Essay On Medicine

Questions

Paper 1 to 4
1. Briefly define the following (i.e., is it a receptor? If so what type of receptor? etc.) And provide a one sentence description of the biological function or role in the study.
a. AhR. AhR is aryl hydrocarbon receptor that is involved in hyperlipidemia (Wu 1260). It is also involved in environmental chemical-induced organ toxicity (Sherr 1245).
b. ApoE-/-. It is apoliprotein. ApoE-/- mice are found to have increased chances of developing ischemic heart diseases as a result of exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and AhR activation (Wu 1260).
c. CH223191. It is an AhR receptor antagonist and it can prevent the toxic effects of TCDD (Wu 1261). Researchers used this to study the immunohistochemistry of ApoE -/- mice (Wu 1261).
d. CSF. This is a colorless fluid in the brain produced by the choroid plexus – a gland in the brain. It acts as buffer that protects the brain against mechanical damages, gives it buoyancy and chemical stability.
e. CXCR2. It is an interleukin 8 receptor that is involved in the development of atherosclerosis mediated by AhR activation (Wu 1261).
f. CYP1A1. This is a protein that is a member of cytochrome P450, its main function is in xenobiotic drug metabolism. Its expression has been used as a control and can be suppressed after transient transfection with siRNA acting on the AhR (Wu 1262).
g. IL-8. It is a chemokine that is produced by macrophages. It is a contributing factor to atherosclerosis having an important role in the development of vascular diseases (Wu 1261).
h. INCB3344. It is a small molecule inhibitor of CCR2 receptor. It can also inhibit CCL2-mediated functional responses. It is not able to reduce the storage of cholesterol in TCDD treated cells (Wu 1263).
i. MCP-1. It is a vital chemokine that is involved in the activation of monocyte chemotaxis. Its receptor is CCR2 (Wu 1261). It has been used to find the effect of TCDD, i.e. increased expression of MCP-1 from TCDD (Wu 1262).
j. MMP-12. It is a protein matrix involved in various body activities such as breaking down of the extracellular matrix. Elevated expression of MMP-12 in macrophages is related to the stimulation of macrophages in atherosclerotic lesions (Wu 1263).
k. MNF. 3’-methoxy-4’nitroflavone (MNF) is an AhR antagonist. It can result in significant suppression of TCDD-induced target genes (Wu 1262).
l. SB225002. It is a potent selective receptor working as an antagonist of CXCR2. Its main function is to cause inhibition of IL8. It can efficiently block TCDD-stimulated cholesterol storage (Wu 1263).
m. TCDD. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a potent compound. It is a poisonous compound. It can result in AhR-dependent stimulation of inflammatory mediators resulting in increased cholesterol problems (Wu 1260).
n. U937. These are cell models that are mostly used in biomedical research. These are helpful in obtaining macrophages in which proinflammatory marker genes can be studied (Wu 1262).
o. VEGF. Vascular endothelial growth factor (VEGF) is a signal protein. Its expression can be increased by CXCR2 resulting in increased angiogenesis (Wu 1261).
2) a. Why was the above data set included in the paper?
It is a supplementary figure in the paper. The data was set to clearly demonstrate how messenger RNA expression influences AhR and IL-8.
b. What does it demonstrate?
In this figure, scrambled siRNA represents the control. The data demonstrates the relationship between mRNA expression and its effects on Receptor AhR and IL-8. This figure shows that mRNA expression is significantly higher in control group/experiment, i.e. scrambled siRNA environment is showing higher expression as compared to the mRNA expression of AhR and IL-8 in the test group having normal siRNA.
c. What is scramble?
Scramble refers to the randomization of nucleotides or reversal of the siRNA sequence to consider it as a control (standard) against the test siRNA on which the experiment is performed. In simple words, scrambled siRNA has the same nucleotide composition as that of test siRNA but its sequence is changed for experimental purposes.
3) What did you find most challenging or most interesting?
Determination of exact mechanism of rheumatoid arthritis is one of the most challenging processes (Kobayashi 1317). Use of AhR antagonism against rheumatoid arthritis can also be considered as a research captivating part (Lahoti 244). The effect on mRNA expression on IL-8 experiment was the most challenging part of the study though it becomes interesting when its results are observed in the western blot analysis. The AhR interaction with TCDD and IL-8 to cause inflammation was amazing though it was in mice. Another interesting part was the PCR part where through reverse transcriptase one could create a whole DNA library.
==============
Question: Which of the following is a correct interpretation of the data in the figure 2? Please see the other file called fig.2
a. MMP-9 and MMP-2 are inhibited by the AhR.
b. IL-1B induces MMP-9 and MMP-2 in an AhR-dependent manner.
c. Inhibition of the AhR significantly inhibits basal MMP-9 and MMP-2 activity.
d. The effects of GNF351 are concentration dependent.
The second option “b. IL-1B induces MMP-9 and MMP-2 in an AhR-dependent manner.” is a correct interpretation.

