Publications by authors named "Xiaojiang Xu"

76 Publications

SIRT1 regulates sphingolipid metabolism and neural differentiation of mouse embryonic stem cells through c-Myc-SMPDL3B.

Elife 2021 May 27;10. Epub 2021 May 27.

Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, Triangle Park, United States.

Sphingolipids are important structural components of cell membranes and prominent signaling molecules controlling cell growth, differentiation, and apoptosis. Sphingolipids are particularly abundant in the brain, and defects in sphingolipid degradation are associated with several human neurodegenerative diseases. However, molecular mechanisms governing sphingolipid metabolism remain unclear. Here, we report that sphingolipid degradation is under transcriptional control of SIRT1, a highly conserved mammalian NAD-dependent protein deacetylase, in mouse embryonic stem cells (mESCs). Deletion of SIRT1 results in accumulation of sphingomyelin in mESCs, primarily due to reduction of SMPDL3B, a GPI-anchored plasma membrane bound sphingomyelin phosphodiesterase. Mechanistically, SIRT1 regulates transcription of through c-Myc. Functionally, SIRT1 deficiency-induced accumulation of sphingomyelin increases membrane fluidity and impairs neural differentiation in vitro and in vivo. Our findings discover a key regulatory mechanism for sphingolipid homeostasis and neural differentiation, further imply that pharmacological manipulation of SIRT1-mediated sphingomyelin degradation might be beneficial for treatment of human neurological diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7554/eLife.67452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8216717PMC
May 2021

Single-cell analysis of pancreatic ductal adenocarcinoma identifies a novel fibroblast subtype associated with poor prognosis but better immunotherapy response.

Cell Discov 2021 May 25;7(1):36. Epub 2021 May 25.

State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.

The current pathological and molecular classification of pancreatic ductal adenocarcinoma (PDAC) provides limited guidance for treatment options, especially for immunotherapy. Cancer-associated fibroblasts (CAFs) are major players of desmoplastic stroma in PDAC, modulating tumor progression and therapeutic response. Using single-cell RNA sequencing, we explored the intertumoral heterogeneity among PDAC patients with different degrees of desmoplasia. We found substantial intertumoral heterogeneity in CAFs, ductal cancer cells, and immune cells between the extremely dense and loose types of PDACs (dense-type, high desmoplasia; loose-type, low desmoplasia). Notably, no difference in CAF abundance was detected, but a novel subtype of CAFs with a highly activated metabolic state (meCAFs) was found in loose-type PDAC compared to dense-type PDAC. MeCAFs had highly active glycolysis, whereas the corresponding cancer cells used oxidative phosphorylation as a major metabolic mode rather than glycolysis. We found that the proportion and activity of immune cells were much higher in loose-type PDAC than in dense-type PDAC. Then, the clinical significance of the CAF subtypes was further validated in our PDAC cohort and a public database. PDAC patients with abundant meCAFs had a higher risk of metastasis and a poor prognosis but showed a dramatically better response to immunotherapy (64.71% objective response rate, one complete response). We characterized the intertumoral heterogeneity of cellular components, immune activity, and metabolic status between dense- and loose-type PDACs and identified meCAFs as a novel CAF subtype critical for PDAC progression and the susceptibility to immunotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41421-021-00271-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8149399PMC
May 2021

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

Gastroenterology 2021 May 7. Epub 2021 May 7.

Molecular Endocrinology Group, Signal Transduction Laboratory, North Carolina. Electronic address:

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1053/j.gastro.2021.04.075DOI Listing
May 2021

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

Hum Factors 2021 Apr 16:187208211005220. Epub 2021 Apr 16.

139261 Queensland University of Technology, Brisbane, Australia.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/00187208211005220DOI Listing
April 2021

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

Int J Biometeorol 2021 Apr 4. Epub 2021 Apr 4.

Biophysics and Biomedical Modeling Division, U.S. Army Research Institute of Environmental Medicine, 10 General Greene Avenue, Natick, MA, 01760-5007, USA.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00484-021-02113-0DOI Listing
April 2021

Single-Cell Transcriptome Analysis Decipher New Potential Regulation Mechanism of ACE2 and NPs Signaling Among Heart Failure Patients Infected With SARS-CoV-2.

Front Cardiovasc Med 2021 23;8:628885. Epub 2021 Feb 23.

Kelly Government Solutions, Rockville, MD, United States.

