Explore the vast range of titles available.

Nuclear Factor IA, a member of the long-studied Nuclear Factor I family of DNA-binding proteins, plays pivotal roles in development and metabolism. Dysregulation or loss of Nuclear Factor IA is associated with severe neurological defects in humans and disruptions in fatty acid metabolism linked to conditions such as osteoarthritis. Despite extensive study, the DNA recognition mechanism of Nuclear Factor I family proteins remains unresolved. Previous studies have proposed that these proteins dimerize via their DNA-binding domains to bind TGGCA-containing dyad sequences. In this study, we demonstrate that both full-length Nuclear Factor IA and its isolated DNA-binding domain are monomeric in solution, challenging dimer models. Genome-wide ChIP-Seq analysis shows TGGCA half-sites are enriched among Nuclear Factor IA binding motifs. We determine Nuclear Factor IA’s crystal and solution structures bound to half-site and dyad-symmetric DNA motifs, providing a structural basis for its monomeric DNA recognition. Furthermore, functional binding assays show that key residues in Nuclear Factor IA, which facilitate base-specific interactions, are critical for DNA sequence recognition and binding. These findings establish the DNA-binding mechanism of Nuclear Factor IA and provide a detailed molecular framework for understanding the functions of this classic transcription factor family. Nuclear Factor IA is important for development and metabolism. Here, the authors present high-resolution molecular structures of Nuclear Factor IA, and detail how it recognizes the TGGCA DNA motif.

FOXP3 + regulatory T cells (Treg cells) are key for immune homeostasis. Here, we reveal that nuclear receptor corepressor 1 (NCOR1) controls naïve and effector Treg cell states. Upon NCOR1 deletion in T cells, effector Treg cell frequencies were elevated in mice and in in vitro-generated human Treg cells. NCOR1-deficient Treg cells failed to protect mice from severe weight loss and intestinal inflammation associated with CD4 + T cell transfer colitis, indicating impaired suppressive function. NCOR1 controls the transcriptional integrity of Treg cells, since effector gene signatures were already upregulated in naïve NCOR1-deficient Treg cells while effector NCOR1-deficient Treg cells failed to repress genes associated with naïve Treg cells. Moreover, genes related to cholesterol homeostasis including targets of liver X receptor (LXR) were dysregulated in NCOR1-deficient Treg cells. However, genetic ablation of LXRβ in T cells did not revert the effects of NCOR1 deficiency, indicating that NCOR1 controls naïve and effector Treg cell subset composition independent from its ability to repress LXRβ-induced gene expression. Thus, our study reveals that NCOR1 maintains naïve and effector Treg cell states via regulating their transcriptional integrity. We also reveal a critical role for this epigenetic regulator in supporting the suppressive functions of Treg cells in vivo.

The offshore wind farm industry has recently experienced significant global growth. This study presents a thorough site investigation and analysis of the cyclic resistance of marine clay for offshore foundation design, using the Shaba wind farm in southern China as a case study. In-situ cone penetrometer (CPTu) tests and borehole sampling are conducted to explore the geotechnical characteristics of the soils. However, the soil conditions are characterized by multiple layers and complex sedimentary components. The classification and mechanical properties, such as water content and cyclic resistances, are compared through CPTu interpretation and laboratory tests. The findings indicated that a single physical indicator cannot determine cyclic resistance. In addition, the well-established method in existing literature proved unsuitable for marine clay. Consequently, multiple regression analysis shows that a linear relationship exist between cyclic resistance and depth-corrected CPTu index [ EXP ( q E / f s ) 0.3 / H ], hence a new evaluation method is developed to predict the cyclic resistance of marine clay based on CPTu data. This research aims to provide more reliable guidance for geotechnical investigations, supporting the rapid expansion of offshore wind farms.

T helper (Th) 17 cells are not only key in controlling infections mediated by extracellular bacteria and fungi but are also triggering autoimmune responses. Th17 cells comprise heterogeneous subsets, some with pathogenic functions. They can cease to secrete their hallmark cytokine IL-17A and even convert to other T helper lineages, a process known as transdifferentiation relying on plasticity. Both pathogenicity and plasticity are tightly linked to IL-23 signaling. Here, we show that the protein tyrosine kinase Tec is highly induced in Th17 cells. Th17 differentiation was enhanced at low interleukin-6 (IL-6) concentrations in absence of Tec, which correlates with increased STAT3 phosphorylation and higher Il23r expression. Therefore, we uncovered a function for Tec in the IL-6 sensing via STAT3 by CD4 + T cells, defining Tec as a fine-tuning negative regulator of Th17 differentiation. Subsequently, by using the IL-17A fate mapping mouse combined with in vivo adoptive transfer models, we demonstrated that Tec not only restrained effector Th17 differentiation but also pathogenicity and plasticity in a T-cell intrinsic manner. Our data further suggest that Tec regulates inflammatory Th17-driven immune responses directly impacting disease severity in a T-cell-driven colitis model. Notably, consistent with the in vitro findings, elevated levels of the IL-23 receptor (IL-23R) were observed on intestinal pre- and postconversion Th17 cells isolated from diseased Tec −/− mice subjected to adoptive transfer colitis, highlighting a fundamental role of Tec in restraining IL-23R expression, likely via the IL-6-STAT3 signaling axis. Taken together, these findings identify Tec as a negative regulator of Th17 differentiation, pathogenicity, and plasticity, contributing to the mechanisms which help T cells to orchestrate optimal immune protection and to restrain immunopathology.