Paper 5-8

4. Briefly define the following (i.e., Is it a receptor? If so what type of receptor? etc.) And provide a one sentence description of the biological function or role in the study.
a. Bay 11-7082. This is an inhibitor of NF-κB and its major role is in the expression of over 150 genes in mice.
b. CCR2. It is a receptor for MCP-1. It is involved in the development of atherosclerotic plaques as a result of AhR activation (Wu 1261).
c. CXCR3. It is a protein coupled receptor that is expressed in synovial cells in rheumatoid arthritis patients (Kobayashi 1319).
d. ERK. Extra-cellular stimulus-activated kinase (ERK) is a signaling molecule that regulates several cell activities like mitosis, postmitotic and meiosis. ERK signal transduction pathways are found to have a role in TCDD–AhR induced IL-1β expression (Kobayashi 1319).
e. IL-6. It acts as both cytokine and myokine in human body. It has the ability to maintain the stimulation of the HPA axis (Procaccini 4).
f. IL-8. It is a chemokine that is produced by macrophages. It can mediate the chances of schizophrenia in adult offspring related to the prenatal maternal infection (Khandaker 143).
g. Infliximab. This is chemeric monoclonal antibody. It is used in the treatment of autoimmune disease because it acts against (TNF-α) which is a necrosis factor (Kobayashi 1319).
h. MMP3. It is an enzyme encoded by MMP3 gene. It is involved in activities like breakdown of extracellular matrix. It has an important role during reproduction and embryonic development.
i. NFkappaB. It is a transcription factor and is a central mediator in the immune system. It regulates several target genes to perform their biological functions in reaction to bacterial or viral attack.
j. alpha-NP. It is a protein signaling enzyme that plays a major role in regulating other proteins.
k. TNF-alpha. TNF-alpha protein is responsible for cell signaling usually involved in inflammation. It can also maintain the stimulation of the HPA axis (Procaccini 4).
l. U0126. It is an inhibitor of ERK activation (Kobayashi 1321). It inhibits the action of MEK1 and its counterpart MEK2, and it does antagonize AP-1 activity through non-competitive inhibition.
5. Ig question (What is Ig?) Explain it.
This is an abbreviation for immunoglobin, it is the antibody which immune system uses to recognize and fight foreign material like viruses, bacteria and other pathogens.
6. Briefly define the following (i.e., Is it a receptor? If so what type of receptor? etc.) And provide a one sentence description of the biological function.
a. Adrenergic receptors. Are G protein-couple receptors, they are the main target for the catecholamine like epinephrine and no-epinephrine in immune system.
b. CD86. It is a protein, it provides co-stimulatory signals which are needed for the T cell activation, and it is encoded by the CD86gene.
c. CD28. It is a protein; the protein is expressed as a co-stimulatory signal in the T cell activation in both human and mice.
d. T helper 1 (Th1) cells. This is the host T helper cell in immune response when the body is reacting against protozoa and bacteria infection.
e. T helper 2 (Th2) cells. T helper cell 2 Are effective when the body is reacting against parasites like helminthes infections, their production is triggered by IL-4.
f. Germinal centers. These are special sites where secondary lymphoid organs which provide a conducive environment for maturity of B lymphocytes.
g. 3’IgH enhancer (also known as 3’IgHRR or 3’α enhancer). This is an enhancer for lymphoid-specific transcription. It is mostly found at the 3’end in the rat immunoglobin.
7. What potential experimental effects would antibodies against surface molecules have?
Antibodies can bind to ligand or cell surface receptors. Such antibodies can prevent binding from external proteins or small molecules that would normally bind to the receptor. Antibodies against surface molecules could show therapeutic effects as, for example, antibodies to EGF receptor can affect the development of some types of tumor.
Antibodies can also bind to surface antigens of bacteria can initiate the complement system and can result in their killing through the process of opsonization, i.e. the process of ingestion of microbes by phagocytes, and bacteriolysis, i.e. direct killing of bacteria.
Antibodies can also be used to differentiate types of cells by the proteins as different combinations of cluster of differentiation molecules are present on different cells for binding with antibodies.
So, antibodies have a wide range of effects shown after binding to or working against surface molecules. These effects range from therapeutic effects to bacterial killing and protein differentiation.
8. Psychotic? Explain it.
This is the abnormal condition that a human brain can undergo due to loss of contact with how one perceives reality. People suffering from it have strange behaviours.
9. What did you find most challenging or most interesting?
Most interesting and research grabbing part is the use of caloric restriction for the treatment of multiple sclerosis. Interestingly, this thing is helpful in many different conditions such as blood pressure and cholesterol (Procaccini 7). In terms of psychotic studies, it would be challenging to find a comprehensive panel of inflammatory markers (Khandaker 143). Study of AhR and IL-8 interaction was challenging due to various experiments performed. Study of the immune system was very interesting since one get to know the protective function of the body. The study of psychotic disorders was more interesting as compared to the atopic study of diseases such as that of asthma, eczema and other infection in people. Relating atopic disorders and inflammatory markers was an interesting research in which further investigations can be made.