COVID-19 patients with comorbidities such as hypertension or heart failure (HF) are associated with poor clinical outcomes. The cellular distribution of Angiotensin-converting enzyme 2 (ACE2), the critical enzyme for SARS-CoV-2 infection, in the human heart is unknown. We explore the underlying mechanism that leads to increased susceptibility to SARS-CoV-2 in patients with cardiovascular diseases and patients of cardiac dysfunction have increased risk of multi-organ injury compared with patients of normal cardiac function. We analyzed single-cell RNA sequencing (scRNA-seq) data in both normal and failing hearts. The results demonstrated that ACE2 is present in cardiomyocytes (CMs) and non-CMs, while the number of ACE2-postive (ACE2+) CMs and ACE2 gene expression in these CMs are significantly increased in the failing hearts. Interestingly, both brain natriuretic peptides (BNP) and atrial natriuretic peptide (ANP) are significantly up-regulated in the ACE2+ CMs, which is consistent with other studies that ACE2, ANP, and BNP increased in HF patients. We found that genes related to virus entry, virus replication and suppression of interferon-gamma signaling are all up-regulated in failing CMs, and the increase was significantly higher in ACE2+ CMs, suggesting that these CMs may be more vulnerable to virus infection. As the level of expression of both ACE2 and BNP in CMs were up-regulated, we further performed retrospective analysis of the plasma BNP levels and clinical outcomes of 91 COVID-19 patients from a single-center. Patients with higher plasma BNP were associated with significantly higher mortality and expression levels of inflammatory and infective markers. In the failing heart, the upregulation of ACE2 and virus infection associated genes could potentially facilitate SARS-CoV-2 virus entry and replication in these vulnerable cardiomyocyte subsets. COVID-19 patients with higher plasma BNP levels had poorer clinical outcomes. These observations may allude to a potential regulatory association between ACE2 and BNP in mediating myocarditis associated with COVID-19.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fcvm.2021.628885DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7952310PMC
February 2021

Histone crotonylation promotes mesoendodermal commitment of human embryonic stem cells.

Cell Stem Cell 2021 04 14;28(4):748-763.e7. Epub 2021 Jan 14.

Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA. Electronic address:

Histone crotonylation is a non-acetyl histone lysine modification that is as widespread as acetylation. However, physiological functions associated with histone crotonylation remain almost completely unknown. Here we report that histone crotonylation is crucial for endoderm differentiation. We demonstrate that key crotonyl-coenzyme A (CoA)-producing enzymes are specifically induced in endodermal cells during differentiation of human embryonic stem cells (hESCs) in vitro and in mouse embryos, where they function to increase histone crotonylation and enhance endodermal gene expression. Chemical enhancement of histone crotonylation promotes endoderm differentiation of hESCs, whereas deletion of crotonyl-CoA-producing enzymes reduces histone crotonylation and impairs meso/endoderm differentiation in vitro and in vivo. Our study uncovers a histone crotonylation-mediated mechanism that promotes endodermal commitment of pluripotent stem cells, which may have important implications for therapeutic strategies against a number of human diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.stem.2020.12.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026719PMC
April 2021

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

Immunity 2021 Feb 8;54(2):308-323.e6. Epub 2021 Jan 8.

Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address:

Th17 cells are known to exert pathogenic and non-pathogenic functions. Although the cytokine transforming growth factor β1 (TGF-β1) 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-β superfamily member closely related to TGF-β1, 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-β1-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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.immuni.2020.12.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878438PMC
February 2021

A multicenter study benchmarking single-cell RNA sequencing technologies using reference samples.

Nat Biotechnol 2020 Dec 21. Epub 2020 Dec 21.

Center for Genomics, School of Medicine, Loma Linda University, Loma Linda, CA, USA.

Comparing diverse single-cell RNA sequencing (scRNA-seq) datasets generated by different technologies and in different laboratories remains a major challenge. Here we address the need for guidance in choosing algorithms leading to accurate biological interpretations of varied data types acquired with different platforms. Using two well-characterized cellular reference samples (breast cancer cells and B cells), captured either separately or in mixtures, we compared different scRNA-seq platforms and several preprocessing, normalization and batch-effect correction methods at multiple centers. Although preprocessing and normalization contributed to variability in gene detection and cell classification, batch-effect correction was by far the most important factor in correctly classifying the cells. Moreover, scRNA-seq dataset characteristics (for example, sample and cellular heterogeneity and platform used) were critical in determining the optimal bioinformatic method. However, reproducibility across centers and platforms was high when appropriate bioinformatic methods were applied. Our findings offer practical guidance for optimizing platform and software selection when designing an scRNA-seq study.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41587-020-00748-9DOI Listing
December 2020

The SKI proto-oncogene restrains the resident CD103CD8 T cell response in viral clearance.

