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Since their discovery almost two decades ago, interleukin-17-producing CD4 + T cells (T H 17 cells) have been implicated in the pathogenesis of multiple autoimmune and inflammatory disorders. In addition, T H 17 cells have been found to play an important role in tissue homeostasis, especially in the intestinal mucosa. Recently, the use of single-cell technologies, along with fate mapping and various mutant mouse models, has led to substantial progress in the understanding of T H 17 cell heterogeneity in tissues and of T H 17 cell plasticity leading to alternative T cell states and differing functions. In this Review, we discuss the heterogeneity of T H 17 cells and the role of this heterogeneity in diverse functions of T H 17 cells from homeostasis to tissue inflammation. In addition, we discuss T H 17 cell plasticity and its incorporation into the current understanding of T cell subsets and alternative views on the role of T H 17 cells in autoimmune and inflammatory diseases. Kuchroo and colleagues review T H 17 cell heterogeneity and discuss how this affects the function of T H 17 cells in homeostasis and disease.

Key Points Emergency granulopoiesis is defined as the well-orchestrated de novo generation of neutrophils in response to systemically disseminated infection. The overall goal of this process is to enhance neutrophil output from the bone marrow to meet the higher demand for neutrophils during severe infection when these cells are consumed in large quantities during the innate immune response. Emergency granulopoiesis can be dissected into three phases: pathogen sensing is followed by translation of this signal into enhanced granulocytic cell production in the bone marrow, and then the subsequent re-establishment of homeostatic steady-state conditions once the infection has been cleared. Pathogen sensing mainly occurs in non-haematopoietic cells through Toll-like receptor signalling and leads to the subsequent initiation of emergency granulopoiesis through the release of granulopoietic cytokines. In addition, pathogen sensing by haematopoietic stem and progenitor cells themselves might contribute to the overall granulopoietic response directly by promoting proliferation and myeloid cell differentiation, and also indirectly through the release of cytokines by early haematopoietic cells that signal in a paracrine and autocrine manner. The biological relevance of direct pathogen sensing by haematopoietic stem and progenitor cells in acute and chronic inflammation remains to be determined. Granulocyte colony-stimulating factor is the major granulopoietic cytokine regulating both steady-state and emergency granulopoiesis. At the transcriptional level, CCAAT-enhancer-binding protein-α (C/EBPα) drives steady-state granulopoiesis, whereas C/EBPβ is the master regulator of emergency granulopoiesis. The mechanisms that restrain emergency granulopoiesis and orchestrate the return to steady-state conditions are incompletely understood but are known to involve suppressor of cytokine signalling proteins. A summary of the molecular and cellular events that coordinate the markedly increased de novo production of neutrophils in response to systemic microbial infection. Neutrophils are a key cell type of the innate immune system. They are short-lived and need to be continuously generated in steady-state conditions from haematopoietic stem and progenitor cells in the bone marrow to ensure their immediate availability for the containment of invading pathogens. However, if microbial infection cannot be controlled locally, and consequently develops into a life-threatening condition, neutrophils are used up in large quantities and the haematopoietic system has to rapidly adapt to the increased demand by switching from steady-state to emergency granulopoiesis. This involves the markedly increased de novo production of neutrophils, which results from enhanced myeloid precursor cell proliferation in the bone marrow. In this Review, we discuss the molecular and cellular events that regulate emergency granulopoiesis, a process that is crucial for host survival.

يترجم للإمام فخر الدين الرازي المفسر الفيلسوف الكلامي الأصولي النظار، الذي بلغت مؤلفاته التي ثبتت نسبتها إليه مائة وثلاثة وتسعين مؤلفا، تناولت سائر العلوم المعروفة في زمانه فهو علم موسوعي وهذا الكتاب أصله القسم الدراسي الذي قدمت به لكتاب «المحصول في علم أصول الفقه» ولم ينشر معه في حينها لئلا يتضخم حجم الكتاب، وها نحن نقدمه ونعرف فيه بالإمام وبكتبه وتراثه الفكري بشكلٍ ميسر غير مخل ولا ممل وتراجم أعلام مثل الإمام الرازي في عصرنا هذا تشتد الحاجة إليها لتقديم النموذج والمثل من علمائنا وأئمتنا للأجيال الجديدة الطالعة التي ينتظر أن تتخذ منهم أمثلة ونماذج تتأسى بها وتحذو حذوها في بناء علوم الأمة ومعارفها.

