The TGF-ß superfamily cytokine Activin-A is induced during autoimmune neuroinflammation and drives pathogenic Th17 cell differentiation.

Th17 cells are known to exert pathogenic and non-pathogenic functions. Although the cytokine transforming growth factor ß1 (TGF-ß1) is instrumental for Th17 cell differentiation, it is dispensable for generation of pathogenic Th17 cells. Here, we examined the T cell-intrinsic role of Activin-A, a TGF-ß superfamily member closely related to TGF-ß1, in pathogenic Th17 cell differentiation. Activin-A expression was increased in individuals with relapsing-remitting multiple sclerosis and in mice with experimental autoimmune encephalomyelitis. Stimulation with interleukin-6 and Activin-A induced a molecular program that mirrored that of pathogenic Th17 cells and was inhibited by blocking Activin-A signaling. Genetic disruption of Activin-A and its receptor ALK4 in T cells impaired pathogenic Th17 cell differentiation in vitro and in vivo. Mechanistically, extracellular-signal-regulated kinase (ERK) phosphorylation, which was essential for pathogenic Th17 cell differentiation, was suppressed by TGF-ß1-ALK5 but not Activin-A-ALK4 signaling. Thus, Activin-A drives pathogenic Th17 cell differentiation, implicating the Activin-A-ALK4-ERK axis as a therapeutic target for Th17 cell-related diseases.

DIS3 ribonuclease is essential for spermatogenesis and male fertility in mice.

Spermatogonial stem cell (SSC) self-renewal and differentiation provide foundational support for long-term, steady-state spermatogenesis in mammals. Here, we have investigated the essential role of RNA exosome associated DIS3 ribonuclease in maintaining spermatogonial homeostasis and facilitating germ cell differentiation. We have established male germ-cell Dis3 conditional knockout (cKO) mice in which the first and subsequent waves of spermatogenesis are disrupted. This leads to a Sertoli cell-only phenotype and sterility in adult male mice. Bulk RNA-seq documents that Dis3 deficiency partially abolishes RNA degradation and causes significant increases in the abundance of transcripts. This also includes pervasively transcribed PROMoter uPstream Transcripts (PROMPTs), which accumulate robustly in Dis3 cKO testes. In addition, scRNA-seq analysis indicates that Dis3 deficiency in spermatogonia significantly disrupts RNA metabolism and gene expression, and impairs early germline cell development. Overall, we document that exosome-associated DIS3 ribonuclease plays crucial roles in maintaining early male germ cell lineage in mice.

SIRT1 regulates cardiomyocyte alignment during maturation.

Cardiomyocyte elongation and alignment, a critical step in cardiomyocyte maturation starting from the perinatal stage, is crucial for formation of the highly organized intra- and inter-cellular structures for spatially and temporally ordered contraction in adult cardiomyocytes. However, the mechanism(s) underlying the control of cardiomyocyte alignment remains elusive. Here, we report that SIRT1, the most conserved NAD+-dependent protein deacetylase highly expressed in perinatal heart, plays an important role in regulating cardiomyocyte remodeling during development. We observed that SIRT1 deficiency impairs the alignment of cardiomyocytes/myofibrils and disrupts normal beating patterns at late developmental stages in an in vitro differentiation system from human embryonic stem cells. Consistently, deletion of SIRT1 at a late developmental stage in mouse embryos induced the irregular distribution of cardiomyocytes and misalignment of myofibrils, and reduced the heart size. Mechanistically, the expression of several genes involved in chemotaxis, including those in the CXCL12/CXCR4 and CCL2/CCR2/CCR4 pathways, was dramatically blunted during maturation of SIRT1-deficient cardiomyocytes. Pharmacological inhibition of CCL2 signaling suppressed cardiomyocyte alignment. Our study identifies a regulatory factor that modulates cardiomyocyte alignment at the inter-cellular level during maturation.

Visualization, benchmarking and characterization of nested single-cell heterogeneity as dynamic forest mixtures.

