Implications of JAK-STAT in disease
So far, we have seen that this pathway is accountable for the transduction of extracellular stimulus into transcriptional factors that regulate several cellular functions. STATs are also known to exert additional functions such as affecting oxidative phosphorylation in mitochondria, regulating chromatin compliance and epigenetic markings in the nucleus and interacting with the microtubule components in the cytoplasm which are responsible for cellular motility (4). This pathway has been observed to play an integral role in the development of mammary gland, stem cells, lymphocytes, neuronal cells, eye cells, cardiomyocytes, adipocytes. Consequently, its dysregulation induces various diseases, including
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STATs contribute significantly to cellular fate decisions of differentiating naïve T cells into regulatory and inflammatory T cells, lymphocyte development, and exercise control over the intensity and duration of inflammatory responses. STAT3 particularly is involved in the regulation of cell death, cell growth and in the transcription of inflammatory genes. This serves as the basis for its contribution to the development of chronic inflammatory diseases and neurodegenerative diseases (8).
This pathway has been associated with several monogenic diseases like the ‘bubble boy’ syndrome (X-linked severe combined immunodeficiency). The extreme susceptibility to pathogens observed is caused by a lack of T and NK cells, which occurs due to loss of function variants of the common γ chain signal transduction. A subset of SCID patients demonstrated mutations in Jak3 kinase specifying the non-redundant in vivo functions for any JAK/STAT component (9). After the initial discovery of JAK3-SCID, many Mendelian disorders were reported. Discoveries made in the past three decades help us to correlate loss of function STAT mutations with specific types of pathogens. STAT1 mutations make patients vulnerable to viral and mycobacterial infections, whereas patients having STAT2 mutations are prone to viral infections and fungal infections are most common in patients with STAT3 mutations (2).
The last 20 years have brought to the fore remarkable connections between JAK-STAT
1. “Give Fees an Inch and They’ll Take a Mile” from the Wall Street Journal, 3/14/2014 - corresponds to Ex 1 in Unit 1
When a man is a product of his environment and the environment is filled with violence and hatred, the possibilities are horrifying. Richard kuklinski is a prime example of just that. His childhood was something no human, let alone a child should go through. His anger built up and his life eventually was overcome by it. He then progressed to a cold-blooded killer, starting small, and then ending with the mob until his capture.
“Distrust naturally creates distrust, and by nothing is good will and kind conduct more speedily changed.” -John Jay
This deficiency leaves a person vulnerable to a multitude of different opportunistic infections. At least 14 different genetic defects can cause SCID.
) Introduction. What is a dominant pathogenic mutation? Is the KID syndrome a dominant pathogenic disease? Explain.
Severe Combine Immunodeficiency(SCID) is a disease that infects infants within the first few months of life. Some of these infections can be life threatening. The cause of SCID is usually a defect in the T- & B-lymphocyte systems. SCID is known as the “Bubble Boy Disease”. According to the article The SCID Homepage, “SCID became widely known during the 1970’s and 80’s, when the world learned of David Vetter, a boy with X-linked SCID, who lived for 12 years in a plastic, germ-free bubble.” There are multiple versions of SCID, but the most common form is caused by the X-chromosome. Because this disease only affects the X-chromosome, it can affect male infants.
RhoA/Rho-kinase expression has been found in various inflammatory cell types including T cells, neutrophils, Schwann cells, smooth muscle cells, and macrophages (Kitano et al.; Luo et al. 2014). Pharmacological analyses have revealed that ROCKs are linked to the development of asthma, pulmonary hypertension, diabetes, glaucoma, rheumatoid arthritis, erectile dysfunction, vascular remodeling, and various other diseases associated with inflammatory cell infiltration and smooth muscle cell contraction (Luo et al. 2014; Nunes et al. 2010). However, since the discovery of ROCKs, researchers have mostly been interested in their function in cardiovascular physiology and pathophysiology (Loirand et al. 2006). The RhoA/Rho-kinase pathway causes a cascade of events that triggers actin-myosin contraction, stress fiber formation, cell adhesion and migration, and blood pressure regulation (Chang et al.; Nunes et al. 2010). Through these actions, the RhoA/Rho-kinase pathway has been implicated in the pathophysiology of various cardiovascular diseases including congenital heart failure, ischemia/reperfusion injury, hypertension, stroke, myocardial hypertrophy, atherosclerosis, cardiomyopathy, cardiac fibrosis, mitral regurgitation, myolysis, etc. (Chen et al. 2015; Kitano et al.; Luo et al. 2014; Nunes et al. 2010; Rikitake and Liao 2005). This interest has been built on the observation that beneficial effects of statins result either completely or
Japheth was the second son of Noah and the ancestor of the Caucasian whites known as the Europeans. The sons of Japheth: Gomer, Magog, Madai, Javan, Tubal, Meshech, and Tiras. The sons of Gomer: Ashkenaz, Riphath, Togarmah. The son of Javan: Elishah, Tarshish, Kittim, and Dodanim. Of these divided in their lands, everyone after his tongue, after their families, in their nations. After the flood, God gave inheritance the descendants of Japheth. Such as lands, nations according to their families and languages throughout the coastlands of Europe for settlement.
