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الكتاب يهدف لتوفير رؤية مبدئية عن كيفية البحث، من عملية اختيار الموضوع وجمع المعلومات والمصادر إلى عملية الكتابة للنتائج، يغطي هذا الكتاب كل ما يتعلق بالبحث العلمي من إعداد وتخطيط وكتابة وإخراج ونشر وهو موجه للباحثين في شتى العلوم بشكل عام من طلاب وأساتذة وموظفين ويحاول المؤلفون على نحو خاص طرح حلول للمعضلات التي تواجه طلاب الدراسات العليا والباحثين (وكثير منهم قد لا يجيد تحدث اللغة الإنجليزية) ومن هذه المشاكل، عملية جمع المعلومات والتحقق منها وتوثيقها والكتابة عنها ويتناول هذا الكتاب مهمة البحث عن مجرد الفكرة، وكيفية صياغتها والبحث عن المشكلة وكيفية النشر في المجلات العلمية وقواعده كما يتطرق المؤلفون أيضا لتنوع أساليب الكتابة وأنواع المصادر وكيف يتم توظيف كل منها وفي أي مرحلة من البحث.

In this study, we extended co-indexing of transcriptomes and epitopes (CITE) to the spatial dimension and demonstrated high-plex protein and whole transcriptome co-mapping. We profiled 189 proteins and whole transcriptome in multiple mouse tissue types with spatial CITE sequencing and then further applied the method to measure 273 proteins and transcriptome in human tissues, revealing spatially distinct germinal center reactions in tonsil and early immune activation in skin at the Coronavirus Disease 2019 mRNA vaccine injection site. Co-indexing of transcriptomes and epitopes is extended to the spatial dimension with large protein panels.

Aberrant T-cell help has been implicated in the expansion of self-reactive B-cell clones and subsequent autoantibody production in many systemic autoimmune diseases, including systemic lupus erythematosus. In this Review, Joseph Craft discusses the T-helper-cell populations, particularly follicular helper T cells, which are key regulators of B-cell survival and maturation during normal immune responses and in autoimmunity. Follicular helper T (T FH ) cells are essential for B-cell maturation and immunoglobulin production after immunization with thymus-dependent antigens. Nevertheless, the development and function of T FH cells have been less clearly defined than classic CD4 + effector T-cell subsets, including T-helper-1 (T H 1), T H 2 and T H 17 cells. As such, our understanding of the genesis of T FH cells in humans and their role in the development of autoimmunity remains incomplete. However, evidence from animal models of systemic lupus erythematosus (SLE) and patients with systemic autoimmune diseases suggests that these cells are necessary for pathogenic autoantibody production, in a manner analogous to their role in promotion of B-cell maturation during normal immune responses. In this Review, I discuss the findings that have increased our knowledge of T FH -cell development and function in normal and aberrant immune responses. Such information might improve our understanding of autoimmune diseases, such as SLE, and highlights the potential of T FH cells as therapeutic targets in these diseases. Key Points Follicular helper T (T FH ) cells—a subset of CD4 + T cells—are located within the B-cell follicles of secondary lymphoid organs T FH cells are important regulators of B-cell maturation within germinal centres during normal immune responses Characterization of the developmental program of T FH cells could aid their identification and provide insight into the function of these cells in normal and autoimmune responses The transcription factor B-cell lymphoma 6 is both necessary and sufficient for development of T FH cells, controlling expression of molecules essential for T FH -cell trafficking and function T FH cells promote pathogenic autoantibody production in systemic autoimmunity, and potentially represent novel therapeutic targets in autoimmune diseases

