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Insights into the genetic basis of natural selection and domestication from Sorghum
Compensatory relationships determine the impact of TGF-β on the humoral immune response to hepatitis B surface antigen
Abstract Despite an effective vaccine against the hepatitis B virus (HBV), there are about 250 million people living with chronic HBV (CHB) worldwide and one million deaths annually. Most children and about 5% of adults exposed to HBV will fail to clear the virus, developing a lifelong infection. Hepatitis B surface antigen (HBsAg)-specific antibody (HBsAb) is protective in uninfected individuals and is considered a component of a functional cure. Immune factors that play important roles in regulating inflammation, such as TGF-β, IL-10, and regulatory T cells (Tregs), may also contribute to CHB pathogenesis. However, the early regulatory factors that promote HBsAg seroconversion are not well understood. To address this, we utilized adeno-associated virus (AAV)-mediated delivery of HBV (AAV-HBV) to mice. In this model, C57BL/6 mice fail to develop effective HBsAb responses, while BALB/c mice more efficiently seroconvert HBsAg. While inhibiting TGF-β, IL-10, or Tregs did not impact serum HBsAg levels in C57BL/6 mice, TGF-β depletion in BALB/c mice ablated the humoral response to HBsAg. Neutralizing IL-10, blocking CTLA-4, or depleting Tregs alone did not affect the HBsAb response in BALB/c mice. However, Treg depletion in the absence of TGF-β restored HBsAg clearance in an IL-10- and CTLA-4-independent manner. These findings highlight the immune balance regulated by TGF-β in the early adaptive response to an HBV antigen, as well as context-dependent compensatory interactions that may directly or indirectly impact antigen-specific humoral immunity.
Engineered novel dually cross-linked hydrogel system embedded with Apigenin–cyclodextrin complex for surgical wound healing
CRISPRi screening identifies SON and MAP4K1 as regulators of type III cytokine expression in innate lymphoid cells
Abstract The cytokines interleukin (IL)-22 and IL-17 are secreted by innate and adaptive immune cells to drive “type III” responses that protect against extracellular pathogens, promote mucosal barrier integrity, and foster microbiota homeostasis. However, dysregulation of IL-22 and/or IL-17 contributes to autoimmunity, chronic inflammation, and malignancy. Thus, a deeper understanding of mechanisms regulating type III cytokine production could provide new therapeutic targets for a spectrum of immune-mediated diseases. Toward this goal, we performed a genome-wide CRISPR inhibition (CRISPRi) screen to identify factors that regulate IL-22/IL-17 expression in a murine type III innate lymphoid cell (ILC3) model, MNK3, following stimulation with IL-23 and IL-1β. In addition to previously known regulators of type III cytokines, including IL-23 receptor components IL23R and IL12Rβ1, the screen identified a large set of new factors that either potentiate or attenuate expression of IL-22 and/or IL-17. A subset of these novel factors was chosen for validation, from which two were selected for further study. Knockdown of nuclear protein, SON, which binds both DNA and RNA, impaired expression of IL12Rβ1 at the levels of de novo transcription and RNA processing. The second, MAP4K1 (HPK1), is a serine/threonine kinase that is required for IL-22 but not IL-17 expression. Depletion of MAP4K1 in MNK3 also enhanced expression of the type I cytokine, IFN-γ, which was co-expressed with IL-17, a phenotype reminiscent of pathogenic Th17 cells. Together, results from the CRISPRi screen broaden our understanding of the factors involved in type III immune responses and offer new targets for modulating IL-22/17 expression.
Combined application of hot water and salicylic acid treatment preserves postharvest quality of mangoes
MHC class II on melanoma cells regulates the anti-tumor T cell response
Abstract In human melanoma, tumor cell-specific MHC class II expression is associated with improved response to programmed death 1 and programmed death-ligand 1 blockade; yet the direct effect of melanoma cell-specific MHC class II expression on anti-melanoma T cell responses remains largely unknown. In the clinically relevant Yale University Mouse Melanoma Exposed to Radiation (YUMMER) cell lines, MHC class II expression was IFN-γ-inducible in a subset of cells. Transduction of melanoma cells with CIITA resulted in uniformly high, constitutive expression of MHC class II. YUMMER.G cells transduced with CIITA vector had increased in vivo tumor growth in wild-type mice compared to melanoma cells transduced with empty vector. YUMMER.G cells transduced with empty or CIITA vectors had the same in vivo tumor growth in RAG−/− mice, indicating that the difference in tumor growth between CIITA- and empty-transduced cells was dependent on an intact adaptive immune system. CIITA-transduced YUMMER.G tumors exhibited an increased frequency and infiltration depth of CD4+ T cells, an increased frequency of T regulatory cells, and a decreased frequency and infiltration depth of CD8+ T cells, compared to empty-transduced tumors. Antibody depletion revealed that CIITA- and empty-transduced YUMMER.G tumors were constrained by CD4+ and CD8+ T cells, but only tumor growth of CIITA-transduced cells was decreased by CD25 blockade, which primarily blocks T regulatory cell function. Overall, this work reveals a potential pro-tumorigenic role of melanoma cell-specific overexpression of MHC class II.