A major topic of debate in developmental biology centers on whether development is continuous, discontinuous, or a mixture of both. Pseudo-time trajectory models, optimal for visualizing cellular progression, model cell transitions as continuous state manifolds and do not explicitly model real-time, complex, heterogeneous systems and are challenging for benchmarking with temporal models. We present a data-driven framework that addresses these limitations with temporal single-cell data collected at discrete time points as inputs and a mixture of dependent minimum spanning trees (MSTs) as outputs, denoted as dynamic spanning forest mixtures (DSFMix). DSFMix uses decision-tree models to select genes that account for variations in multimodality, skewness and time. The genes are subsequently used to build the forest using tree agglomerative hierarchical clustering and dynamic branch cutting. We first motivate the use of forest-based algorithms compared to single-tree approaches for visualizing and characterizing developmental processes. We next benchmark DSFMix to pseudo-time and temporal approaches in terms of feature selection, time correlation, and network similarity. Finally, we demonstrate how DSFMix can be used to visualize, compare and characterize complex relationships during biological processes such as epithelial-mesenchymal transition, spermatogenesis, stem cell pluripotency, early transcriptional response from hormones and immune response to coronavirus disease. Our results indicate that the expression of genes during normal development exhibits a high proportion of non-uniformly distributed profiles that are mostly right-skewed and multimodal; the latter being a characteristic of major steady states during development. Our study also identifies and validates gene signatures driving complex dynamic processes during somatic or germline differentiation.

Mapping dynamic molecular changes in hippocampal subregions after traumatic brain injury through spatial proteomics.

BACKGROUND: Traumatic brain injury (TBI) often results in diverse molecular responses, challenging traditional proteomic studies that measure average changes at tissue levels and fail to capture the complexity and heterogeneity of the affected tissues. Spatial proteomics offers a solution by providing insights into sub-region-specific alterations within tissues. This study focuses on the hippocampal sub-regions, analyzing proteomic expression profiles in mice at the acute (1 day) and subacute (7 days) phases of post-TBI to understand subregion-specific vulnerabilities and long-term consequences. METHODS: Three mice brains were collected from each group, including Sham, 1-day post-TBI and 7-day post-TBI. Hippocampal subregions were extracted using Laser Microdissection (LMD) and subsequently analyzed by label-free quantitative proteomics. RESULTS: The spatial analysis reveals region-specific protein abundance changes, highlighting the elevation of FN1, LGALS3BP, HP, and MUG-1 in the stratum moleculare (SM), suggesting potential immune cell enrichment post-TBI. Notably, established markers of chronic traumatic encephalopathy, IGHM and B2M, exhibit specific upregulation in the dentate gyrus bottom (DG2) independent of direct mechanical injury. Metabolic pathway analysis identifies disturbances in glucose and lipid metabolism, coupled with activated cholesterol synthesis pathways enriched in SM at 7-Day post-TBI and subsequently in deeper DG1 and DG2 suggesting a role in neurogenesis and the onset of recovery. Coordinated activation of neuroglia and microtubule dynamics in DG2 suggest recovery mechanisms in less affected regions. Cluster analysis revealed spatial variations post-TBI, indicative of dysregulated neuronal plasticity and neurogenesis and further predisposition to neurological disorders. TBI-induced protein upregulation (MUG-1, PZP, GFAP, TJP, STAT-1, and CD44) across hippocampal sub-regions indicates shared molecular responses and links to neurological disorders. Spatial variations were demonstrated by proteins dysregulated in both or either of the time-points exclusively in each subregion (ELAVL2, CLIC1 in PL, CD44 and MUG-1 in SM, and SHOC2, LGALS3 in DG). CONCLUSIONS: Utilizing advanced spatial proteomics techniques, the study unveils the dynamic molecular responses in distinct hippocampal subregions post-TBI. It uncovers region-specific vulnerabilities and dysregulated neuronal processes, and potential recovery-related pathways that contribute to our understanding of TBI's neurological consequences and provides valuable insights for biomarker discovery and therapeutic targets.

