Neurology Flashcards
Define ‘sustained threat’
An aversive emotional state caused by prolonged (i.e., weeks to months) exposure to internal and/or external condition(s), state(s), or stimuli that are adaptive to escape or avoid.
Define ‘pathophysiology’
The disordered physiological processes associated with disease or injury.
Define ‘allostatic load’
“the wear and tear on the body” which accumulates as an individual is exposed to repeated or chronic stress.
Define ‘functional connectivity’
the temporal coincidence of spatially distant neurophysiological events
Are placebos efficacious in the treatment of GAD?
The meta-trial says no
Are placebos ethical in the treatment of GAD?
Nocebo:
link neurology to symptoms to definition
Describe the role of glutamate in ASCs
Different ratio of inhibition/excitation - synchronicity
Stats relating GAD and ASCs
- Roughly 40% have symptoms of at least one anxiety disorder at any time, compared with up to 15% in the general population
- anxiety disorders are the most common comorbid conditions in these patients
Define ‘pathogenesis’
the manner of development of a disease
Define neurodegeneration
progressive atrophy and loss of function of neurons
Describe postbiotic bacteriotherapies
target downstream signaling pathways of the microbiome and act by mitigating the negative effects of an excess, scarcity, or dysregulation of metabolites involved in these pathways
Describe propionate pharmacokinesis
Major component of SCFAs
Produced by Clostridia
How did Gertrude Elion prevent vertical HIV transmission
synthesised zidovudine, an antiretroviral nucleoside analogue of thymidine triphosphate, with the hydroxyl group replaced with an azide group - suppression of viral load
Describe the feats of Gertrude Elion
Synthesisinng antimetabolites such as diaminopurine and thioguanine (structural analogs of adenine and guanine) to prevent incorporation of these natural purines, on which bacterial DNA synthesis is dependent
Synthesised 6-mercaptopurine (by substituting an oxygen atom with a sulfur atom on a purine molecule)
Describe the work of Jane Cooke Wright
- research into folic acid antagonists as chemotherapeutics
- pioneered the biopsy
Describe the work of Flossie-Wong Stahl
Researched HIV gene therapy to achieve intracellular immunisation, pursued through HIV-based lentiviral vectors in cell cultures, with the aim of modifying both CD4 cells and red blood cells to have antiviral genes coding for immunotherapeutic features.
Genetic modification was done on hematopoietic stem cells using a hammerhead ribozyme in order to produce HIV-resistant cell progenies, to re-establish a functional immune system and control HIV replication.
Describe the work of Irene Curie
Bombarded elements with α-particles emitted from polonium - emission of positrons and radioisotope of phosphorus, nitrogen and silicon. β-decay overturned the Dalton atomic model of a solid sphere.
Describe the work of Chien Shiung-Wu
Used a cobalt-60 β-source polarized by the demagnetization method.” Using a sample of radioactive cobalt-60 (undergoes β-decay - replacing a neutron with a proton, electron and neutrino) cooled to cryogenic temperatures (needed to reduce thermal vibration of the atoms to almost zero). Constant and uniform magnetic field was applied so that the spin axes of the atomic nuclei lined up in the same direction. The β-particles were emitted asymmetrically along the nuclear spin and opposite to the spin, disproving the law of the conservation of parity for weak nuclear interactions (such as β-decay). This caused re-evaluation of previous assumptions, and developments in quantum theory - an integral step in the development of the Standard Model of particle physics used today.[47]
Describe venom
Cleave the sn-3-glycerophospholipids into fatty acids and lysophospholipids through hydrolysis of the sn-2 acyl ester linkage at the envelope, causing envelope degradation and RNA exposure
Describe termite microbiota
in the hindgut of Macrotermitinae, which host exosymbiotic Termitomyces fungus and gram-negative nitrogenase-positive endosymbiotic mutualistic diazotrophic γ-proteobacteria containing RSN-TKY17 and NKN19 niFh clusters
Describe oxidative stress
One of the types of change found in essentially all neurological degenerative diseases is the over-expression of oxidative free radical compounds that cause lipid, protein and genetic structural changes
Evidence of neurodegeneration in autism
1) significantly decreasing amount of Purkinje cells in the brain
2) neuronal cell loss,
3) activated microglia and astrocytes,
4) proinflammatory cytokines,
5) oxidative stress,
6) elevated 8-oxo-guanosine levels
8-oxo-guanosine
one of the most common DNA lesions resulting from reactive oxygen species modifying guanine
microglia
the resident macrophage cells, they act as the first and main form of active immune defense in the central nervous system (CNS).
