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The paper presents a study of the comparative and contrasting features of the standard formalism and the generalized formalism associated with the mathematical framework of the Spacer component matrices and related set of mathematical elements, the analytical results are presented and numerically demonstrated using an appropriate case study.

ObjectivesDrug reaction with eosinophilia and systemic symptoms (DRESS) is a severe, delayed hypersensitivity reaction (DHR). We observed DRESS to inhibitors of interleukin 1 (IL-1) or IL-6 in a small group of patients with Still’s disease with atypical lung disease. We sought to characterise features of patients with Still’s disease with DRESS compared with drug-tolerant Still’s controls. We analysed human leucocyte antigen (HLA) alleles for association to inhibitor-related DHR, including in a small Kawasaki disease (KD) cohort.MethodsIn a case/control study, we collected a multicentre series of patients with Still’s disease with features of inhibitor-related DRESS (n=66) and drug-tolerant Still’s controls (n=65). We retrospectively analysed clinical data from all Still’s subjects and typed 94/131 for HLA. European Still’s-DRESS cases were ancestry matched to International Childhood Arthritis Genetics Consortium paediatric Still’s cases (n=550) and compared for HLA allele frequencies. HLA association also was analysed using Still’s-DRESS cases (n=64) compared with drug-tolerant Still’s controls (n=30). KD subjects (n=19) were similarly studied.ResultsStill’s-DRESS features included eosinophilia (89%), AST-ALT elevation (75%) and non-evanescent rash (95%; 88% involving face). Macrophage activation syndrome during treatment was frequent in Still’s-DRESS (64%) versus drug-tolerant Still’s (3%; p=1.2×10−14). We found striking enrichment for HLA-DRB1*15 haplotypes in Still’s-DRESS cases versus INCHARGE Still’s controls (p=7.5×10-13) and versus self-identified, ancestry-matched Still’s controls (p=6.3×10−10). In the KD cohort, DRB1*15:01 was present only in those with suspected anakinra reactions.ConclusionsDRESS-type reactions occur among patients treated with IL-1/IL-6 inhibitors and strongly associate with common HLA-DRB1*15 haplotypes. Consideration of preprescription HLA typing and vigilance for serious reactions to these drugs are warranted.

The Research paper presents a mathematical method to construct a real, positive valued scalar function of matrices belonging to the strictly rectangular complex matrix spaces. The formulated method leads to association of a strictly rectangular complex matrix with a positive vector whose components sum to unity and belongs to the real co-ordinate space of dimensionality equal to that of the embedding dimension associated with the input degrees of freedom of the rectangular complex matrix space. These vector components act as the respective weights to the ordered eigenvalues (ordered from largest to smallest) of a real, hermitian and positive definite matrix, termed as the Reference matrix, which is uniquely determined by the Spacer component matrices associated with the strictly rectangular complex matrix space. The resulting weighted sum of these eigenvalues, expressed as an appropriate Inner product, is the numerical value which the scalar function assigns as the output for the input complex strictly rectangular matrix under consideration.

The Research paper presents a mathematical framework on strictly rectangular complex matrix spaces that preserve the Frobenius norm but allow for possible readjustment of variance contribution per degrees of freedom as a result of allowed flexibility of the rank modification and alteration of the Principal axes. This is achieved through the utilization of Spacer component matrices and matrices generated from them and the use of a specific Completely Positive Trace preserving transformation determined solely based on the embedding dimension, which is the order of the embedded square matrix space associated with the strictly rectangular input matrix space.

The article presents a mathematical framework to associate a Matrix Shell system (even type or of the odd type) with a unit trace, hermitian, positive definite or positive semi-definite matrix of order ‘2’ (Density matrix representation of single qubit quantum states). This framework therefore, allows any evolution scheme defined on the fundamental matrix space associated with the Matrix Shell system and consistent with the Matrix shell model formalism to be mapped to an evolution on or inside of the unit solid sphere, centered at the origin, in the three dimensional space( Bloch sphere representation of single qubit quantum states) Demonstration of the proposed mathematical framework is presented through its application on certain subsets of the Complex Matrix spaces M2×2(C) and M4×4(C) and on certain numerical examples from M3×3(C).