Cell Mol Immunol 2020 Jul 1. Epub 2020 Jul 1.

Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.

Acute viral infection causes illness and death. In addition, an infection often results in increased susceptibility to a secondary infection, but the mechanisms behind this susceptibility are poorly understood. Since its initial identification as a marker for resident memory CD8 T cells in barrier tissues, the function and regulation of CD103 integrin (encoded by ITGAE gene) have been extensively investigated. Nonetheless, the function and regulation of the resident CD103CD8 T cell response to acute viral infection remain unclear. Although TGFβ signaling is essential for CD103 expression, the precise molecular mechanism behind this regulation is elusive. Here, we reveal a TGFβ-SKI-Smad4 pathway that critically and specifically directs resident CD103CD8 T cell generation for protective immunity against primary and secondary viral infection. We found that resident CD103CD8 T cells are abundant in both lymphoid and nonlymphoid tissues from uninfected mice. CD103 acts as a costimulation signal to produce an optimal antigenic CD8 T cell response to acute viral infection. There is a reduction in resident CD103CD8 T cells following primary infection that results in increased susceptibility of the host to secondary infection. Intriguingly, CD103 expression inversely and specifically correlates with SKI proto-oncogene (SKI) expression but not R-Smad2/3 activation. Ectopic expression of SKI restricts CD103 expression in CD8 T cells in vitro and in vivo to hamper viral clearance. Mechanistically, SKI is recruited to the Itgae loci to directly suppress CD103 transcription by regulating histone acetylation in a Smad4-dependent manner. Our study therefore reveals that resident CD103CD8 T cells dictate protective immunity during primary and secondary infection. Interfering with SKI function may amplify the resident CD103CD8 T cell response to promote protective immunity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41423-020-0495-7DOI Listing
July 2020

Single-cell Transcriptome Analysis Indicates New Potential Regulation Mechanism of ACE2 and NPs signaling among heart failure patients infected with SARS-CoV-2.

medRxiv 2020 May 15. Epub 2020 May 15.

Integrative Bioinformatics, ESCBL, NIEHS, National Institutes of Health, Research Triangle Park, NC, 27709, USA.

Background: COVID-19 patients with comorbidities such as hypertension or heart failure (HF) are associated with poor clinical outcomes. Angiotensin-converting enzyme 2 (ACE2), the critical enzyme for SARS-CoV-2 infection, is broadly expressed in many organs including heart. However, the cellular distribution of ACE2 in the human heart, particularly the failing heart is unknown.

Methods: We analyzed single-cell RNA sequencing (scRNA-seq) data in both normal and failing hearts, and characterized the ACE2 gene expression profile in various cell subsets, especially in cardiomyocyte subsets, as well as its interaction with gene networks relating to various defense and immune responses at the single cell level.

Results: The results demonstrated that ACE2 is present in cardiomyocytes (CMs), endothelial cells, fibroblasts and smooth muscle cells in the heart, while the number of ACE2-postive (ACE2+) CMs and ACE2 gene expression in these CMs are significantly increased in the failing hearts. Interestingly, both brain natriuretic peptides (BNP) and atrial natriuretic peptide (ANP) are significantly up-regulated in the ACE2+ CMs. Further analysis shows that ANP, BNP and ACE2 may form a negative feedback loop with a group of genes associated with the development of heart failure. To our surprise, we found that genes related to virus entry, virus replication and suppression of interferon-gamma(IFN-γ)signaling are all up-regulated in CMs in failing hearts, and the increases were significantly higher in ACE2+ CMs as compared with ACE2 negative (ACE2-) CMs, suggesting that these ACE2+ CMs may be more vulnerable to virus infection. Since ACE2 expression is correlated with BNP expression, we further performed retrospective analysis of the plasma BNP levels and clinic outcome of 91 COVID-19 patients from a single-center. Patients with higher plasma BNP were associated with significantly higher mortality rate and expression levels of inflammatory and infective markers such as procalcitonin and C-reactive protein.