Followed paper 5-8

1. Briefly define the following (i.e., Is it a receptor? If so what type of receptor? etc.) And provide a one sentence description of the biological function.
c. TCR. This is the T-cell receptor found in the lymphocytes, it does recognize antigens, it is made up of protein chains.
e. 3’IgH enhancer (also known as 3’IgHRR or 3’α enhancer). This is an enhancer for lymphoid-specific transcription. It is mostly found at the 3’end in the rat immunoglobin.
f. Odds ratio. It refers to the association of exposure with outcome. Occurrence of a particular outcome with a specific exposure shows the odds ratio, i.e. increased association means increased odds ratio.

This is a special measure that deals with odd outcomes that occurs in the absence of proper exposure.

g. Atopic vs. non-atopic. Atopic refers to the susceptibility towards developing some hypersensitive allergic reactions. This susceptibility can be due to hereditary factors. On the other hand, non-atopic refers to the condition that is not precipitated by allergens or genetic disposition of an allergic reaction.
h. CD40. Is a protein, it is very important in cell because it is needed for cell activation.
2. Give an example of a direct vs. an indirect effect of neurotransmitters on immune cells or function.
An example for the direct effect is the effect of norepinephrine on T cell activity. On the other hand, an example for indirect effect is that of norepinephrine on T cell activity through IL-12 produced by APC (Kin 1098). Another example of direct effect of neurotransmitters on immune cells or function may include the release of cytokines from activated immune cells during severe infections posing an immediate threat to life. On the other hand, less severe infections may need only the local neuroregulatory mechanisms and that could be considered as an example of indirect effect of neurotransmitter on immune functions (Kin 1096).
3. What can you conclude from Table 2? Please see the other file called Table 2.
This table shows that alleles at 766 position – terminal portion of 9α, which is a cortisol binding domain – show more chances of mutation in case of systemic lupus erythematosus (SLE) as compared to other autoimmune diseases and normal people. Variances (sigma squared values) are showing that data points of the allele frequency for SLE show different distances from the mean, i.e. very spread out from the mean.
4. Hypothesize a potential functional effect of the indicated SNP on the glucocorticoid receptor (GR) and how that may impact immune regulation and autoimmune disease.
Specified SNP shows thymine (T) to cytosine (C) substitution at codon 766 of the GR gene as shown in the figure. This substitution (mutation) is possibly related to the glucocorticoid resistance, i.e. insensitivity to glucocorticoids resulting in inflammatory and autoimmune disorders. In this condition, T-cells start producing lower than usual levels of IL-2 (Lee 74), thereby reducing tolerance as well as immunity.

Works Cited

Khandaker, G. M., et al. "A Population-Based Study of Atopic Disorders and Inflammatory Markers in Childhood before Psychotic Experiences in Adolescence." Schizophr Res 152.1 (2014): 139-45. Print.
Kin, Nicholas W, and Virginia M Sanders. "It Takes Nerve to Tell T and B Cells What to Do." Journal of leukocyte biology 79.6 (2006): 1093-104. Print.
Kobayashi, S., et al. "A Role for the Aryl Hydrocarbon Receptor and the Dioxin Tcdd in Rheumatoid Arthritis." Rheumatology (Oxford) 47.9 (2008): 1317-22. Print.
Lahoti, T. S., et al. "Aryl Hydrocarbon Receptor Antagonism Attenuates Growth Factor Expression, Proliferation, and Migration in Fibroblast-Like Synoviocytes from Patients with Rheumatoid Arthritis." J Pharmacol Exp Ther 348.2 (2014): 236-45. Print.
Lee, Young Moo, et al. "A Mutation of the Glucocorticoid Receptor Gene in Patients with Systemic Lupus Erythematosus." The Tohoku journal of experimental medicine 203.2 (2004): 69-76. Print.
Procaccini, C., et al. "Neuro-Endocrine Networks Controlling Immune System in Health and Disease." Front Immunol 5 (2014): 143. Print.
Sherr, D. H. "Another Important Biological Function for the Aryl Hydrocarbon Receptor." Arterioscler Thromb Vasc Biol 31.6 (2011): 1247-8. Print.
Wu, D., et al. "Activation of Aryl Hydrocarbon Receptor Induces Vascular Inflammation and Promotes Atherosclerosis in Apolipoprotein E-/- Mice." Arterioscler Thromb Vasc Biol 31.6 (2011): 1260-7. Print.