Multi-omics analysis reveals the molecular basis of flavonoid accumulation in fructus of Gardenia (Gardenia jasminoides Ellis).

BACKGROUND: The fruits of Gardenia are rich in flavonoids and geniposides, which have various pharmacological effects such as antioxidant, anti-inflammatory and anticancer. In this study, we analyzed the transcriptome and metabolome of gardenia peel and kernel at different growth stages, revealed the regulatory network related to flavonoid synthesis, and identified the key regulatory genes. RESULTS: The results showed that in terms of flavonoid metabolic pathways, gardenia fruits mainly synthesized cinnamic acid through the phenylpropanoid pathway, and then synthesized flavonoids through the action of catalytic enzymes such as 4-coumaroyl-CoA ligase, chalcone synthase, chalcone isomerase and flavanol synthase, respectively. In addition, we found that the metabolomics data showed a certain spatial and temporal pattern in the expression of genes related to the flavonoid metabolism pathway and the relative content of metabolites, which was related to the development and ripening process of the fruit. CONCLUSIONS: In summary, this study successfully screened out the key genes related to the biosynthesis metabolism of flavonoids in gardenia through the joint analysis of transcriptome and metabolome. This is of certain significance to the in-depth study of the formation mechanism of gardenia efficacy components and the improvement of quality.

Reversing SKI-SMAD4-mediated suppression is essential for TH17 cell differentiation.

T helper 17 (TH17) cells are critically involved in host defence, inflammation, and autoimmunity. Transforming growth factor ß (TGFß) is instrumental in TH17 cell differentiation by cooperating with interleukin-6 (refs 6, 7). Yet, the mechanism by which TGFß enables TH17 cell differentiation remains elusive. Here we reveal that TGFß enables TH17 cell differentiation by reversing SKI-SMAD4-mediated suppression of the expression of the retinoic acid receptor (RAR)-related orphan receptor γt (RORγt). We found that, unlike wild-type T cells, SMAD4-deficient T cells differentiate into TH17 cells in the absence of TGFß signalling in a RORγt-dependent manner. Ectopic SMAD4 expression suppresses RORγt expression and TH17 cell differentiation of SMAD4-deficient T cells. However, TGFß neutralizes SMAD4-mediated suppression without affecting SMAD4 binding to the Rorc locus. Proteomic analysis revealed that SMAD4 interacts with SKI, a transcriptional repressor that is degraded upon TGFß stimulation. SKI controls histone acetylation and deacetylation of the Rorc locus and TH17 cell differentiation via SMAD4: ectopic SKI expression inhibits H3K9 acetylation of the Rorc locus, Rorc expression, and TH17 cell differentiation in a SMAD4-dependent manner. Therefore, TGFß-induced disruption of SKI reverses SKI-SMAD4-mediated suppression of RORγt to enable TH17 cell differentiation. This study reveals a critical mechanism by which TGFß controls TH17 cell differentiation and uncovers the SKI-SMAD4 axis as a potential therapeutic target for treating TH17-related diseases.

Three dimensional models of human thermoregulation: A review.

Numerous human thermoregulatory models have been developed and widely used in various applications such as aerospace, medicine, public health, and physiology research. This paper is a review of three dimensional (3D) models for human thermoregulation. This review begins with a short introduction of thermoregulatory model development followed by key principles for mathematical description of human thermoregulation systems. Different representations of 3D human bodies are discussed with respect to their detail and prediction capability. The human body was divided into fifteen layered cylinders in early 3D models (cylinder model). Recent 3D models have utilized medical image datasets to develop geometrically correct human models (realistic geometry model). The finite element method is mostly used to solve the governing equations and get numerical solutions. The realistic geometry models provide a high degree of anatomical realism and predict whole-body thermoregulatory responses at high resolution and at organ and tissue levels. Thus, 3D models extend to a wide range of applications where temperature distribution is critical, such as hypothermia/hyperthermia therapy and physiology research. The development of thermoregulatory models will continue with the growth in computational power, advancement in numerical methods and simulation software, advances in modern imaging techniques, and progress in the basic science of thermal physiology.