The present article addresses the issue of determining the most stable configuration pair(s) of a Matrix Shell, and thereby, of determining the set of most stable configurations of the associated Matrix Shell System. The problem is resolved using the criteria of spectral proximity w.r.t. the Ordered Eigenspectrum of a defined Baseline Matrix (both for Individual constituent Matrix Shells and the Matrix Shell System) and quantified in terms of an appropriate Proximity Function, the article presents the analytic expressions of the Matrix Shell Baseline elements, corresponding to A n A n A n A n (0,2 ), (0,2 1), (1,2 ), (1,2 1)   and A t n A t n ( ,2 ), ( ,2 1)  where t  2 , type Matrix Shells and defines the Baseline Matrices in terms of these Baseline elements, the article then provides a mathematical framework to determine the most stable Configuration pair(s) of constituent Matrix Shells and the set of most stable configurations of the Matrix Shell System and concludes with demonstration of the working of the presented framework through hypothetical examples based case studies

The effector activity of IgG antibodies is regulated at several levels, including IgG subclass, modifications of the Fc glycan, and the distribution of Type I and II Fcγ receptors (FcγR) on effector cells. Here, we explore how Fc glycosylation, particularly sialylation and fucosylation, tunes cellular responses to immune complexes. We review the current understanding of the pathways and mechanisms underlying this biology, address FcγR in antigen presentation, and discuss aspects of the clinical understanding of Fc glycans in therapies and disease.

In addition to their role as antibody producing cells, B cells make a critical contribution to adaptive immune responses by functioning as professional antigen-presenting cells (APC). Distinctive features of B cells as APC include the expression of the B cell receptor (BCR) for antigen and regulated expression of HLA-DO. Here, we discuss recent progress in investigation of B cells as APC. We start with an update on the canonical MHC class II antigen presentation pathway in B cells and alternative pathways, including generation of extracellular vesicles. Turning to APC function, we highlight the roles of B cells as thymic APC, as APC for T follicular helper (TFH), as APC for CD4 memory T cells and as presenters of idiotypic BCR determinants. We also note recent examples that link B cell Ag-presentation to disease. Emerging evidence indicates that, in addition to unique features of B cells compared to other professional APC, there is appreciable heterogeneity among B cells, arising from, for example, B cell activation state or the microenvironment.

The spleen is a complex secondary lymphoid organ that plays a crucial role in controlling blood‐stage infection with Plasmodium parasites. It is tasked with sensing and removing parasitized RBCs, erythropoiesis, the activation and differentiation of adaptive immune cells, and the development of protective immunity, all in the face of an intense inflammatory environment. This paper describes how these processes are regulated following infection and recognizes the gaps in our current knowledge, highlighting recent insights from human infections and mouse models., Graphical Abstract Reviews the spleen's function during malaria infection; shows how this organ serves as a central hub for activating and exerting effector mechanisms within the immune response to control blood‐stage infection with Plasmodium parasites.

Gammaherpesviruses (GHVs) establish life-long infections and cause cancer in humans and other animals. To facilitate chronic infection, GHV oncoproteins promote cellular proliferation and differentiation. Aberrant cell-cycle progression driven by viral oncogenes should trigger activation of tumor suppressor p53, unless p53 is functionally deactivated during GHV latency establishment. However, interactions of GHVs with the p53 pathway during the establishment and maintenance of latent infection are poorly defined. Here we demonstrate in vivo that p53 is induced specifically in infected cells during latency establishment by murine gammaherpesvirus 68 (MHV68). In the absence of p53, MHV68 latency establishment was significantly increased, especially in germinal center B cells, and correlated with enhanced cellular proliferation. However, enhanced latency was not sustainable, and MHV68 exhibited a defect in long-term latency maintenance in p53-deficient mice. Moreover, IgH/c-Myc translocations were readily detected in B cells from infected p53-null mice indicating virus-driven genomic instability. These data demonstrate that p53 intrinsically restricts MHV68 latency establishment and reveal a paradigm in which a host restriction factor provides a long-term benefit to a chronic pathogen by limiting infection-associated damage.