Key Points Following immunization, CD4 + T cells promote the induction of a robust primary CD8 + T cell response through numerous mechanisms, including licensing of dendritic cells (DCs) and promoting the interaction between DCs and CD8 + T cells. CD4 + T cells regulate the secondary responsiveness of CD8 + T cells during immunization through suppression of TNF-related apoptosis-inducing ligand (TRAIL) through a process dependent on licensing of DCs to produce interleukin-15 (IL-15) and autocrine secretion of IL-2 by CD8 + T cells. Following infection, CD4 + T cell help is necessary for the induction of a memory CD8 + T cell pool capable of mediating protective immunity but is largely dispensable for a robust primary response. Regulatory T (T Reg ) cells act during the resolution phase of infection to protect CD8 + T cells from inflammatory signals and promote the survival of a CD8 + T cell pool capable of robustly expanding upon secondary infection. CD4 + T cell help promotes the induction of tissue-resident memory CD8 + T cells during mucosal infection through guidance of CD8 + T cells into a microenvironment where they can become exposed to the signals necessary for their continued maintenance within the tissue. During chronic infection, effector CD4 + T cells support the maintenance of functional CD8 + T cells through secretion of IL-21, whereas T Reg cells dampen the CD8 + T cell response through suppression of DCs. The development and maintenance of protective CD8 + T cell memory require help. This is provided by CD4 + T cells in many ways. Here, the authors review the latest insights into this multifaceted role for CD4 + T cells, and the implications for vaccine design and T cell-based therapies. Following infection, T cells differentiate into a heterogeneous population of effector T cells that can mediate pathogen clearance. A subset of these effector T cells possesses the ability to survive long term and mature into memory T cells that can provide long-term immunity. Understanding the signals that regulate the development of memory T cells is crucial to efforts to design vaccines capable of eliciting T cell-based immunity. CD4 + T cells are essential in the formation of protective memory CD8 + T cells following infection or immunization. However, until recently, the mechanisms by which CD4 + T cells act to support memory CD8 + T cell development following infection were unclear. Here, we discuss recent studies that provide insight into the multifaceted role of CD4 + T cells in the regulation of memory CD8 + T cell differentiation.

Tissue injury is a major cause of morbidity and mortality in SLE. Yet, there is limited knowledge of the mechanistic pathways that cause organ damage in lupus. This lack of insight hampers targeted use of current therapeutics and application of those in development. We have identified a T cell effector program associated with tissue damage in lupus nephritis, analogous to programs of effector cell development and function in states of continual antigen stimulation such as cancer and chronic infection. Our data, and by analogy, data from humans and mice with chronic infection and cancer, lead to our hypothesis, that canonical immune effector programs conserved across vertebrate evolution that are operative upon organismal insult, for example in infection or upon cellular transformation, also drive tissue injury in lupus. These programs proceed along an epigenetically regulated pathway that leads to organ injury.

Cellular function in tissue is dependent on the local environment, requiring new methods for spatial mapping of biomolecules and cells in the tissue context 1 . The emergence of spatial transcriptomics has enabled genome-scale gene expression mapping 2 – 5 , but the ability to capture spatial epigenetic information of tissue at the cellular level and genome scale is lacking. Here we describe a method for spatially resolved chromatin accessibility profiling of tissue sections using next-generation sequencing (spatial-ATAC-seq) by combining in situ Tn5 transposition chemistry 6 and microfluidic deterministic barcoding 5 . Profiling mouse embryos using spatial-ATAC-seq delineated tissue-region-specific epigenetic landscapes and identified gene regulators involved in the development of the central nervous system. Mapping the accessible genome in the mouse and human brain revealed the intricate arealization of brain regions. Applying spatial-ATAC-seq to tonsil tissue resolved the spatially distinct organization of immune cell types and states in lymphoid follicles and extrafollicular zones. This technology progresses spatial biology by enabling spatially resolved chromatin accessibility profiling to improve our understanding of cell identity, cell state and cell fate decision in relation to epigenetic underpinnings in development and disease. Spatial-ATAC-seq—spatially resolved chromatin accessibility profiling of tissue sections using next-generation sequencing—delineated tissue-region-specific epigenetic landscapes in mouse embryos and identified gene regulators involved in the development of the central nervous system and the lymphoid tissue.

