteases that execute apoptosis by cleaving specific cellular proteins. Initiator caspases (e.g., caspase-8, -9) initiate the process, while executioner caspases (e.g., caspase-3, -7) carry out the cell death program.

Question 17

Describethemorphologicalandbiochemicalhallmarksofapoptosis.

Answer 17

Morphological: Cell shrinkage, chromatin condensation, nuclear fragmentation (pyknosis), and formation of apoptotic bodies.
Biochemical: Activation of caspases, cleavage of specific cellular substrates (e.g., PARP), exposure of phosphatidylserine on the cell membrane, and DNA fragmentation.

Question 18

Understandtheextracellularsurvivalfactors.

Answer 18

Extracellular survival factors are external signals that promote cell survival and inhibit apoptosis.
Examples include growth factors (e.g., EGF, PDGF), cytokines, and cell-cell interactions.
These factors activate intracellular signaling pathways (e.g., PI3K/Akt pathway) to inhibit pro-apoptotic signals and promote cell survival.

Question 19

Understandhowtheapoptoticcellsareremoved.

Answer 19

Apoptotic cells are removed by phagocytic cells, primarily macrophages and neighboring healthy cells.
Phagocytic cells recognize apoptotic cells through exposure of “eat me” signals such as phosphatidylserine on the cell surface.
The phagocytes engulf the apoptotic cells, leading to their degradation and clearance from the tissue.

Question 20

Understandwhatassaysareavailablefordetectingapoptosis.

Answer 20

TUNEL assay: Detects DNA fragmentation, a hallmark of apoptosis, using terminal deoxynucleotidyl transferase (TdT) to label DNA strand breaks.
Annexin V assay: Detects phosphatidylserine exposure on the outer membrane of apoptotic cells using fluorescently labeled annexin V.
Caspase activation assays: Measure the activity of caspases, key enzymes in the apoptotic pathway, using fluorescent substrates or immunoblotting.

Question 21

Understandtheconsequencesofpathologicalapoptosis.

Answer 21

Excessive apoptosis can lead to tissue degeneration, organ dysfunction, and diseases such as neurodegenerative disorders.
Insufficient apoptosis can result in the accumulation of damaged or abnormal cells, contributing to cancer development or autoimmune diseases.
Dysregulation of apoptosis can also affect embryonic development, immune response, and tissue homeostasis, leading to various pathological conditions.

Question 22

Explain the process of mRNA transcription and the components responsible for splicing.

Answer 22

Transcription occurs in the nucleus, where RNA polymerase binds to the DNA template and synthesizes mRNA.
During transcription initiation, RNA polymerase recognizes and binds to the promoter region of the gene.
Elongation follows, where RNA polymerase moves along the DNA template, synthesizing a complementary mRNA strand.
Termination occurs when RNA polymerase reaches the terminator sequence, leading to mRNA release.
Splicing removes introns from pre-mRNA and joins exons to form mature mRNA.
Components involved in splicing include spliceosomes (composed of snRNPs) and splice sites (5’ splice site, branch point, and 3’ splice site).

Question 23

Outline the processes involved in cytoplasmic post-transcriptional gene control

Answer 23

mRNA export: Mature mRNA is exported from the nucleus to the cytoplasm through nuclear pores.
mRNA stability: Regulatory factors control the stability of mRNA molecules, determining their lifespan in the cytoplasm.
Translation regulation: Processes such as mRNA localization, translational repression, and RNA interference control protein synthesis from mRNA transcripts.

Question 24

Describe the role of non-coding RNA, ribonucleoprotein complexes, and nuclear bodies in post-transcription and its relevance to cellular homeostasis.

Answer 24

Role of non-coding RNA, ribonucleoprotein complexes, and nuclear bodies in post-transcription and cellular homeostasis:

Non-coding RNA molecules, such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), regulate gene expression at the post-transcriptional level.
Ribonucleoprotein complexes, such as ribosomes, facilitate translation of mRNA into proteins.
Nuclear bodies, like Cajal bodies and P-bodies, play roles in RNA processing, storage, and degradation, contributing to cellular homeostasis.

Question 25

Describe how dysfunctions to transcription and translation can impact cellular processes that lead to disease.

Answer 25

Dysregulation of transcription and translation can lead to aberrant gene expression, resulting in diseases such as cancer, neurodegenerative disorders, and metabolic diseases.
Mutations in transcription factors, RNA processing machinery, or ribosomal components can disrupt gene expression, leading to cellular dysfunction and disease progression.
Imbalances in non-coding RNA expression or function can disrupt regulatory networks, contributing to disease states.
Therapeutic strategies targeting transcriptional and translational processes are being developed to treat diseases caused by dysfunctions in these pathways.