astrocytes
a sub-type of glial cells in the central nervous system - envelop synapses
microglia
- the resident macrophage cells, they act as the first and main form of active immune defense in the central nervous system (CNS)
- maintain cerebral homeostasis
Describe the vicious cycle of oxidative stress
1) Oxidative stress causes damage to mtDNA
2) Damaged mtDNA leads to decrease in coding for proteins needed for electron transport chain
3) Decreased function of electron transport chain leads to decreased energy and increased free radicals (oxidative stress)
4) Increased oxidative stress causes damage to the cell membrane
5) Damage to the cell membrane leads to release of cytochrome C leading to apoptosis or cell death
6) Cell death leads to more oxidative stress
Describe microglial activation
- Rapid proliferation of microglial cells
- Migrate to site of infection
- M1 activated microglia: neurotoxic with release of pro-inflammatory cytokines
- Engulf dying cells, infectious agents, toxic proteins, and cell debris
List some pro-inflammatory cytokines
TNFalpha, IL-1B, IL-6, COX, Reactive oxygen species (ROS), Nitric oxide
M1 microglia
Responsible for inflammation
Functions of astrocytes
1) Induce formation of neuronal synapses
2) Formation and maintenance of BBB
3) Neurotransmission: component of tripartite synapse model
4) Homeostasis and turnover of glutamate
5) Metabolic regulation
6) Ion balance maintenance
7) Key role in development of the nervous system
Neuroinflammatory markers in ASCs
1) Microglial activation
2) Astrocytic activation with elevated levels of GFAP(glial fibrillary acidic protein)
3) Proinflammatory profile of cytokines in the brain, CSF and blood
4) Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation
Evidence of autoimmunity in autism
accumulation of T cells and astrocytes in postmortem brain tissue
brain blebs may be formed in response to the infiltration of T cells into the space between blood vessels and neural tissue, while the cell fragments they contain could come from the astrocytes that make up the glia limitans
Glia limitans
the final wall of defense separating neural tissue from foreign and toxic substances circulating in the blood
What is the BBB
The blood-brain barrier is a dynamic interface between the peripheral blood supply and the cerebral parenchyma, controlling the transport of material to and from the brain
BBB dysfunction in ASCs - specifics
Perturbation of these processes:
Tight junctions between the endothelial cells of the cerebral microvasculature limit the passage of large, negatively charged molecules via paracellular diffusion.
Transcellular transportation across the endothelial cell is controlled by a number of mechanisms including transporter proteins, endocytosis, and diffusion.
BBB dysfunction in ASCs - basics
Increased permeability of the BBB leading to increased infiltration of peripheral material into the brain culminating in neuroinflammation and oxidative stress.
Microglial role in development
- help to set up the circuits of the brain by strengthening appropriate cell-to-cell connections and by eliminating improper connections in the brain
- regulate the plasticity of brain cells and prune synapses
Gliosis
proliferation or hypertrophy of several different types of glial cells, including astrocytes, microglia, and oligodendrocytes
Clostridia metabolites:
3-(3-hydroxyphenl)-3-hydroxypropionic acid (HPHPA) and 4-cresol
Clostridia metabolite effect
inactivate dopamine beta-hydroxylase, which is needed for the conversion of dopamine to norepinephrine
Nocebo effect
‘symptoms related to the patient’s negative expectations not only in a clinical trial setting, but also in a routine care setting’
GAD - anticipation and neurovegetative signs
Pharmacokinetics
refers to the movement of drug into, through, and out of the body—the time course of its absorption, bioavailability, distribution, metabolism, and excretion.
viral load
the number of viral particles present in the bloodstream
Describe how zidovudine works
Retroviral RNA must undergo reverse transcription using RT (involving phosphorylation of thymidine to thymidine monophosphate). Zidovudine competitively inhibits thymidine phosphorylation through the high affinity of zidovudine 5-triphosphate (zidovudine’s active compound) to RT, catalysed by thymidine kinase 2. This decreases viral reproduction because subsequent nucleosides cannot bind to the azide group, causing latently infected cells to produce fewer viruses and therefore decreasing viral load.
How do retroviruses store their genetic info
Retroviruses store their genetic information as an RNA chain of nine genes, along with reverse transcriptase (RT) and integrase – synthesis of proviral complementary DNA for integration into the cell DNA for viral replication.
