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Risk of Guillain–Barré Syndrome after Laboratory-Confirmed Dengue Infection
Investigating behavioral intentions toward DeepSeek adoption using a moderated-mediation analysis with PLS-SEM and fsQCA
Asundexian for Secondary Stroke Prevention
Evolutionary game model for public health emergency management in universities
Glucocorticoids in Kawasaki Disease — Refining Indications and the Science
In vivo site-specific engineering to reprogram T cells
Abstract Engineered T cells, reprogrammed to express chimeric antigen receptors (CAR) or T cell receptors (TCR), have transformed cancer treatment and are being explored as therapeutics for autoimmune and infectious diseases. Enhancing T cell function through genome editing, either by disrupting endogenous genes or precisely inserting DNA payloads, has shown considerable promise 1 . However, the ex vivo manufacturing process is lengthy and costly, limiting accessibility of these therapies. In vivo generation of CAR T cells could overcome these barriers, but current methods rely either on transient expression with limited durability, or on random integration of DNA payloads that lack specificity. Here we demonstrate that stable and cell-specific transgene expression can be achieved through in vivo site-specific integration of large DNA payloads. We developed a two-vector system to deliver CRISPR–Cas9 ribonucleoproteins and a DNA donor template, using enveloped delivery vehicles and adeno-associated viruses, respectively. We optimized both vectors for T cell-specific delivery and gene-targeting efficiency. By integrating a CAR transgene into a T cell-specific locus, we generate therapeutic levels of CAR T cells in vivo in humanized mouse models of B cell aplasia, and haematological and solid malignancies. These findings offer a pathway to more efficient, precise and widely accessible T cell therapies.
Natural antisense transcript Nat9a suppresses Scn9a (NaV1.7) expression in parvalbumin-positive proprioceptive and inhibitory neurons
Abstract Natural antisense transcripts (NATs) are important spatial and temporal regulators of gene expression. We previously cloned a NAT ( Nat9a) to Scn9a , which encodes the Na V 1.7 voltage-gated sodium channel that is essential for pain perception. By studying a novel Nat9a global knockout mouse model, we demonstrate that the deletion of Nat9a does not affect pain sensitivity but instead partially impairs motor coordination. We show that Nat9a is expressed throughout the peripheral and central nervous systems and its expression is enriched, but not limited to, cells that express parvalbumin ( Pvalb), which is a marker for proprioceptors in DRG and a subclass of interneurons in spinal cord and brain. Nat9a knockout leads to an increase in Scn9a expression, confirming Nat9a ’s physiological role as a negative regulator of Scn9a . Furthermore, CRISPR activation of Nat9a transcription in Cad cells suppresses endogenous Scn9a expression. Notably Nat9a expression in Pvalb + neurons coincides with that of the Scn1a gene (Na V 1.1 sodium channel) with both genes sharing a divergent bi-part promoter region. This suggests a mechanism by which Nat9a transcription leads to suppression of Scn9a and promotes neuronal expression of Na V 1.1 over Na V 1.7.
Intraosseous Abscess from Subacute Osteomyelitis
Operational checks for real-time urinary biomarker measurements for assessment of the quality of deceased donor kidneys
Adult-Onset Still’s Disease
Dehydroandrographolide attenuates Toll-like receptor signaling by dual inhibition of MyD88- and TRIF-dependent pathways
Abstract Toll-like receptors (TLRs) are key mediators of innate immune responses, and their dysregulation contributes to inflammatory diseases. Dehydroandrographolide (DAG), a diterpene lactone from Andrographis paniculata , is known for its anti-inflammatory activity, but its effects on individual branches of TLR signaling remain unclear. RAW264.7 and 293T cells were used to evaluate the effects of DAG on MyD88- and TRIF-dependent signaling pathways. Luciferase reporter assays, Western blotting, RT-PCR, and nitrite assays were employed to assess NF-κB and IRF3 activation and inflammatory mediator expression. Statistical analysis was performed using one-way ANOVA. DAG significantly inhibited activation of NF-κB and IRF3 induced by TLR agonists (LPS, MALP-2, and Poly[I:C]) and by overexpression of MyD88- and TRIF-associated downstream molecules. Correspondingly, DAG suppressed iNOS, IFNβ, and IP-10 expression, indicating dual inhibition of both TLR signaling branches. DAG exerts dual inhibitory effects on MyD88- and TRIF-dependent TLR signaling, attenuating inflammatory mediator expression. DAG may represent a promising molecular scaffold or mechanistic candidate for modulating TLR-mediated inflammatory signaling.
The Dismantling of Environmental Protections — A Grave Threat to America’s Health
Low-cost Kirigami-inspired deployable dual-polarized MIMO antenna with angular pattern diversity
Rainfall regionalization in Thailand based on statistically validated clustering and its application to spatial rainfall interpolation
Abstract Rainfall regionalization plays an essential role in identifying homogeneous rainfall patterns and supporting hydrological and climate analyses. In Thailand, the regionalization adopted by the Thai Meteorological Department (TMD) is primarily based on monsoon wind systems and broad geographic boundaries, which may not adequately represent sub-regional variability in rainfall behavior. This study proposes a data-driven framework to identify homogeneous rainfall regions using monthly rainfall observations from 67 stations across Thailand over the period 1983–2018. Two representations are examined: a standardized representation and a principal component analysis (PCA)-based standardized representation. K-means clustering is applied to both representations, and the resulting clusters are then evaluated using L-moment homogeneity testing, principal component visualization, and statistical and spatial validity indices. The PCA-standardized dataset produces clusters with improved separation and stronger homogeneity relative to the standardized dataset, and the resulting rainfall regions are further interpreted in terms of their physical rainfall characteristics. The practical relevance of the identified regions is further demonstrated through leave-one-out cross-validation comparing inverse distance weighting (IDW), K-nearest-neighbor IDW, and cluster-based IDW approaches using the proposed regions, existing data-driven regions, and TMD regions. The proposed cluster-based IDW approach achieves interpolation error reductions of approximately 9.18–11.55% compared with conventional IDW- and TMD-based alternatives, while providing performance comparable to that obtained using other recent data-driven regional classifications.
Trends and shifts in groundwater levels across metropolitan France
Coral microbiomes as reservoirs of unknown genomic and biosynthetic diversity
Abstract Coral reefs are marine biodiversity hotspots that provide a wide range of ecosystem services 1 . They are reservoirs of bioactive metabolites, many produced by microorganisms associated with reef invertebrate hosts 2 . However, for the keystone species of coral reefs—the reef-building corals—we still lack a systematic assessment of their microbially encoded biosynthetic potential and the molecular resources at stake due to the alarming decline in reef biodiversity. Here we analysed microbial genomes reconstructed from 820 reef-building coral samples of three representative coral genera collected at 99 reefs across 32 islands throughout the Pacific Ocean ( Tara Pacific expedition) 3 . By contextualizing our analyses with the microbiomes of other reef species, we found that only 10% of the 4,224 microbial species and less than 1% of the 645 species exclusively identified in Tara Pacific samples had genomic information available. Furthermore, the biosynthetic potential of reef-building coral microbiomes rivalled or surpassed that of traditional natural product sources such as sponges. Among the biosynthetically rich bacteria in the reef microbiome, we identified new groups of Acidobacteriota that encode previously unknown enzymology, in turn opening promising avenues for functional protein engineering. Together, this study underscores the importance of conserving coral reefs as vital reservoirs of molecular diversity.