Question 26

Outline the different metabolic substrates and biochemical processes

Answer 26

Carbohydrates: Broken down into glucose through glycolysis for energy production.
Lipids: Metabolized through beta-oxidation to produce acetyl-CoA for the citric acid cycle and ATP synthesis.
Proteins: Degraded into amino acids for energy production or protein synthesis.
Nucleic acids: Broken down into nucleotides for nucleic acid synthesis or energy production.

Question 27

Describe the role of chaperones, heat shock proteins and the unfolded protein response in synthesising proteins

Answer 27

Chaperones: Assist in protein folding and prevent misfolding or aggregation of newly synthesized proteins.
Heat shock proteins: Specialized chaperones induced by cellular stress to help refold or degrade damaged proteins.
Unfolded Protein Response (UPR): Cellular response to unfolded or misfolded proteins in the endoplasmic reticulum (ER), aimed at restoring ER homeostasis by increasing chaperone expression and reducing protein synthesis.

Question 28

Describe the two main protein degradation pathways

Answer 28

Ubiquitin-Proteasome System: Targets proteins for degradation by tagging them with ubiquitin molecules, followed by proteasomal degradation.
Autophagy-Lysosome Pathway: Degrades cellular components, including proteins, organelles, and macromolecules, by sequestering them into autophagosomes and fusing them with lysosomes for degradation.

Question 29

Describe the importance of lysosomes in degrading extracellular and intracellular contents

Answer 29

Lysosomes contain hydrolytic enzymes that break down proteins, lipids, carbohydrates, and nucleic acids into smaller molecules.
Lysosomes play a crucial role in degrading extracellular material taken up by endocytosis and intracellular material through autophagy.
Dysfunction of lysosomal enzymes or impairment of lysosomal function can lead to lysosomal storage disorders and other diseases.

Question 30

Outline the mechanisms of ER-GA transport following protein synthesis

Answer 30

Proteins synthesized on ribosomes attached to the ER membrane are translocated into the ER lumen.
These proteins are then modified, folded, and sorted in the ER before being transported to the Golgi apparatus.
Transport vesicles bud off from the ER and fuse with the Golgi apparatus, delivering the newly synthesized proteins for further processing and sorting.

Question 31

Explain how defective protein synthesis can lead to human disorders

Answer 31

Mutations in genes encoding for chaperones, heat shock proteins, or components of the protein degradation pathways can lead to protein misfolding, aggregation, and accumulation.
Dysfunctional protein synthesis can result in diseases such as Alzheimer’s disease, Parkinson’s disease, cystic fibrosis, and lysosomal storage disorders.
Impaired ER-Golgi transport can disrupt protein trafficking and secretion, leading to diseases like cystic fibrosis and familial hypercholesterolemia.

Question 32

Distinguish between specific models (e.g. in vitro vs in vivo) to study human disease

Answer 32

In vitro models: Use isolated cells or tissues cultured in a controlled environment outside of a living organism. They provide a simplified system for studying cellular processes and responses to drugs or treatments.
In vivo models: Involve studying diseases or treatments within a living organism, such as animal models (e.g., mice, rats) or human clinical studies. They allow for the investigation of complex interactions between different tissues and organs, as well as the evaluation of systemic effects.

Question 33

Develop an understanding of and be able to discuss the principles of validating a model for its intended application

Answer 33

Reproducibility: Ensuring consistent results are obtained when the experiment is repeated.
Predictive validity: Demonstrating that the model accurately predicts outcomes observed in human disease.
Face validity: Ensuring the model displays relevant characteristics or symptoms of the disease being studied.
Construct validity: Confirming that the model reflects the underlying biological mechanisms of the disease.
Ethical considerations: Ensuring that the use of the model complies with ethical guidelines and regulations.

Question 34

Correlate knowledge of the use of different models to design a project or set of experiments

Answer 34

Choose the most appropriate model based on the research question, resources, and ethical considerations.
Consider the advantages and limitations of each model in terms of relevance, complexity, cost, and feasibility.
Design experiments that leverage the strengths of the chosen model to address specific hypotheses or objectives.
Validate the chosen model through rigorous testing and comparison with established standards or known outcomes.
Interpret the results within the context of the chosen model and consider how they may translate to human disease or clinical applications.

Question 35

Describe the role of the mitochondrion and mitochondrial dynamics

Answer 35

Mitochondria are organelles responsible for generating energy in the form of ATP through oxidative phosphorylation.
Mitochondrial dynamics refer to the processes of fusion, fission, and movement of mitochondria within cells, which are essential for maintaining mitochondrial function, distribution, and quality control.