Studies of the regulation of erythropoietin (EPO) production by the liver and kidneys, one of the classical physiological responses to hypoxia, led to the discovery of human oxygen-sensing mechanisms, which are now being targeted therapeutically. The oxygen-sensitive signal is generated by 2-oxoglutarate-dependent dioxygenases that deploy molecular oxygen as a co-substrate to catalyse the post-translational hydroxylation of specific prolyl and asparaginyl residues in hypoxia-inducible factor (HIF), a key transcription factor that regulates transcriptional responses to hypoxia. Hydroxylation of HIF at different sites promotes both its degradation and inactivation. Under hypoxic conditions, these processes are suppressed, enabling HIF to escape destruction and form active transcriptional complexes at thousands of loci across the human genome. Accordingly, HIF prolyl hydroxylase inhibitors stabilize HIF and stimulate expression of HIF target genes, including the EPO gene. These molecules activate endogenous EPO gene expression in diseased kidneys and are being developed, or are already in clinical use, for the treatment of renal anaemia. In this Review, we summarize information on the molecular circuitry of hypoxia signalling pathways underlying these new treatments and highlight some of the outstanding questions relevant to their clinical use.

يتناول كتاب \"الجهود النحوية لأبي موسى الجزولي\" للدكتور هاشم جعفر حسين في حوالي (352) صفحة من القطع المتوسط موضوع (النحو العربي)، مستعرضا المحتويات التالية : المقدمة، التمهيد : عصر الجزولي وسيرته، الفصل الأول : كتاب (القانون) للجزولي، الفصل الثاني : أصول النحو عند الجزولي، ...، الفصل الخامس : شخصية الجزولي العلمية.

Fibroblast growth factor 23 (FGF23) was initially characterized as an important regulator of phosphate and calcium homeostasis. New research advances demonstrate that FGF23 is also linked to iron economy, inflammation and erythropoiesis. These advances have been fuelled, in part, by the serendipitous development of two distinct FGF23 assays that can substitute for invasive bone biopsies to infer the activity of the three main steps of FGF23 regulation in bone: transcription, post-translational modification and peptide cleavage. This ‘liquid bone biopsy for FGF23 dynamics’ enables large-scale longitudinal studies of FGF23 regulation that would otherwise be impossible in humans. The balance between FGF23 production, post-translational modification and cleavage is maintained or perturbed in different hereditary monogenic conditions and in acquired conditions that mimic these genetic disorders, including iron deficiency, inflammation, treatment with ferric carboxymaltose and chronic kidney disease. Looking ahead, a deeper understanding of the relationships between FGF23 regulation, iron homeostasis and erythropoiesis can be leveraged to devise novel therapeutic targets for treatment of anaemia and states of FGF23 excess, including chronic kidney disease.

Key Points Erythropoietin production is controlled by hypoxia inducible factor (HIF); the prolyl hydroxylase domain-containing (PHD) enzymes regulate HIF and act as molecular oxygen sensors Small-molecule inhibitors of the PHD enzymes increase erythropoietin production and are in clinical development for the treatment of renal anaemia Advantages of PHD enzyme inhibitors over conventional erythropoiesis-stimulating agents (ESAs) include oral administration, lower production costs, product stability and low immunogenicity PHD enzyme inhibitors have effects besides increasing production of erythropoietin. Some of these effects could be beneficial, including improvements in uptake and utilization of iron The balance of risks and benefits in treating renal anaemia with PHD enzyme inhibitors is currently being addressed in randomized controlled trials PHD inhibitors might be useful for therapeutic indications other than the management of renal anaemia Renal anaemia, resulting from impaired renal production of erythropoietin, is a common occurrence in patients with chronic kidney disease. Conventional erythropoiesis stimulating agents can be used to treat the condition, but small-molecule inhibitors of prolyl hydroxylase domain-containing (PHD) enzymes might provide a more efficient and tolerable approach to anaemia management. Here, Maxwell and Eckardt describe the rationale for targeting PHD enzymes to increase erythropoietin production. They also discuss other potential on-target consequences of HIF activation and possible off-target effects on enzymes that are structurally similar to PHD enzymes. Small-molecule stabilizers of hypoxia inducible factor (HIF) are being developed for the treatment of renal anaemia. These molecules inhibit prolyl hydroxylase domain-containing (PHD) enzymes, resulting in HIF activation and increased production of erythropoietin. Currently, renal anaemia is treated with recombinant human erythropoietin or related analogues, referred to as conventional erythropoiesis stimulating agents (ESAs). Advantages of PHD enzyme inhibitors over conventional ESAs include their oral administration and their simpler — and potentially cheaper — production. Importantly, inhibition of PHD enzymes is likely to have a range of consequences other than increasing levels of erythropoietin, and these effects could be beneficial — for instance by reducing the need for parenteral iron — but might in some instances be harmful. Several companies are currently testing PHD enzyme inhibitors in patients with renal anaemia and have reported clear evidence of efficacy without serious safety concerns. A central question that current studies are beginning to address is whether using PHD enzyme inhibitors will influence hard end points, including mortality and the rate of cardiovascular events. In terms of approaches to therapy, the exquisite specificity of conventional ESAs is a striking contrast to the pleiotropic effects of activating HIF. Excitingly, PHD inhibitors could also be useful for conditions besides renal anaemia, such as protection from ischaemic injury.