Conclusion: In the failing heart, the upregulation of ACE2 and virus infection associated genes, as well as the increased expression of ANP and BNP could facilitate SARS-CoV-2 virus entry and replication in these vulnerable cardiomyocyte subsets. These findings may advance our understanding of the underlying molecular mechanisms of myocarditis associated with COVID-19.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/2020.04.30.20081257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7241106PMC
May 2020

scRNA-seq Profiling of Human Testes Reveals the Presence of the ACE2 Receptor, A Target for SARS-CoV-2 Infection in Spermatogonia, Leydig and Sertoli Cells.

Cells 2020 04 9;9(4). Epub 2020 Apr 9.

Integrative Bioinformatics, ESCBL, NIEHS, National Institutes of Health, Research Triangle Park, NC 27709, USA.

In December 2019, a novel coronavirus (SARS-CoV-2) was identified in COVID-19 patients in Wuhan, Hubei Province, China. SARS-CoV-2 shares both high sequence similarity and the use of the same cell entry receptor, angiotensin-converting enzyme 2 (ACE2), with severe acute respiratory syndrome coronavirus (SARS-CoV). Several studies have provided bioinformatic evidence of potential routes of SARS-CoV-2 infection in respiratory, cardiovascular, digestive and urinary systems. However, whether the reproductive system is a potential target of SARS-CoV-2 infection has not yet been determined. Here, we investigate the expression pattern of ACE2 in adult human testes at the level of single-cell transcriptomes. The results indicate that ACE2 is predominantly enriched in spermatogonia and Leydig and Sertoli cells. Gene Set Enrichment Analysis (GSEA) indicates that Gene Ontology (GO) categories associated with viral reproduction and transmission are highly enriched in ACE2-positive spermatogonia, while male gamete generation related terms are downregulated. Cell-cell junction and immunity-related GO terms are increased in ACE2-positive Leydig and Sertoli cells, but mitochondria and reproduction-related GO terms are decreased. These findings provide evidence that the human testis is a potential target of SARS-CoV-2 infection, which may have significant impact on our understanding of the pathophysiology of this rapidly spreading disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cells9040920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226809PMC
April 2020

Bacteria Boost Mammalian Host NAD Metabolism by Engaging the Deamidated Biosynthesis Pathway.

Cell Metab 2020 03;31(3):564-579.e7

Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA. Electronic address:

Nicotinamide adenine dinucleotide (NAD), a cofactor for hundreds of metabolic reactions in all cell types, plays an essential role in metabolism, DNA repair, and aging. However, how NAD metabolism is impacted by the environment remains unclear. Here, we report an unexpected trans-kingdom cooperation between bacteria and mammalian cells wherein bacteria contribute to host NAD biosynthesis. Bacteria confer resistance to inhibitors of NAMPT, the rate-limiting enzyme in the amidated NAD salvage pathway, in cancer cells and xenograft tumors. Mechanistically, a microbial nicotinamidase (PncA) that converts nicotinamide to nicotinic acid, a precursor in the alternative deamidated NAD salvage pathway, is necessary and sufficient for this protective effect. Using stable isotope tracing and microbiota-depleted mice, we demonstrate that this bacteria-mediated deamidation contributes substantially to the NAD-boosting effect of oral nicotinamide and nicotinamide riboside supplementation in several tissues. Collectively, our findings reveal an important role of bacteria-enabled deamidated pathway in host NAD metabolism.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cmet.2020.02.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7194078PMC
March 2020

Inhibition of miR-378a-3p by Inflammation Enhances IL-33 Levels: A Novel Mechanism of Alarmin Modulation in Ulcerative Colitis.

Front Immunol 2019 20;10:2449. Epub 2019 Nov 20.

Innate Immunity Laboratory, Immunology Program, Faculty of Medicine, Biomedical Sciences Institute, Universidad de Chile, Santiago, Chile.

Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) characterized by mucosa damage associated with an uncontrolled inflammatory response. This immunological impairment leads to altered inflammatory mediators such as IL-33, which is shown to increase in the mucosa of active UC (aUC) patients. MicroRNAs present a distorted feature in inflamed colonic mucosa and are potential IL-33 regulating candidates in UC. Therefore, we studied the microRNA and mRNA profiles in inflamed colonic samples of UC patients, evaluating the effect of a microRNA (selected by analysis and its expression in UC patients), on IL-33 under inflammatory conditions. We found that inflamed mucosa ( = 8) showed increased expression of 40 microRNAs and 2,120 mRNAs, while 49 microRNAs and 1,734 mRNAs were decreased, as determined by microarrays. In particular, IL-33 mRNA showed a 3.8-fold increase and eight members of a microRNA family (miR-378), which targets IL-33 mRNA in the 3'UTR, were decreased (-3.9 to -3.0 times). We selected three members of the miR-378 family (miR-378a-3p, miR-422a, and miR-378c) according to background information and interaction energy analysis, for further correlation analyses with IL-33 expression through qPCR and ELISA, respectively. We determined that aUC ( = 24) showed high IL-33 levels, and decreased expression of miR-378a-3p and miR-422a compared to inactive UC ( = 10) and controls ( = 6). Moreover, both microRNAs were inversely correlated with IL-33 expression, while miR-378c does not show a significant difference. To evaluate the effect of TNFα on the studied microRNAs, aUC patients with anti-TNF therapy were compared to aUC receiving other treatments. The levels of miR-378a-3p and miR-378c were higher in aUC patients with anti-TNF. Based on these findings, we selected miR-378a-3p to exploring the molecular mechanism involved by assays, showing that over-expression of miR-378a-3p decreased the levels of an IL-33 target sequence β-gal-reporter gene in HEK293 cells. Stable miR-378a-3p over-expression/inhibition inversely modulated IL-33 content and altered viability of HT-29 cells. Additionally, in an inflammatory context, TNFα decreased miR-378a-3p levels in HT-29 cells enhancing IL-33 expression. Together, our results propose a regulatory mechanism of IL-33 expression exerted by miR-378a-3p in an inflammatory environment, contributing to the understanding of UC pathogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2019.02449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6879552PMC
November 2020

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

J Therm Biol 2019 Dec 9;86:102435. Epub 2019 Oct 9.

Biophysics and Biomedical Modeling Division, U.S. Army Research Institute of Environmental Medicine, 10 General Greene Avenue, Natick, MA, 01760-5007, USA.

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 m °C·W and from 5.9 to 12.82 m Pa·W, respectively. Ensemble intrinsic thermal and evaporative resistances ranged from 0.23 to 0.31 m °C·W and 51.7-67.8 m Pa·W, respectively. Predicted endurance times varied from 170 to 300 min at 20 °C/50% RH/2 m s and 26 °C/55% RH/9 m s conditions, and varied from 91 to 98 min at 30 °C/75% RH/2 m s and 40 °C/20% RH/2 m s 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtherbio.2019.102435DOI Listing
December 2019

Sertoli cell-only phenotype and scRNA-seq define PRAMEF12 as a factor essential for spermatogenesis in mice.

Nat Commun 2019 11 15;10(1):5196. Epub 2019 Nov 15.

Laboratory of Cellular and Developmental Biology, NIDDK, National Institutes of Health, Bethesda, MD, 20892, USA.

Spermatogonial stem cells (SSCs) have the dual capacity to self-renew and differentiate into progenitor spermatogonia that develop into mature spermatozoa. Here, we document that preferentially expressed antigen of melanoma family member 12 (PRAMEF12) plays a key role in maintenance of the spermatogenic lineage. In male mice, genetic ablation of Pramef12 arrests spermatogenesis and results in sterility which can be rescued by transgenic expression of Pramef12. Pramef12 deficiency globally decreases expression of spermatogenic-related genes, and single-cell transcriptional analysis of post-natal male germline cells identifies four spermatogonial states. In the absence of Pramef12 expression, there are fewer spermatogonial stem cells which exhibit lower expression of SSC maintenance-related genes and are defective in their ability to differentiate. The disruption of the first wave of spermatogenesis in juvenile mice results in agametic seminiferous tubules. These observations mimic a Sertoli cell-only syndrome in humans and may have translational implications for reproductive medicine.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-019-13193-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858368PMC
November 2019

Mass spectrometric identification of candidate RNA-binding proteins associated with Transition Nuclear Protein mRNA in the mouse testis.

Sci Rep 2019 09 20;9(1):13618. Epub 2019 Sep 20.

Epigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, 27709, USA.