Finite element model of female thermoregulation with geometry based on medical images.

INTRODUCTION: this study describes the development of a female finite element thermoregulatory model (FETM) METHOD: the female body model was developed from medical image datasets of a median U.S. female and was constructed to be anatomically correct. The body model preserves the geometric shapes of 13 organs and tissues, including skin, muscles, fat, bones, heart, lungs, brain, bladder, intestines, stomach, kidneys, liver, and eyes. Heat balance within the body is described by the bio-heat transfer equation. Heat exchange at the skin surface includes conduction, convection, radiation, and sweat evaporation. Vasodilation, vasoconstriction, sweating, and shivering are controlled by afferent and efferent signals to and from the skin and hypothalamus. RESULTS: the model was validated with measured physiological data during exercise and rest in thermoneutral, hot, and cold conditions. Validations show the model predicted the core temperature (rectal and tympanic temperatures) and mean skin temperatures with acceptable accuracy (within 0.5 °C and 1.6 °C, respectively) CONCLUSION: this female FETM predicted high spatial resolution temperature distribution across the female body, which provides quantitative insights into human thermoregulatory responses in females to non-uniform and transient environmental exposure.

The effect of APN, hs-CRP and APN/hs-CRP in periodontitis with DAA.

BACKGROUND: Common chronic infections induced low-grade inflammation has been correlated with atherosclerosis as supported by strong evidence. The balance between pro-and anti-inflammatory factors was exploited to elucidate the effects of chronic periodontitis on diabetes-associated atherosclerosis. METHODS: Study subjects encompassed 30 SPF male rats randomly divided into four groups: A group (NC), B group (T2DM), C group (CP), D group (DM + CP). After developing the model, blood samples were collected from the angular vein analyze serum APN, hs-CRP, and blood lipid. the carotid artery was isolated for HE staining. RESULT: Compared with group A, the serum APN in group B, C and D decreased gradually with the progression of the disease. Serum hs-CRP in group B, C and D was significantly increased. At T3, T4 and T5 in group B, C and D, APN/hs-CRP significantly decreased. TC, LDL and TG significantly increased in group B, D; HDL significantly decreased in group C. Carotid artery HE staining showed: compared with group A, different degrees of endothelial defect, destruction of elastic fibers in the middle membrane, disorder of smooth muscle arrangement, and partial dissolution 、 fragmentation and Calcium salt deposition necrosis occurred in group B, C and D. CONCLUSION: Enhanced systemic inflammation, decreased adiponectin level, and disorganized lipid metabolism with or without type 2 diabetes attributed to local inflammation of periodontitis can result in an imbalance of pro-inflammatory and anti-inflammatory effects. Therefore, it's more meaningful to predict the progression of DAA with anti-inflammatory/pro-inflammatory variation.

Genetically predicted obstructive sleep apnea is causally associated with an increased risk for periodontitis.

BACKGROUND: Although obstructive sleep apnea (OSA) and periodontitis are associated, whether this association is causative is uncertain. METHODS: We conducted a bidirectional Mendelian randomization (MR) analysis using data from publically accessible genome-wide association studies. The single-nucleotide polymorphisms (SNPs) for OSA were derived from 16,761 cases and 201,194 controls. The pooled data of periodontitis association involved up to 17,353 individuals. Disease-associated single-nucleotide polymorphisms were selected as an instrumental variable at the genome-wide significance level (p < 5.0 × 10- 6). Subsequently, the causal effects were estimated using three different methods: inverse variance weighting (IVW), MR-Egger, and weighted median. Then, these causal estimates were expressed as dominance ratios [odds ratio (OR)]. RESULTS: The MR analysis revealed that genetically determined OSA promotes the development of periodontitis [ IVW OR = 1.117, 95% confidence interval (CI) = 1.001-1.246, p = 0.048). Furthermore, no causal effect of genetically predicted periodontitis on OSA was noted in the reverse MR analysis (IVW OR = 1, 95% CI: 0.95-1.06, p = 0.87). The trend in results from the MR-Egger regression and weighted median (WM) was consistent with that in results from the IVW method. The robustness of the results was confirmed by the sensitivity analysis. CONCLUSIONS: In summary, the results of our MR investigation suggest an association between OSA and periodontitis, proposing that early screening and treatment of OSA is beneficial for the prevention and prognosis of periodontitis.