Skeletal muscle is essential for voluntary movement and exhibits a remarkable capacity for regeneration following injury. NFIX, a member of the Nuclear Factor I (NFI) family of transcription factors, plays a critical role in both skeletal muscle development and regeneration. Despite its emerging importance, the molecular basis of NFIX‐mediated DNA recognition and transcriptional regulation in skeletal muscle remains poorly defined. Here, we demonstrate that NFIX promotes key cellular processes in skeletal muscle cells, as siRNA‐mediated knockdown of NFIX significantly reduces cell proliferation, increases apoptosis, and impairs differentiation. Transcriptomic analysis revealed that NFIX regulates a network of genes involved in muscle metabolism, stress responses, and immune inflammatory responses. Biophysical characterization showed that NFIX exists as a monomer in solution and binds palindromic DNA with a 1:1 stoichiometry. A high‐resolution crystal structure of the NFIX DBD bound to palindromic DNA reveals a monomeric binding mode driven by base‐specific recognition of the TGGCA motif. Mutations that disrupt key DNA‐contacting residues abolished both DNA binding and transcriptional activation in luciferase reporter assays. Together, these findings define the molecular mechanism of NFIX‐dependent gene regulation in skeletal muscle and establish a structural framework for its function, providing new insights into the potential therapeutic targeting of NFIX in muscle diseases. An atomic view of the NFIX–DNA complex uncovers its role in skeletal muscle development and disease. NFIX directs muscle‐related transcriptional programs via sequence‐specific recognition of the TGGCA motif. Integrated biophysical and structural analyses provide the molecular basis of TGGCA major‐groove recognition by NFIX.

To identify risk factors for enteral feeding intolerance screening in critically ill patients, thereby, provide some reference for healthcare staff to assess the risk of feeding intolerance, and lay the foundation for future scale development.  Methods: This study used a mixed methodology, including a literature review, semi-structured interviews, the Delphi technique, and the analytic hierarchy process. We used the literature review and semi-structured interviews (n=22) to draft a preliminarily item pool for feeding intolerance, Delphi technique (n=30) to screen and determine the items, and the analytic hierarchy process to calculate the weight of each item. The study was conducted between June 2014 and September 2015 in Daping Hospital, Third Military Medical University, Chongqing, China.  Results. Twenty-three risk factors were selected for the scale, including 5 dimensions. We assigned a weight to each item according to their impact on the feeding intolerance, with a higher score indicating a greater impact. The weight of each dimension was decreasing as follows: patient conditions, weight score equals 42; general conditions, weight score equals 23; gastrointestinal functions, weight score equals 15; biochemical indexes, weight score equals 14; and treatment measures, weight score equals 6. Conclusion. Developed list of risk factors based on literature review, survey among health care professionals and expert consensus should provide a basis for future studies assessing the risk of feeding intolerance in critically ill patients.

The differentiation of naïve CD4 T cells into T helper (Th) subsets is key for a functional immune response and has to be tightly controlled by transcriptional and epigenetic processes. However, the function of cofactors that connect gene-specific transcription factors with repressive chromatin-modifying enzymes in Th cells is yet unknown. Here we demonstrate an essential role for nuclear receptor corepressor 1 (NCOR1) in regulating naïve CD4 T cell and Th1/Th17 effector transcriptomes. Moreover, NCOR1 binds to a conserved -regulatory element within the locus and controls the extent of IFNγ expression in Th1 cells. Further, NCOR1 controls the survival of activated CD4 T cells and Th1 cells , while Th17 cell survival was not affected in the absence of NCOR1. , effector functions were compromised since adoptive transfer of NCOR1-deficient CD4 T cells resulted in attenuated colitis due to lower frequencies of IFNγ and IFNγ IL-17A Th cells and overall reduced CD4 T cell numbers. Collectively, our data demonstrate that the coregulator NCOR1 shapes transcriptional landscapes in CD4 T cells and controls Th1/Th17 effector functions.