Core stability versus postural control training for pain, disability, and sensorimotor function in chronic non-specific low back pain
Increased Nur77 is disconnected from TCR affinity in insulin-specific Tregs
Abstract Foxp3+ regulatory T cells (Tregs) are capable suppressors of aberrant self-reactivity. However, how differences in affinity and specificity may support Treg function compared with autoimmune T cell function remains unresolved. In this study, we analyzed the T cell receptor (TCR) repertoires of the regulatory and effector T cells that spontaneously infiltrate pancreatic islets of nonobese diabetic mice and therefore share antigen specificity. Using 2-dimensional micropipette measurements of TCR affinity, we show that effector and regulatory T cell-derived TCRs possess similar wide-ranging affinities for self-antigen. Treg-derived TCRs conferred variable protective function and Treg suppressive capacity was, in part, determined by the relative antigen-reactivity of effector T cells. Interestingly, when expressing the same TCR, Tregs showed higher Nur77-GFP expression than effector T cells in vivo, suggesting a Treg-intrinsic ability to compete for antigen. In vitro, we observed accelerated Treg TCR activation, suggesting that Tregs are poised for faster response to antigen than T effectors. Our findings expose a subpopulation of Tregs possessing low-affinity, suboptimal TCRs, obscured by apparent higher Nur77 expression in Tregs as a whole.
Spatial scaling of metagenomic diversity reveals ecological disruption in the gut microbiome of gout patients
Rhodium(III)‐Catalyzed Asymmetric Synthesis of Silanes and Cyclopropanes From Diazo Compounds Using Chiral <i>α</i> ‐Pinene‐Derived Indenyl Ligands
ABSTRACT Rhodium‐catalyzed asymmetric organic reactions are efficient tools for the synthesis of pharmaceuticals and natural compounds, but the search for readily available chiral catalysts remains a challenge. In this work, we describe a straightforward synthesis of a set of chiral tetrahydrofluorenyl rhodium(III) complexes bearing donor substituents on the benzene ring. These complexes are readily accessible via a simple four‐step procedure starting from naturally occurring (−)‐α‐pinene, without the need for multi‐step and time‐consuming techniques such as chiral HPLC or diastereomeric resolution. With the dimethyl‐substituted complex, the first asymmetric reactions of diazo compounds with hydrosilanes and electron‐rich alkenes catalyzed by Rh(III)‐complexes were performed, giving the corresponding chiral silanes and cyclopropanes (up to 96% ee). The complexes also showed excellent results in asymmetric C─H annulation of aryl hydroxamates with alkenes, affording various chiral dihydroisoquinolones (up to 97% ee). DFT calculations revealed that methoxy groups exert a crucial influence on the stereoselectivity of both the C─H activation step and the alkene insertion step. The developed protocol was used for the synthesis of precursors of protoberberine alkaloids ( S )‐tetrahydropalmatine and ( S )‐O‐methylbharatamine.
BPTF is essential for vaccine-induced germinal center B cell responses
Abstract Germinal centers (GCs) are microanatomical structures in which antigen-specific B cells undergo proliferation, somatic hypermutation, and affinity-based competition to select high-affinity clones that differentiate into memory B cells and plasma cells (PCs). B cell progression through the GC is tightly regulated, and the molecular determinants that modulate GC B cell proliferation and survival are still under investigation. Here, we use a conditional deletion mouse model to demonstrate that bromodomain PHD finger transcription factor (BPTF), a subunit of the nucleosome remodeling factor chromatin remodeling complex, is required for robust GC B cell responses following vaccination. In GC B cells, Bptf loss induces a stress-like transcriptional profile and a shift toward PC identity-defining transcriptional programing, although this does not lead to accumulation of functional PCs. Rather, we show that BPTF-deficient GC B cells are prone to cell death. Cumulatively, our data demonstrate that BPTF is necessary for GC B cell maintenance and robust antigen-specific B cell responses.