Glucocorticoids and Androgens Protect From Gastric Metaplasia by Suppressing Group 2 Innate Lymphoid Cell Activation.

BACKGROUND & AIMS: The immune compartment is critical for maintaining tissue homeostasis. A weak immune response increases susceptibility to infection, but immune hyperactivation causes tissue damage, and chronic inflammation may lead to cancer development. In the stomach, inflammation damages the gastric glands and drives the development of potentially preneoplastic metaplasia. Glucocorticoids are potent anti-inflammatory steroid hormones that are required to suppress gastric inflammation and metaplasia. However, these hormones function differently in males and females. Here, we investigate the impact of sex on the regulation of gastric inflammation. METHODS: Endogenous glucocorticoids and male sex hormones were removed from mice using adrenalectomy and castration, respectively. Mice were treated with 5α-dihydrotestosterone (DHT) to test the effects of androgens on regulating gastric inflammation. Single-cell RNA sequencing of gastric leukocytes was used to identify the leukocyte populations that were the direct targets of androgen signaling. Type 2 innate lymphoid cells (ILC2s) were depleted by treatment with CD90.2 antibodies. RESULTS: We show that adrenalectomized female mice develop spontaneous gastric inflammation and spasmolytic polypeptide-expressing metaplasia (SPEM) but that the stomachs of adrenalectomized male mice remain quantitatively normal. Simultaneous depletion of glucocorticoids and sex hormones abolished the male-protective effects and triggered spontaneous pathogenic gastric inflammation and SPEM. Treatment of female mice with DHT prevented gastric inflammation and SPEM development when administered concurrent with adrenalectomy and also reversed the pathology when administered after disease onset. Single-cell RNAseq of gastric leukocytes revealed that ILC2s expressed abundant levels of both the glucocorticoid receptor (Gr) and androgen receptor (Ar). We demonstrated that DHT treatment potently suppressed the expression of the proinflammatory cytokines Il13 and Csf2 by ILC2s. Moreover, ILC2 depletion protected the stomach from SPEM development. CONCLUSIONS: Here, we report a novel mechanism by which glucocorticoids and androgens exert overlapping effects to regulate gastric inflammation. Androgen signaling within ILC2s prevents their pathogenic activation by suppressing the transcription of proinflammatory cytokines. This work revealed a critical role for sex hormones in regulating gastric inflammation and metaplasia.

Periodontitis exacerbates endothelial dysfunctions partly via endothelial-mesenchymal transition in streptozotocin-induced diabetes rats.

OBJECTIVES: Periodontal infections are related to the expansion of diabetes cardiovascular problems. However, the pathological process and probable mechanism remain unexplained. This study investigated the impact of periodontitis on streptozotocin (STZ)-induced diabetes rats' carotid artery. METHODS: We randomized 24 Sprague-Dawley (SD) rats into four groups: control, chronic periodontitis (CP), diabetes mellitus (DM), and DM +CP groups. Fasting blood glucose (FBG) and hemoglobin A1c (HBA1c ) were measured to verify the establishment of the DM model. After euthanasia, the maxillary was collected for further studies like hematoxylin-eosin (HE), Masson staining, and micro-computed tomography (micro-CT) analysis. Immunofluorescence (IF) staining was used to detect endothelial-mesenchymal transition (EndMT)-related markers in carotid artery wall. We further used ELISA and quantitative real-time PCR to investigate the effect of high glucose (HG) and Porphyromonas gingivalis lipopolysaccharide (P.g-LPS) on human umbilical vein endothelial cells (HUVECs). RESULTS: Compared with DM and CP groups, bone resorption and pathological changes of the vascular wall were the most serious in the DM+CP group. The vascular wall of the DM+CP group had a higher level of interleukin (IL)-6 and vascular cell adhesion molecule 1 (VCAM-1). The carotid artery vascular wall of the DM+CP group contained more cells that expressed both mesenchymal and endothelial cell markers, along with elevated transcription factor levels. Furthermore, P.g-LPS and HG upregulated the inflammatory cytokines expression and caused phenotypic changes of HUVECs in vitro. CONCLUSION: Periodontitis exacerbates endothelial dysfunctions partly via endothelial-mesenchymal transition in STZ-induced diabetes rats.