The absorptive capacity of the gut is decreased after severe head injury (SHI), and this may be related to poor recovery. Probiotics may be a promising approach to improving gut absorption. The aim of this study was to investigate the effect of probiotics on gut absorptive capacity (GAC) after SHI. A rat model in which SHI was induced by air percussion was used. One hundred fourteen Sprague-Dawley rats were randomized into three groups: SHI followed by standard enteral nutrition (group A); SHI followed by standard enteral nutrition plus probiotics (group B); and standard chow diet ad libitum (group C, sham-operated). The enteral diets were infused for 14 d after SHI. SHI induced weight loss and decreased the serum concentration of D-xylose and the apparent protein digestibility. Probiotics significantly improved GAC after SHI. Apparent protein digestibility and the concentration of D-xylose were lower in group A than in B or C after 14 d. The rats receiving probiotics showed less weight loss than group A. SHI induced intestinal flora dysfunction and a decrease in villus height and surface area. Digestive enzyme activities and gut motion were also depressed significantly, and these changes were closely related to the decrease in GAC. Probiotics increased villus height and surface area; Escherichia coli counts decreased significantly, and anaerobic counts increased. Probiotics improve the GAC after SHI, perhaps because of enhanced villus surface area, and correction of intestinal flora dysfunction.

Hypoxia-induced microtubule disruption and mitochondrial permeability transition (mPT) are crucial events leading to fatal cell damage and recent studies showed that microtubules (MTs) are involved in the modulation of mitochondrial function. Dynein light chain Tctex-type 1 (DYNLT1) is thought to be associated with MTs and mitochondria. Previously we demonstrated that DYNLT1 knockdown aggravates hypoxia-induced mitochondrial permeabilization, which indicates a role of DYNLT1 in hypoxic cytoprotection. But the underlying regulatory mechanism of DYNLT1 remains illusive. Here we aimed to investigate the phosphorylation alteration of DYNLT1 at serine 82 (S82) in hypoxia (1% O2). We therefore constructed recombinant adenoviruses to generate S82E and S82A mutants, used to transfect H9c2 and HeLa cell lines. Development of hypoxia-induced mPT (MMP examining, Cyt c release and mPT pore opening assay), hypoxic energy metabolism (cellular viability and ATP quantification), and stability of MTs were examined. Our results showed that phosph-S82 (S82-P) expression was increased in early hypoxia; S82E mutation (phosphomimic) aggravated mitochondrial damage, elevated the free tubulin in cytoplasm and decreased the cellular viability; S82A mutation (dephosphomimic) seemed to diminish the hypoxia-induced injury. These data suggest that DYNLT1 phosphorylation at S82 is involved in MTs and mitochondria regulation, and their interaction and cooperation contribute to the cellular hypoxic tolerance. Thus, we provide new insights into a DYNLT1 mechanism in stabilizing MTs and mitochondria, and propose a potential therapeutic target for hypoxia cytoprotective studies.

Background24-Nor-ursodeoxycholic acid (NorUDCA) is a novel therapeutic bile acid for treating immune-mediated cholestatic liver diseases, such as primary sclerosing cholangitis (PSC).ObjectiveSince PSC strongly associates with T helper-type-like 17 (TH17)-mediated intestinal inflammation, we explored NorUDCA’s immunomodulatory potential on TH17 cells.DesignNorUDCA’s impact on TH17 differentiation was assessed using a CD4+TNaive adoptive transfer mouse model, and on intraepithelial TH17 pathogenicity and transdifferentiation using an αCD3 stimulation model combined with interleukin-17A-fate-mapping. Mechanistic studies used molecular and multiomics approaches, flow cytometry and metabolic assays with pathogenic (p) TH17. Pathogenicity of pTH17 exposed to NorUDCA in vitro was evaluated following adoptive transfer in intestinal tissues or the central nervous system (CNS). Key findings were validated in an αCD3-stimulated humanised NSG mouse model reconstituted with peripheral blood mononuclear cells from patients with PSC.ResultsNorUDCA suppressed TH17 effector function and enriched regulatory T cell (Treg) abundance upon CD4+TNaive cell transfer. NorUDCA mitigated intraepithelial TH17 pathogenicity and decreased the generation of proinflammatory ‘TH1-like-TH17’ cells, and enhanced TH17 transdifferentiation into Treg and Tr1 (regulatory type 1) cells in the αCD3-model. In vivo ablation revealed that Treg induction is crucial for NorUDCA’s anti-inflammatory effect on TH17 pathogenicity. Mechanistically, NorUDCA restrained pTH17 effector function and simultaneously promoted functional Treg formation in vitro, by attenuating a glutamine-mTORC1-glycolysis signalling axis. Exposure of pTH17 to NorUDCA dampened their pathogenicity and expansion in the intestine or CNS upon transfer. NorUDCA’s impact on TH17 inflammation was corroborated in the humanised NSG mouse model.ConclusionNorUDCA restricts TH17 inflammation in multiple mouse models, potentiating future clinical applications for treating TH17-mediated intestinal diseases and beyond.