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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.

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.

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.

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.

The barriers presented by immune suppression in the ovarian tumor microenvironment present one of the biggest challenges to development of successful tumor vaccine strategies for prevention of disease recurrence and progression following primary surgery and chemotherapy. New insights gained over the last decade have revealed multiple mechanisms of immune regulation, with ovarian tumor-associated macrophages/DC likely to fulfill a central role in creating a highly immunosuppressive milieu that supports disease progression and blocks anti-tumor immunity. This review provides an appraisal of some of the key signaling pathways that may contribute to immune suppression in ovarian cancer, with a particular focus on the potential involvement of the c-KIT/PI3K/AKT, wnt/β-catenin, IL-6/STAT3 and AhR signaling pathways in regulation of indoleamine 2,3-dioxygenase expression in tumor-associated macrophages. Knowledge of intercellular and intracellular circuits that shape immune suppression may afford insights for development of adjuvant treatments that alleviate immunosuppression in the tumor microenvironment and enhance the clinical efficacy of ovarian tumor vaccines.

Toll-like receptors (TLRs) are important for recognizing a variety of pathogens, including protozoan parasites, and initiating innate immune responses against them. TLRs are localized on the cell surface as well as in the endosome, and are implicated in innate sensing of these parasites. In this review, we will discuss recent findings on the identification of parasite-derived pathogen associated molecular patterns and the TLRs that bind them. The role of these TLRs in initiating the immune response against protozoan parasitic infections in vivo will be presented in the context of murine models of infection utilizing TLR-deficient mice. Additionally, we will explore evidence that TLRs and genetic variants of TLRs may impact the outcome of these parasitic infections in humans.

Leishmania donovani (LD), the causative agent of visceral leishmaniasis (VL), extracts membrane cholesterol from macrophages and disrupts lipid rafts, leading to their inability to stimulate T cells. Restoration of membrane cholesterol by liposomal delivery corrects the above defects and offers protection in infected hamsters. To reinforce further the protective role of cholesterol in VL, mice were either provided a high-cholesterol (atherogenic) diet or underwent statin treatment. Subsequent LD infection showed that an atherogenic diet is associated with protection, whereas hypocholesterolemia due to statin treatment confers susceptibility to the infection. This observation was validated in apolipoprotein E knockout mice (AE) mice that displayed intrinsic hypercholesterolemia with hepatic granuloma, production of host-protective cytokines, and expansion of antileishmanial CD8(+)IFN- γ (+) and CD8(+)IFN- γ (+)TNF- α (+) T cells in contrast to the wild-type C57BL/6 (BL/6) mice when infected with LD. Normal macrophages from AE mice (N-AE-MΦ) showed 3-fold higher membrane cholesterol coupled with increased fluorescence anisotropy (FA) compared with wild-type macrophage (N-BL/6-MΦ). Characterization of in vitro LD-infected AE macrophage (LD-AE-MΦ) revealed intact raft architecture and ability to stimulate T cells, which were compromised in LD-BL/6-MΦ. This study clearly indicates that hypercholesterolemia, induced intrinsically or extrinsically, can control the pathogenesis of VL by modulating immune repertoire in favor of the host.

Blood-stage Plasmodium chabaudi chabaudi AS infection requires cell- and Ab-mediated immunity to control acute and persistent infection, respectively. ICOS regulates CD4+ T cell activation and promotes the induction of follicular Th (TFH) cells, CD4+ T cells that support B cell affinity maturation within germinal centers (GCs), resulting in the production of high-affinity Abs. In this article, we demonstrate that, in response to P. c. chabaudi AS infection, the absence of ICOS resulted in an enhanced Th1 immune response that reduced peak parasitemia. Despite the absence of ICOS, CD4+ T cells were capable of expressing PD-1, B cell lymphoma 6, and CXCR5 during early infection, indicating TFH development was not impaired. However, by day 21 postinfection, Icos−/− mice accumulated fewer splenic TFHs compared with Icos+/+ mice, leading to substantially fewer GC B cells and a decrease in affinity, but not production, of parasite-specific isotype-switched Abs. Moreover, treatment of mice with anti–ICOS ligand Abs to modulate ICOS–ICOS ligand signaling revealed a requirement for ICOS in TFH differentiation only after day 6 postinfection. Ultimately, the quality and quantity of isotype-switched Abs produced in Icos−/− mice declined over time, resulting in impaired control of persistent parasitemia. Collectively, these data suggest ICOS is not required for TFH induction during P. c. chabaudi AS infection or production of isotype-switched Abs, but it is necessary for maintenance of a sustained high-affinity, protective Ab response.