Describe folic acid antagonists
Cell-cycle specific - induce apoptosis by partially inhibiting the intracellular enzyme dihydrofolate reductase. This targets the uncontrolled high proliferation rate of cancerous cells that have had their contact inhibition mechanism disabled
Why are folic acids necessary
amino acid and purine production
Describe biopsy
culturing surgically excised tumour cells from in the body to a primary tissue
Describe ribozymes
Ribozymes are RNA molecules that have the ability to catalyze specific biochemical reactions, including RNA splicing in gene expression, similar to the action of protein enzymes
What is a hammerhead ribozyme?
The hammerhead ribozyme is an RNA motif that catalyzes reversible cleavage and ligation reactions at a specific site within an RNA molecule.
How did Wong-Stahl clone HIV?
study of intracisternal A-particles (endogenous retroviral sequences)
Describe CRISPR in nature
Immune response of bacteria and archaea - create CRISPR arrays, coded between repeat DNA sequences. This allows transcription of the CRISPR arrays into crRNA segments of one array and one repeat, to target and slice parasitic viral DNA using the Cas9 enzyme, disabling the virus.
What does CRISPR stand for?
‘clustered regularly interspaced short palindromic repeats and CRISPR-associated protein 9’
What are CRISPR arrays?
copies of parasitic viral DNA that enzymes have sliced and collected
Describe CRISPR in the lab
Guide RNA (with scaffolding complementary to the target DNA sequence) binds using two domains, making a double-stranded break in the DNA at the target location, allowing the insertion, deletion or substitution of genes with customizable DNA. Protospacer adjacent motifs must be present adjacent to the target DNA, breaking the hydrogen bonds to allow CRISPR’s function, preventing off-course cuts. She also solved the problem of unwanted mutations by filling the DNA break with a nucleotide sequence, using a short DNA template strand of her devising.
What is guide RNA?
a fusion of pre-designed RNA sequence, Cas9 enzyme and trans-activating crRNA (crispr array + repeat)
What are protospacer adjacent motifs?
short DNA sequences
What are positrons?
positively charged subatomic particles having the same mass and magnitude of charge as the electron - constituting the antiparticle of a negative electron
What were the ramifications of the Wu experiment?
1) Disproved the scientific assumption that parity is conserved in all interactions.
2) Solved the puzzle of the θ and τ K-mesons - τ decayed to three pions with a net parity of -1, whereas θ decayed to two pions with a net parity of +1.
What are θ and τ K-mesons?
sub-atomic particles with the same mass, spin and lifetime, but with different decay modes and resultant parity states
How do ribozymes work?
complementary to RNA and bind using hydrogen bonds, incorporating a sequence that cuts the target RNA, disabling it, or inserting a gene coding for prevention of growth.
Describe gamma tracers
radionuclides with a short half-life that emit positrons combine with electrons to emit two γ-rays, which are used in diagnosis and photographic medical radiology, and sterilising of medical equipment
Describe mustard agents
triethyl-enemelamine and thio-phosphoramide - antineoplastic agents; alkylating agents.
Describe alkylation
Alkylation is cell cycle non-specific (acts in interphase) and prevents mitosis by adding alkyl groups to guanine DNA bases, preventing hydrogen bonds from forming between polynucleotide chains.
Describe HIV action
1) Undergoes intracellular replication by infecting cells with CD4 surface receptors by attaching to their receptors using glycoprotein120 and another co-receptor (CCR5 or CXCR4) and fusing using glycoprotein41, allowing the capsid to enter the cell.
2) Hijacks cellular DNA by conversion and integration and replicates these proteins into particles through assembly, budding and maturation, sending them into the bloodstream.
3) Destruction of CD4 cells damages the humoural and cell mediated immune responses, and cripples the immune system, providing ideal conditions for ‘opportunistic infections’.
Describe HIV
lentiviral tumorigenic retrovirus
Cells with CD4 surface receptors
T-lymphocytes, monocytes, macrophages and dendritic cells
Conversion and integration
Changing genetic material so that a virus can enter and hijack the nucleus to replicate proteins
What are surface (E) proteins?
Allow bacteria to adhere to host cells and tissues, to invade non-phagocytic epithelial and endothelial cells, to form biofilm and to evade immune responses.
What are Vero cells?
A lineage of cells used in cell cultures. The ‘Vero’ lineage was isolated from kidney epithelial cells extracted from an African green monkey.
what is fungal isogamy?
when the gametes are morphologically similar. It is the opposite of anisogamous, which has a sexual dimorphism.
why is fungal isogamy relevant to queer theory?