SIRT1-mediated deacetylation of CRABPII regulates cellular retinoic acid signaling and modulates embryonic stem cell differentiation.

Retinoid homeostasis is critical for normal embryonic development. Both the deficiency and excess of these compounds are associated with congenital malformations. Here we demonstrate that SIRT1, the most conserved mammalian NAD⁺-dependent protein deacetylase, contributes to homeostatic retinoic acid (RA) signaling and modulates mouse embryonic stem cell (mESC) differentiation in part through deacetylation of cellular retinoic acid binding protein II (CRABPII). We show that RA-mediated acetylation of CRABPII at K102 is essential for its nuclear accumulation and subsequent activation of RA signaling. SIRT1 interacts with and deacetylates CRABPII, regulating its subcellular localization. Consequently, SIRT1 deficiency induces hyperacetylation and nuclear accumulation of CRABPII, enhancing RA signaling and accelerating mESC differentiation in response to RA. Consistently, SIRT1 deficiency is associated with elevated RA signaling and development defects in mice. Our findings reveal a molecular mechanism that regulates RA signaling and highlight the importance of SIRT1 in regulation of ESC pluripotency and embryogenesis.

Heat Stress Management in the Military: Wet-Bulb Globe Temperature Offsets for Modern Body Armor Systems.

OBJECTIVE: The aim of this study was to model the effect of body armor coverage on body core temperature elevation and wet-bulb globe temperature (WBGT) offset. BACKGROUND: Heat stress is a critical factor influencing the health and safety of military populations. Work duration limits can be imposed to mitigate the risk of exertional heat illness and are derived based on the environmental conditions (WBGT). Traditionally a 3°C offset to WBGT is recommended when wearing body armor; however, modern body armor systems provide a range of coverage options, which may influence thermal strain imposed on the wearer. METHOD: The biophysical properties of four military clothing ensembles of increasing ballistic protection coverage were measured on a heated sweating manikin in accordance with standard international criteria. Body core temperature elevation during light, moderate, and heavy work was modeled in environmental conditions from 16°C to 34°C WBGT using the heat strain decision aid. RESULTS: Increasing ballistic protection resulted in shorter work durations to reach a critical core temperature limit of 38.5°C. Environmental conditions, armor coverage, and work intensity had a significant influence on WBGT offset. CONCLUSION: Contrary to the traditional recommendation, the required WBGT offset was >3°C in temperate conditions (<27°C WBGT), particularly for moderate and heavy work. In contrast, a lower WBGT offset could be applied during light work and moderate work in low levels of coverage. APPLICATION: Correct WBGT offsets are important for enabling adequate risk management strategies for mitigating risks of exertional heat illness.

Methionine metabolism is essential for SIRT1-regulated mouse embryonic stem cell maintenance and embryonic development.

