It is therefore advisable to seek clarification from the experienced dealers.
Despite intense study, there remain substantial gaps in understanding how the cascades are activated and regulated. All four JAK and seven STAT family members have been deleted in the mouse, in addition to the creation of conditional alleles for genes whose loss of function leads to embryonic or perinatal lethality Stat3, combined deficiency of Stat5a and Stat5b, and Jak2.
In humans, detailed genetic studies have been performed in people bearing mutant Jak or Stat genes. Crystallographic studies have illuminated structural information for multiple STAT family members in different forms.
Pharmacological inhibitors have been developed for clinical use where JAK-STAT signaling is implicated in disease pathology and progression. Finally, in most cases, a specific JAK-STAT combination has been paired with each cytokine receptor, and this information translated into cell-type specific patterns of cytokine responsiveness and gene expression.
Major questions remain concerning how the JAK-STAT cascade functions to control specific gene expression patterns, and how the cascades are regulated.
First, I will address an unexpected experimental complication that arises from the analysis of mice and cells that lack one or more STAT family member. Third, we have yet to explain how STAT activation is negatively regulated.
Moreover, additional inhibitory pathways have also been proposed to block the production of activated STATs. Collectively, I will argue that our understanding of the pathway from cytokine receptor to gene expression profile is in its infancy, but remains one of the best opportunities to dissect signal transduction.
Overview of the proximal JAK-STAT activation mechanism The current model of JAK-STAT signaling holds that cytokine receptor engagement activates the associated JAK combination, which in turn phosphorylates the receptor cytoplasmic domain to allow recruitment of a STAT, which in turn is phosphorylated, dimerizes and moves to the nucleus to bind specific sequences in the genome and activate gene expression.
The postulated role of JAKs in trafficking or chaperoning the receptors to the cell surface is debated 23456. Regardless of the when and where cytokine receptors and JAKs associate, their close apposition at the membrane is required to stimulate the kinase activity of the JAK following cytokine binding.
At this stage in the activation of the pathway, we understand next to nothing about the structural basis of the JAK-receptor interaction, how receptor intracellular domains reorient upon cytokine binding and physically contact the JAK to receive the phosphorylation modification.
STAT recruitment is followed by tyrosine, and in some cases, serine phosphorylation on key residues by the JAKs and other closely associated kinases that leads to transit into the nucleus.
Furthermore, it is unclear how many configurations of STAT homo- and heterocomplexes are present in cells before, during, and after cytokine stimulation 89 We do not understand the detailed structural basis for the preference of one SH2 domain for a given receptor, and we have little knowledge of how other non-JAK kinases are recruited to the receptors and phosphorylate the STATs.
Many receptors signal through a small number of JAKs Cytokine receptors signal through two types of pathways: Although the latter will not be discussed here, it is worth noting that elegant genetic studies have demonstrated the importance of these pathways in various pathological systems 111213 Different cells and tissues express distinct receptor combinations that respond to cytokine combinations unique to the microenvironment or systemic response of the organism.
Hence, at any given time, a single cell may integrate signals from multiple cytokine receptors. Genetic studies have established that the cytokine receptor system is restrictive in that different classes of receptors preferentially use one JAK or JAK combination 7: Unexplained is the selective use of these combinations: In contrast, human TYK2 seems to be essential for signaling through a broader range of cytokine receptors The majority of cytokine receptors use three JAK combinations.
Shown are well-studied cases where JAK usage by each cytokine receptor has been established by genetic and biochemical studies. The preferential association of JAKs to certain receptor classes raises several issues.
First, how did the JAK-receptor combinations evolve?
Because the number of receptors is relatively large, why has the number of JAKs remained small? Why have the combinations of JAK pairs also remained small given that there are 10 possible combinations that can be used Fig. Second, how flexible is the cytokine receptor-JAK pair?
That is, can receptors be engineered for interchangeable JAK use, or is a given JAK combination fixed for a specific receptor class? These questions allude to a fundamental issue that concerns the function of the JAK in cytokine receptor activation: If these receptors retain identical downstream gene expression profiles, then the signal generated by the JAK is generic and functions primarily to activate the receptor 6.
AP® UNITED STATES HISTORY SCORING GUIDELINES Visit the College Board on the Web: urbanagricultureinitiative.com Question 1 — Document-Based Question. How and why did the goals of United States foreign policy change from the end of the First World War • United States defense spending closely correlates with war and peace. Acing the Document Based Question on the AP US History Exam. March 19 You can also find a very detailed overview of the exam and curriculum in the official College Board AP United States History Course and Exam Description, available on the College Board The DBQ is the first of two essay questions you’ll face on the AP US History exam. Gerald Horne, professor of history and African American studies at the University of Houston, was interviewed on Democracy Now! on "the great disparity between how people in the United States talk about the creation myth of the United States.
Conversely, it is also possible that each receptor-JAK combination retains crucial specificity functions and swapping, for example, JAK1 for JAK2 on the EpoR will modify or destroy a specific function in erythrogenesis. These questions can be addressed experimentally by replacing one preferred JAK binding site for another in genes encoding different receptors.
The EpoR is a good test example because the activity of the receptor and its signaling pathway is essential for life and erythropoiesis is readily assayed. Core versus cell-type specific STAT signaling Microarray experiments designed to monitor changes in gene expression induced by JAK-STAT signaling have revealed that both cell-type specific transcription and core, or stereotypic, mRNA profiles are induced by activated cytokine receptors in different cell types Fig.
Collectively these data argue that STATs activate defined gene sets, depending on their genomic accessibility, and possibly on cofactors that further refine gene expression profiles. STAT3 signaling illustrates a more complex system and will be discussed below to illustrate the distinctions between IL-6 and IL signaling.
Core signaling by STATs.Acing the Document Based Question on the AP US History Exam. March 19 You can also find a very detailed overview of the exam and curriculum in the official College Board AP United States History Course and Exam Description, available on the College Board The DBQ is the first of two essay questions you’ll face on the AP US History exam.
Sample Essays. Share Tweet Post Message. Use these sample AP U.S. History essays to get ideas for your own AP essays.
These essays are examples of good AP-level writing. President Abraham Lincoln was faced with a monumental challenge during his two terms as Commander-in-chief of the United States: reuniting the shattered halves .
Presents a thesis that makes a historically defensible claim and responds to all parts of the question. The thesis must consist of one or more. AP US History Exam Document-Based Question - College Board. Half of the united states has atleast owned a converse shoe in his life span and it was certainly a unique fast of his life.
Converse absolutely are a portion of yank wish and it was chosen of each of the rebels as obvious by numerous photos of all star on the tunes handles.
Below are links to DBQs created by students / teachers for the following AP US History exams.
Use them for review. AHAP Exam DBQ period --> AHAP Exam DBQ period --> AHAP Exam DBQ period --> AHAP Core Documents of United States History: Daryle Cagle's Professional .