To reproduce, fungi have ‘mating types’ - they produce morphologically similar gametes with the same investment in offspring. If investment of offspring (due to gametic size) is how we define sex, then fungi have a ‘continuum of compatibility types’ - there is no female-male dichotomy imposed by nature.
Resting state functional connectivity
delineates the functional architecture of intrinsically coupled brain networks
GAD pathophysiology - the basics:
- disrupted amygdala functional connectivity in subregions and with cortex and subcortical regions
- correlation between abnormal functional connectivity and disease severity
If you have higher state anxiety, you increase
trait anxiety, through increased functional coupling between amygdala and dorsolateral prefrontal cortex- it is a neural correlate
State anxiety
adaptive function
Trait anxiety:
personality type; risk factor
Amygdala subregions
- basolateral amygdala
- centromedial amygdala
Applications of research into GAD pathophysiology
- In clinal diagnosis and target treatment
- Identify GAD on a neuropathological basis
How to conduct a trial into GAD pathophysiology:
- Drug-naïve, non-comorbitity patients (reduces the generalisability in the clinical setting)
- age and sex matched healthy controls
How to make fMRI data valid:
- first 10 volumes removed to allow for signal equilibration effects
- ignore non-neuronal BOLD fluctuations
- spatial normalisation, spatial smoothing
- foam pads used to cancel noise
- don’t fall asleep!
Why study GAD?
It has a lower recognition rate and a higher degree of differentiation than other anxiety disorders
GAD pathophysiology - in detail:
- increased functional connectivity of the centromedial right amygdala with the insula - significant positive correlation with disease severity
- increased functional connectivity with the striatum extending to the parahippocampal gyrus – results in ‘all or nothing’ mentality and greater sensitivity to reward and punishment
- increased functional connectivity with cerebellum negatively correlated with disease severity as compensatory mechanism
amygdala-insula functional connectivity
a biological marker of anxiety
The insula could receive signals of
discomfort from the body, and then integrate the signals and send the discomfort information to the amygdala, resulting in air hunger
How did I test GAD pathophysiology?
- measured breathing rate in response to different images before and after social media break
Patients are more sensitive to
noise in resting state – requires the amygdala to co-process the unpleasant emotional response due to enhanced functional connectivity with the temporal gyrus
Limitations of GAD trials:
- rapid brain development
- synaptic pruning
- mild severity not measured
Why are NCDs proliferating?
More people now survive into the high-risk period for neurocognitive disorders.
What did you learn from Anaerobe 2021?
Termite microbiota
nifh clusters coding for nitrogenase
possible application in non-leguminous plants for more efficient nitrogen fixation
What else did you learn from microbiology MOOC?
Analysis of soil nitrogen pools and fluxes involves diazatrophic, nitrogenase-positive endophytes as phyllospheric inoculants, specifically for phosphate solubilization, in legumes.
what is the phyllosphere?
total above-ground surface of a plant when viewed as a habitat for microorganisms
How can soil nitrogen pool flux be studied?
The study of these mutualisms in planta through integration green fluorescent protein cassette biomarking and nif overexpression
How to measure nitrogen fixation
Nitrogen from soil usually has a higher abundance of the nitrogen stable isotope than nitrogen from fixation. This allows researchers to estimate the proportion of nitrogen a plant obtains from soil versus fixation.
How to get rid of excess nitrogen?
Leach your soil
How to test for nitrogen?
Mass spectrometry
Social répertoire
Albatross - mating dance
Courting behaviours
- The idea of sexual selection
Sexual selection
- often powerful enough to produce features that are harmful to the individual’s survival
- exaggerated traits
Intersexual selection
often referred to as mate choice, involves individuals of one sex choosing among members of the opposite sex based on the attractiveness of certain traits that those individuals possess
Intrasexual selection
mate competition, involves one sex competing with members of the same sex for access to mates
Maternal parental investment
- anisogamy
- parental care
- placental transfer
The holobiont theory
- the microbiome must be considered in the ‘unit of evolution’ - on top of Dawkin’s theory
- through the enteric nervous system
- horizontal gene transfer
- superorganism
Symbiogenesis
- aka endosymbiotic theory
- or: the cooperation of species to increase their survival
- the phenomenon of evolution occurring in tandem
- enhanced mutualism
Coevolution
predator and prey relationship