Methionine metabolism is critical for epigenetic maintenance, redox homeostasis, and animal development. However, the regulation of methionine metabolism remains unclear. Here, we provide evidence that SIRT1, the most conserved mammalian NAD+-dependent protein deacetylase, is critically involved in modulating methionine metabolism, thereby impacting maintenance of mouse embryonic stem cells (mESCs) and subsequent embryogenesis. We demonstrate that SIRT1-deficient mESCs are hypersensitive to methionine restriction/depletion-induced differentiation and apoptosis, primarily due to a reduced conversion of methionine to S-adenosylmethionine. This reduction markedly decreases methylation levels of histones, resulting in dramatic alterations in gene expression profiles. Mechanistically, we discover that the enzyme converting methionine to S-adenosylmethionine in mESCs, methionine adenosyltransferase 2a (MAT2a), is under control of Myc and SIRT1. Consistently, SIRT1 KO embryos display reduced Mat2a expression and histone methylation and are sensitive to maternal methionine restriction-induced lethality, whereas maternal methionine supplementation increases the survival of SIRT1 KO newborn mice. Our findings uncover a novel regulatory mechanism for methionine metabolism and highlight the importance of methionine metabolism in SIRT1-mediated mESC maintenance and embryonic development.

A digital tool for prevention and management of cold weather injuries-Cold Weather Ensemble Decision Aid (CoWEDA).

This paper describes a Cold Weather Ensemble Decision Aid (CoWEDA) that provides guidance for cold weather injury prevention, mission planning, and clothing selection. CoWEDA incorporates current science from the disciplines of physiology, meteorology, clothing, and computer modeling. The thermal performance of a cold weather ensemble is defined by endurance times, which are the time intervals from initial exposure until the safety limits are reached. These safety limits correspond to conservative temperature thresholds that provide a warning of the approaching onset of frostbite and/or hypothermia. A validated six-cylinder thermoregulatory model is used to predict human thermal responses to cold while wearing different ensembles. The performance metrics, model, and a database of clothing properties were integrated into a user-friendly software application. CoWEDA is the first tool that allows users to build their own ensembles from the clothing menu (i.e., jackets, footwear, and accessories) for each body region (i.e., head, torso, lower body, hands, feet) and view their selections in the context of physiological strain and the operational consequences. Comparison of predicted values to skin and core temperatures, measured during 17 cold exposures ranging from 0 to -40°C, indicated that the accuracy of CoWEDA prediction is acceptable, and most predictions are within measured mean ± SD. CoWEDA predicts the risk of frostbite and hypothermia and ensures that a selected clothing ensemble is appropriate for expected weather conditions and activities. CoWEDA represents a significant enhancement of required clothing insulation (IREQ, ISO 11079) and wind chill index-based guidance for cold weather safety and survival.

The phosphorylation status of T522 modulates tissue-specific functions of SIRT1 in energy metabolism in mice.

SIRT1, the most conserved mammalian NAD+-dependent protein deacetylase, is an important metabolic regulator. However, the mechanisms by which SIRT1 is regulated in vivo remain unclear. Here, we report that phosphorylation modification of T522 on SIRT1 is crucial for tissue-specific regulation of SIRT1 activity in mice. Dephosphorylation of T522 is critical for repression of its activity during adipogenesis. The phospho-T522 level is reduced during adipogenesis. Knocking-in a constitutive T522 phosphorylation mimic activates the ß-catenin/GATA3 pathway, repressing PPARγ signaling, impairing differentiation of white adipocytes, and ameliorating high-fat diet-induced dyslipidemia in mice. In contrast, phosphorylation of T522 is crucial for activation of hepatic SIRT1 in response to over-nutrition. Hepatic SIRT1 is hyperphosphorylated at T522 upon high-fat diet feeding. Knocking-in a SIRT1 mutant defective in T522 phosphorylation disrupts hepatic fatty acid oxidation, resulting in hepatic steatosis after high-fat diet feeding. In addition, the T522 dephosphorylation mimic impairs systemic energy metabolism. Our findings unveil an important link between environmental cues, SIRT1 phosphorylation, and energy homeostasis and demonstrate that the phosphorylation of T522 is a critical element in tissue-specific regulation of SIRT1 activity in vivo.

Heat strain in chemical protective ensembles: Effects of fabric thermal properties.