Summary The etiological role of NSD2 enzymatic activity in solid tumors is unclear. Here we show that NSD2, via H3K36me2 catalysis, cooperates with oncogenic KRAS signaling to drive lung adenocarcinoma (LUAD) pathogenesis. In vivo expression of NSD2E1099K, a hyperactive variant detected in individuals with LUAD, rapidly accelerates malignant tumor progression while decreasing survival in KRAS-driven LUAD mouse models. Pathologic H3K36me2 generation by NSD2 amplifies transcriptional output of KRAS and several complementary oncogenic gene expression programs. We establish a versatile in vivo CRISPRi-based system to test gene functions in LUAD and find that NSD2 loss strongly attenuates tumor progression. NSD2 knockdown also blocks neoplastic growth of PDXs (patient-dervived xenografts) from primary LUAD. Finally, a treatment regimen combining NSD2 depletion with MEK1/2 inhibition causes nearly complete regression of LUAD tumors. Our work identifies NSD2 as a bona fide LUAD therapeutic target and suggests a pivotal epigenetic role of the NSD2-H3K36me2 axis in sustaining oncogenic signaling.

Lineage−Sca-1+c-Kit− (LSK−) cells are a lymphoid progenitor population that expands in the spleen and preferentially differentiates into mature B cells in response to Plasmodium yoelii infection in mice. Furthermore, LSK− derived B cells can subsequently contribute to the ongoing immune response through the generation of parasite-specific Ab-secreting cells, as well as germinal center and memory B cells. However, the factors that promote their differentiation into B cells in the spleen postinfection are not defined. In this article, we show that LSK− cells produce the cytokine IL-17 in response to Plasmodium infection. Using Il-17ra−/− mice, IL-17R signaling in cells other than LSK− cells was found to support their differentiation into B cells. Moreover, primary splenic stromal cells grown in the presence of IL-17 enhanced the production of CXCL12, a chemokine associated with B cell development in the bone marrow, by a population of IL-17RA–expressing podoplanin+CD31− stromal cells, a profile associated with fibroblastic reticular cells. Subsequent blockade of CXCL12 in vitro reduced differentiation of LSK− cells into B cells, supporting a direct role for this chemokine in this process. Immunofluorescence indicated that podoplanin+ stromal cells in the red pulp were the primary producers of CXCL12 after P. yoelii infection. Furthermore, podoplanin staining on stromal cells was more diffuse, and CXCL12 staining was dramatically reduced in Il-17ra−/− mice postinfection. Together, these results identify a distinct pathway that supports lymphoid development in the spleen during acute Plasmodium infection.

Pulse-chase analysis is a commonly used technique for studying the synthesis, processing, and transport of proteins. Cultured cells expressing proteins of interest are allowed to take up radioactively labeled amino acids for a brief interval ("pulse"), during which all newly synthesized proteins incorporate the label. The cells are then returned to nonradioactive culture medium for various times ("chase"), during which proteins may undergo conformational changes, trafficking, or degradation. Proteins of interest are isolated (usually by immunoprecipitation) and resolved by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), and the fate of radiolabeled molecules is examined by autoradiography. This chapter describes a pulse-chase protocol suitable for studies of major histocompatibility complex (MHC) class II biosynthesis and maturation. We discuss how results are affected by the recognition by certain anti-class II antibodies of distinct class II conformations associated with particular biosynthetic states. Our protocol can be adapted to follow the fate of many other endogenously synthesized proteins, including viral or transfected gene products, in cultured cells.

Hematopoietic stem and progenitor cells (HSPCs) function to replenish the immune cell repertoire under steady-state conditions and in response to inflammation due to infection or stress. Whereas the bone marrow serves as the primary niche for hematopoiesis, extramedullary mobilization and differentiation of HSPCs occur in the spleen during acute Plasmodium infection, a critical step in the host immune response. In this study, we identified an atypical HSPC population in the spleen of C57BL/6 mice, with a lineage−Sca-1+c-Kit− (LSK−) phenotype that proliferates in response to infection with nonlethal Plasmodium yoelii 17X. Infection-derived LSK− cells upon transfer into naive congenic mice were found to differentiate predominantly into mature follicular B cells. However, when transferred into infection-matched hosts, infection-derived LSK− cells gave rise to B cells capable of entering into a germinal center reaction, and they developed into memory B cells and Ab-secreting cells that were capable of producing parasite-specific Abs. Differentiation of LSK− cells into B cells in vitro was enhanced in the presence of parasitized RBC lysate, suggesting that LSK− cells expand and differentiate in direct response to the parasite. However, the ability of LSK− cells to differentiate into B cells was not dependent on MyD88, as myd88−/− LSK− cell expansion and differentiation remained unaffected after Plasmodium infection. Collectively, these data identify a population of atypical lymphoid progenitors that differentiate into B lymphocytes in the spleen and are capable of contributing to the ongoing humoral immune response against Plasmodium infection.