Question 36

Distinguish between the mechanisms of mitochondrial fusion and mitochondrial fission in the context of human disease

Answer 36

Fusion: Mitochondrial fusion involves the merging of mitochondria to maintain mitochondrial network integrity and facilitate exchange of contents, including DNA and proteins. Dysregulation of fusion can lead to mitochondrial dysfunction and contribute to neurodegenerative diseases like Alzheimer’s and Parkinson’s.
Fission: Mitochondrial fission is the process of dividing mitochondria into smaller fragments, which is important for mitochondrial distribution, quality control, and apoptosis regulation. Abnormal fission can lead to excessive fragmentation and contribute to diseases such as cancer, cardiovascular diseases, and neurodegenerative disorders.

Question 37

Examine the role of mitophagy and summarise the main proteins involved in this pathway

Answer 37

Mitophagy is a selective form of autophagy that targets damaged or dysfunctional mitochondria for degradation.
Key proteins involved in mitophagy include PINK1 (PTEN-induced kinase 1), Parkin, and mitophagy receptors such as FUNDC1, BNIP3, and NIX.
These proteins work together to identify damaged mitochondria, tag them with ubiquitin, and target them for degradation by autophagosomes.

Question 38

Explain how diseases can affect mitochondrial dynamics and overall cell health

Answer 38

Dysfunctional mitochondrial dynamics, including impaired fusion, fission, and mitophagy, are implicated in various diseases.
Disruption of mitochondrial dynamics can lead to mitochondrial dysfunction, oxidative stress, energy depletion, and accumulation of damaged mitochondria.
Diseases such as neurodegenerative disorders, cardiovascular diseases, metabolic disorders, and cancer are associated with defects in mitochondrial dynamics, leading to cellular dysfunction and disease progression.

Question 39

List the latest development of mitochondria-targeted antioxidant therapies in humans

Answer 39

Mitochondria-targeted antioxidants are designed to selectively deliver antioxidants to mitochondria, where they can neutralize reactive oxygen species (ROS) and protect against oxidative damage.
Examples of mitochondria-targeted antioxidants include MitoQ, MitoTEMPO, and SS-31.
These therapies are being investigated for their potential in treating various diseases associated with mitochondrial dysfunction and oxidative stress, including neurodegenerative diseases, cardiovascular diseases, and metabolic disorders.

Question 40

List the approaches and workflows typically used for discovery science * Genome-Wide Screen (GWAS), Metabolomics, Proteomics, Transcriptomics, Cell Biology, Biochemical studies

Answer 40

Genome-Wide Screen (GWAS): Identifies genetic variations associated with diseases.
Metabolomics: Analyzes metabolites to understand metabolic pathways and disease mechanisms.
Proteomics: Studies proteins to identify biomarkers or therapeutic targets.
Transcriptomics: Analyzes gene expression patterns to understand disease mechanisms.
Cell Biology: Studies cellular processes and interactions relevant to disease.
Biochemical studies: Investigate molecular mechanisms underlying diseases.

Question 41

Explain the steps required from the early discovery of target
identification to approval of a therapy

Answer 41

Target Identification: Identify molecular targets involved in disease pathogenesis.
Lead Discovery and Optimization: Screen compounds or molecules to find potential drugs and optimize their efficacy and safety.
Pre-clinical Models: Test candidate drugs in cell cultures or animal models to evaluate efficacy, safety, and pharmacokinetics.
Clinical Trials: Conduct phases I-III clinical trials to evaluate safety and efficacy in humans.
Regulatory Approval: Submit data to regulatory agencies for approval of the therapy.
Post-market Surveillance: Monitor therapy efficacy and safety in real-world settings.

Question 42

Describe a medical example and scientific concepts of how a basic
discovery has led to a marketable therapy.

Answer 42

Spinal Muscular Atrophy (SMA) and Spinraza: Basic research identified the SMN1 gene mutation as the cause of SMA. Spinraza, an antisense oligonucleotide therapy, was developed to increase SMN protein production, leading to improved muscle function and survival in SMA patients.

Question 43

Outline the characteristics of how to develop an ideal therapy to be
administered for patients

Answer 43

Characteristics of an ideal therapy:

Effective: Demonstrates significant clinical benefit in treating the targeted disease.
Safe: Has minimal side effects or adverse reactions.
Specific: Targets the underlying cause of the disease with high selectivity.
Durable: Provides long-lasting therapeutic effects with minimal need for repeat administration.
Pharmacokinetics and Pharmacodynamics (PK/PD) and ADME:

PK/PD: Studies the absorption, distribution, metabolism, and excretion of drugs, as well as their pharmacological effects.
ADME: Evaluates the absorption, distribution, metabolism, and excretion properties of drugs to assess their pharmacokinetic profile.
Types of therapy and delivery systems:

Inhibitor therapy: Targets specific molecules or pathways involved in disease progression.
Gene therapy: Introduces therapeutic genes into cells to correct genetic defects.
Delivery systems: Include viruses, nanoparticles, liposomes, etc., to transport drugs or genetic material to target cells.