An ongoing challenge in material science has been to reduce heat strain experienced by individuals wearing chemical protective ensembles. The objective of this study is to analyze the relationship between the thermal properties of eight chemical protective fabrics and heat strain in ten chemical protective ensembles constructed with those fabrics. The fabric samples were tested on a sweating guarded hot plate to measure fabric thermal and evaporative resistance. The ensembles were then tested on thermal manikins to measure ensemble thermal and evaporative resistance. An empirical thermoregulatory model, the Heat Strain Decision Aid (HSDA), was used to predict thermal responses of core temperature and endurance times. Model inputs included ensemble thermal and evaporative resistances, four environmental conditions and a metabolic rate of 400 W. The fabric intrinsic thermal and evaporative resistances ranged from 0.01 to 0.05 m2 °C·W-1 and from 5.9 to 12.82 m2 Pa·W-1, respectively. Ensemble intrinsic thermal and evaporative resistances ranged from 0.23 to 0.31 m2 °C·W-1 and 51.7-67.8 m2 Pa·W-1, respectively. Predicted endurance times varied from 170 to 300 min at 20 °C/50% RH/2 m s-1 and 26 °C/55% RH/9 m s-1 conditions, and varied from 91 to 98 min at 30 °C/75% RH/2 m s-1 and 40 °C/20% RH/2 m s-1 conditions. Improved fabric thermal properties reduced heat strain and extended endurance times, but the magnitude of the extended times is dependent on the environmental conditions. Consequently, the benefits of improved fabric thermal properties may only be observed under certain environmental conditions.

Intestinal Epithelial Sirtuin 1 Regulates Intestinal Inflammation During Aging in Mice by Altering the Intestinal Microbiota.

BACKGROUND & AIMS: Intestinal epithelial homeostasis is maintained by complex interactions among epithelial cells, commensal gut microorganisms, and immune cells. Disruption of this homeostasis is associated with disorders such as inflammatory bowel disease (IBD), but the mechanisms of this process are not clear. We investigated how Sirtuin 1 (SIRT1), a conserved mammalian NAD+-dependent protein deacetylase, senses environmental stress to alter intestinal integrity. METHODS: We performed studies of mice with disruption of Sirt1 specifically in the intestinal epithelium (SIRT1 iKO, villin-Cre+, Sirt1flox/flox mice) and control mice (villin-Cre-, Sirt1flox/flox) on a C57BL/6 background. Acute colitis was induced in some mice by addition of 2.5% dextran sodium sulfate to drinking water for 5-9 consecutive days. Some mice were given antibiotics via their drinking water for 4 weeks to deplete their microbiota. Some mice were fed with a cholestyramine-containing diet for 7 days to sequester their bile acids. Feces were collected and proportions of microbiota were analyzed by 16S rRNA amplicon sequencing and quantitative PCR. Intestines were collected from mice and gene expression profiles were compared by microarray and quantitative PCR analyses. We compared levels of specific mRNAs between colon tissues from age-matched patients with ulcerative colitis (n=10) vs without IBD (n=8, controls). RESULTS: Mice with intestinal deletion of SIRT1 (SIRT1 iKO) had abnormal activation of Paneth cells starting at the age of 5-8 months, with increased activation of NF-κB, stress pathways, and spontaneous inflammation at 22-24 months of age, compared with control mice. SIRT1 iKO mice also had altered fecal microbiota starting at 4-6 months of age compared with control mice, in part because of altered bile acid metabolism. Moreover, SIRT1 iKO mice with defective gut microbiota developed more severe colitis than control mice. Intestinal tissues from patients with ulcerative colitis expressed significantly lower levels of SIRT1 mRNA than controls. Intestinal tissues from SIRT1 iKO mice given antibiotics, however, did not have signs of inflammation at 22-24 months of age, and did not develop more severe colitis than control mice at 4-6 months. CONCLUSIONS: In analyses of intestinal tissues, colitis induction, and gut microbiota in mice with intestinal epithelial disruption of SIRT1, we found this protein to prevent intestinal inflammation by regulating the gut microbiota. SIRT1 might therefore be an important mediator of host-microbiome interactions. Agents designed to activate SIRT1 might be developed as treatments for IBDs.