Immunoglobulin E (IgE) is a type of antibody associated with allergies and response to parasites such as worms. When high-affinity, allergen-specific IgE binds its target, it can cross-link receptors on mast cells that induce anaphylaxis. It remains unclear, however, how B cells are instructed to generate high-affinity IgE. Gowthaman et al. discovered a subset of T follicular helper cells (T FH 13) that direct B cells to do just that. T FH 13 cells are induced by allergens but not during parasite infection. Transgenic mice lacking these cells show impaired production of high-affinity, anaphylactic IgE. T FH 13 cells, which are elevated in patients with food and aeroallergies, may be targeted in future antianaphylaxis therapies. Science , this issue p. eaaw6433 So-called T FH 13 cells promote the production of high-affinity immunoglobulin E involved in allergic anaphylaxis. Cross-linking of high-affinity immunoglobulin E (IgE) results in the life-threatening allergic reaction anaphylaxis. Yet the cellular mechanisms that induce B cells to produce IgE in response to allergens remain poorly understood. T follicular helper (T FH ) cells direct the affinity and isotype of antibodies produced by B cells. Although T FH cell–derived interleukin-4 (IL-4) is necessary for IgE production, it is not sufficient. We report a rare population of IL-13–producing T FH cells present in mice and humans with IgE to allergens, but not when allergen-specific IgE was absent or only low-affinity. These “T FH 13” cells have an unusual cytokine profile (IL-13 hi IL-4 hi IL-5 hi IL-21 lo ) and coexpress the transcription factors BCL6 and GATA3. T FH 13 cells are required for production of high- but not low-affinity IgE and subsequent allergen-induced anaphylaxis. Blocking T FH 13 cells may represent an alternative therapeutic target to ameliorate anaphylaxis.

Tissue repair is a subset of a broad repertoire of interleukin-4 (IL-4)– and IL-13–dependent host responses during helminth infection. Here we show that IL-4 or IL-13 alone was not sufficient, but IL-4 or IL-13 together with apoptotic cells induced the tissue repair program in macrophages. Genetic ablation of sensors of apoptotic cells impaired the proliferation of tissue-resident macrophages and the induction of anti-inflammatory and tissue repair genes in the lungs after helminth infection or in the gut after induction of colitis. By contrast, the recognition of apoptotic cells was dispensable for cytokine-dependent induction of pattern recognition receptor, cell adhesion, or chemotaxis genes in macrophages. Detection of apoptotic cells can therefore spatially compartmentalize or prevent premature or ectopic activity of pleiotropic, soluble cytokines such as IL-4 or IL-13.

T follicular helper (TFH) cells select high-affinity, antibody-producing B cells for clonal expansion in germinal centers (GCs), but the nature of their interaction is not well defined. Using intravital imaging, we found that selection is mediated by large but transient contacts between TFH and GC B cells presenting the highest levels of cognate peptide bound to major histocompatibility complex II. These interactions elicited transient and sustained increases in TFH intracellular free calcium (Ca2+) that were associated with TFH cell coexpression of the cytokines interleukin-4 and -21. However, increased intracellular Ca2+ did not arrest TFH cell migration. Instead, TFH cells remained motile and continually scanned the surface of many GC B cells, forming short-lived contacts that induced selection through further repeated transient elevations in intracellular Ca2+.

During chronic viral infection, the inflammatory function of CD4 T-cells becomes gradually attenuated. Concurrently, Th1 cells progressively acquire the capacity to secrete the cytokine IL-10, a potent suppressor of antiviral T cell responses. To determine the transcriptional changes that underlie this adaption process, we applied a single-cell RNA-sequencing approach and assessed the heterogeneity of IL-10-expressing CD4 T-cells during chronic infection. Here we show an IL-10-producing population with a robust Tfh-signature. Using IL-10 and IL-21 double-reporter mice, we further demonstrate that IL-10 + IL-21 + co-producing Tfh cells arise predominantly during chronic but not acute LCMV infection. Importantly, depletion of IL-10 + IL-21 + co-producing CD4 T-cells or deletion of Il10 specifically in Tfh cells results in impaired humoral immunity and viral control. Mechanistically, B cell-intrinsic IL-10 signaling is required for sustaining germinal center reactions. Thus, our findings elucidate a critical role for Tfh-derived IL-10 in promoting humoral immunity during persistent viral infection. During chronic infection CD4+ T cells can progressively acquire IL-10 producing functionality. Here the authors use single cell RNA sequencing to interrogate the IL10 CD4+ T cell compartment in a murine model of chronic infection and identify Il10-producing Tfh involved in promotion of the antiviral humoral immune response.