Hybrid CNN BiLSTM architecture for smart grid cyberattack detection using smart meter data
TGF-β controls developmental fate and functional identity of thymic γδ T cells
Abstract Gamma delta (γδ) T cells undergo a distinct developmental pathway within the thymus, where transforming growth factor β (TGF-β) exerts pivotal regulatory influence. However, the precise mechanistic contributions of TGF-β to γδ T cells differentiation and functional maturation remain incompletely understood. Here, we show that TGF-β regulates the activation state, migration capacity and inflammatory cytokine production during the development of γδ T cells in the thymus. Specifically, γδ T cells deficient in TGF-β signaling (Tgfbr1 deficient or Smad2 and Smad3 double deficient) predominantly acquired a CD44+CD45RB+ phenotype and showed impaired thymic egress, with reduced expression of CCR9, CD24, and Cxcr4. These knockout γδ T cells also exhibited elevated production of proinflammatory cytokines (interferon γ, interleukin-17A, tumor necrosis factor α) specifically in the thymus. RNA sequencing revealed that Tgfbr1-deficient γδ T cells upregulated genes associated with T cell receptor signaling, cytotoxicity, and immune activation while downregulating migration-related genes. T cell receptor repertoire sequencing further demonstrated that thymic γδ T cells lacking TGF-β signaling exhibited reduced clonal diversity accompanied by expansion of dominant clonotypes, indicating a role for TGF-β in maintaining repertoire breadth during γδ T cell development. However, we found that the differentiation of Vγ1+, Vγ4+, and Vγ7+ subsets in the thymus of the TGF-β signal–deficient mice remained largely intact. Our findings advance mechanistic understanding of γδ T cell ontogeny and underscore the role of TGF-β in balancing effector function with thymic retention or peripheral dissemination.
Computational analysis of radiative heat transfer and free convective flow over a vertical wavy surface with Lorentz forces
BACH1 orchestrates macrophage state transitions to coordinate regenerative inflammation
Abstract Efficient tissue regeneration requires the precise coordination of inflammatory and regenerative programs, principally mediated by monocyte-derived macrophages. However, the transcriptional wiring and epigenomic processes behind complex macrophage subtype specification and transition between the different states are not known. Here we have identified the transcriptional repressor BACH1 as a critical, cell-intrinsic regulator of monocyte-derived macrophage specification during skeletal muscle regeneration. Using a myeloid-specific BACH1 knockout mouse model, we demonstrate that BACH1 deficiency disrupts the temporal coordination of monocyte-to-macrophage differentiation, leading to aberrant macrophage subsets with concurrent opposing pro- and anti-inflammatory features. Single-cell RNA-sequencing profiling reveals that BACH1 controls a core transcriptional network, including Nfkb1, Cebpb, and interferon signaling, governing inflammatory resolution and functional macrophage specialization. Mechanistically, BACH1 loss accelerates macrophage differentiation but also affects its core cellular identity, resulting in sustained, rather than declining inflammatory programs including upregulation of Il1b and thus, defective tissue remodeling. These immune alterations compromise the paracrine landscape during regenerative inflammation and impair muscle stem cell differentiation. Our findings establish BACH1 as a molecular tuner or controller that integrates early innate immune signaling with regenerative output, positioning it as a central node linking transcriptional control, immune fate decisions, and tissue repair.
A fractal-enhanced deep learning framework for forecasting agricultural production in India
MAPK-activated protein kinase 2 orchestrates memory T-cell inflation in cytomegalovirus infection
Abstract Memory T-cell inflation is a distinctive immunological phenomenon observed during persistent viral infections such as cytomegalovirus (CMV). Unlike conventional memory T-cell responses, which contract after infection resolution, a subset of CMV-specific T cells undergoes a progressive and sustained expansion, termed “inflation”, which is thought to be critical for long-term immune surveillance. The molecular mechanisms that govern memory T-cell inflation remain incompletely understood, yet they are pivotal for understanding immune persistence and designing strategies against chronic viral infections. In this study, we investigated the role of MAPK-activated protein kinase 2 (MK2), a key downstream effector of p38 MAPK signaling, in regulating T-cell responses during murine CMV (MCMV) infection. Using MK2 knockout (MK2-KO) mice, we demonstrate that MK2 deficiency alters the dynamics of MCMV-specific CD8+ T-cell responses without impairing viral control or tissue replication. MK2 deficiency led to a reduction in noninflationary MCMV-specific CD8+ T cells during acute infection, followed by enhanced expansion of inflationary CD8+ T-cell subsets during latent infection. Furthermore, MK2-KO mice exhibited impaired effector differentiation, as evidenced by decreased expression of the terminal differentiation marker KLRG1 on MCMV-specific CD8+ T cells. Collectively, these findings identify MK2 as an important regulator of CD8+ T-cell magnitude, kinetics, and phenotype during both acute and latent MCMV infection. By demonstrating a role of MK2 in the regulation of memory T-cell inflation, this study provides new mechanistic insight into immune regulation with implications for vaccination, chronic infection, and immune aging.