Let’s say that an undifferentiated stem cell, which is just a stem cell that hasn’t been changed into another cell, is just hanging around in your bone marrow waiting to do something. Along comes a nice looking cytokine. Cytokines are proteins, and certain cytokines are signalling cytokines. They send a message to the cell to help it differentiate. On the cell, there is a specific receptor for that cytokine. Since we’re making an NK Cell, this first cytokine is interleukin 3. The receptors are linked to a Janus Kinase, which send signals along the JAK-STAT pathway. It’s really just a fancy name for something that sends messages into your cells for differentiation. Anyways, that receptor and Janus Kinase will take the cytokine’s information, and send biochemical signals into the cell. The signals reach the STAT protein, and it promptly carries the signals into the nucleus. DNA transcription, or where certain genes are turned into mRNA, happens. The mRNA then is changed into protein. This continues with different cytokines until the cells are fully differentiated into what is required of
The first X-SCID gene therapy trial used a moloney murine viral vector with the c transgene in two patients with X-SCID. One patient had a missense mutation in IL2RG which resulted in a receptor in the cellular membrane but without a cytoplasmic tail and therefore not functional. The other patient had a frameshift IL2RG mutation which deleted exon 6 and resulted in a truncated receptor that was not expressed on the membrane. Their CD34+ T cells were removed and transfected for three days, at which point they were infused back in to the patient. Around 40% of the infused cells contained the transgene. 15 days after transfusion, circulating T cells containing the transgene were able to be detected circulating in both patients by PCR. The
Research has demonstrated that South Korea has the most reduced ripeness rate on the planet, at under 1.1 births for every lady. Yet, Kahn isn't wedded, and he doesn't plan to have children. He jokes that Koreans will soon be terminated.
The defining characteristic is commonly a sever defect in both the T- and B-lymphocyte systems. Usually leading to one or more serious infectious diseases within the first few months of life. The diseases that are contracted are usually serious and may even become life threating, they include pneumonia, meningitis or blood stream infections. Children that are affected by SCID have the ability to become seriously ill from viruses present in some vaccines. The vaccines, chickenpox, measles, rotavirus, contain viruses and bacteria that are weakened to not harm children with healthy immune systems. However with SCID patients these weakened viruses have the potential to cause severe, life-threating infections. After a single round of treatment, six out of seven boys whom had been through gene therapy were successful, a T-cell count greater than 300 cells per microliter of blood and T-cell proliferation in response to stimulation with phytohemagglutinin (a test to measure T-cells’ ability to react to pathogens). (SCID Homepage,
As people survived in the Earth, they experienced four different seasons: spring, summer, fall, and winter. Each season have different weather conditions and our body had to adjust
Do you remember the first time you were told to write a poem? A poem about yourself, someone you love or just something that has a basic rhyme pattern. A lot of our first poems were written in grade school as a class project. I remember my first poem, a poem for someone I love, my mother. Starting off with “roses are red and violets are blue” then explaining my love for her. Telling my story about her through the poem. One can think of a poem as a way of telling a story with so much emotion behind it. According to Cambridge Dictionary a poem is defined as “a piece of writing in which the words are carefully chosen for the images and ideas they suggest, and in which the sounds of the words when read aloud, often follow a particular
Nuclear localization sequences or NLS, is a necessary component of nuclear transport. It is an amino acid sequence that will “tag” a protein for import. By disrupting this sequence, the way a protein is imported is altered and can lead to numerous defects. Where it may localize can change the functionality of the protein. This can be seen in the case of spleen tyrosine kinase, Syk. Spleen tyrosine kinase is “a candidate tumor (metastasis) suppressor that is highly expressed in mammary epithelial cells” (Wang). Lei Wang and associates looked at two different variants of Syk;