Spermatogenesis is a differentiation process that requires dramatic changes to DNA architecture, a process governed in part by Transition Nuclear Proteins 1 and 2 (TNP1 and TNP2). Translation of Tnp1 and Tnp2 mRNAs is temporally disengaged from their transcription. We hypothesized that RNA regulatory proteins associate specifically with Tnp mRNAs to control the delayed timing of their translation. To identify potential regulatory proteins, we isolated endogenous mRNA/protein complexes from testis extract and identified by mass spectrometry proteins that associated with one or both Tnp transcripts. Five proteins showed strong association with Tnp transcripts but had low signal when Actin mRNA was isolated. We visualized the expression patterns in testis sections of the five proteins and found that each of the proteins was detected in germ cells at the appropriate stages to regulate Tnp RNA expression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-019-50052-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6754440PMC
September 2019

Controllable organic magnetoresistance in polyaniline coated poly(p-phenylene-2,6-benzobisoxazole) short fibers.

Chem Commun (Camb) 2019 Aug;55(68):10068-10071

Shanghai Key Lab of Chemical Assessment and Sustainability, School of Chemical Science and Engineering, Tongji University, Shanghai 200092, People's Republic of China.

Herein, we first report a tunable organic magnetoresistance (OMAR) effect in polyaniline (PANI) coated acid treated poly(p-phenylene-2,6-benzobisoxazole) (t-PBO) short fibers. This unique OMAR is interpreted using the paramagnetic nature of PBO molecules combined with the localization length a0 calculated from the wave-function shrinkage model and forward interference model.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/c9cc04789aDOI Listing
August 2019

Divers risk accelerated fatigue and core temperature rise during fully-immersed exercise in warmer water temperature extremes.

Temperature (Austin) 2019 13;6(2):150-157. Epub 2019 Apr 13.

Navy Experimental Diving Unit (NEDU), Panama City, Florida, USA.

Physiological responses to work in cold water have been well studied but little is known about the effects of exercise in warm water; an overlooked but critical issue for certain military, scientific, recreational, and professional diving operations. This investigation examined core temperature responses to fatiguing, fully-immersed exercise in extremely warm waters. Twenty-one male U.S. Navy divers (body mass, 87.3 ± 12.3 kg) were monitored during rest and fatiguing exercise while fully-immersed in four different water temperatures (Tw): 34.4, 35.8, 37.2, and 38.6°C (Tw, Tw, Tw, and Tw respectively). Participants exercised on an underwater cycle ergometer until volitional fatigue or core temperature limits were reached. Core body temperature and heart rate were monitored continuously. Trial performance time decreased significantly as water temperature increased (Tw, 174 ± 12 min; Tw, 115 ± 13 min; Tw, 50 ± 13 min; Tw, 34 ± 14 min). Peak core body temperature during work was significantly lower in Tw water (38.31 ± 0.49°C) than in warmer temperatures (Tw, 38.60 ± 0.55°C; Tw, 38.82 ± 0.76°C; Tw, 38.97 ± 0.65°C). Core body temperature rate of change increased significantly with warmer water temperature (Tw, 0.39 ± 0.28°C·h; Tw, 0.80 ± 0.19°C·h; Tw, 2.02 ± 0.31°C·h; Tw, 3.54 ± 0.41°C·h). Physically active divers risk severe hyperthermia in warmer waters. Increases in water temperature drastically increase the rate of core body temperature rise during work in warm water. New predictive models for core temperature based on workload and duration of warm water exposure are needed to ensure warm water diving safety.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/23328940.2019.1599182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6620004PMC
April 2019

Deletion of the Cardiomyocyte Glucocorticoid Receptor Leads to Sexually Dimorphic Changes in Cardiac Gene Expression and Progression to Heart Failure.

J Am Heart Assoc 2019 08 17;8(15):e011012. Epub 2019 Jul 17.

Signal Transduction Laboratory National Institute of Environmental Health Sciences National Institutes of Health Department of Health and Human Services Research Triangle Park NC.

Background The contribution of glucocorticoids to sexual dimorphism in the heart is essentially unknown. Therefore, we sought to determine the sexually dimorphic actions of glucocorticoid signaling in cardiac function and gene expression. To accomplish this goal, we conducted studies on mice lacking glucocorticoid receptors (GR) in cardiomyocytes (cardioGRKO mouse model). Methods and Results Deletion of cardiomyocyte GR leads to an increase in mortality because of the development of spontaneous cardiac pathology in both male and female mice; however, females are more resistant to GR signaling inactivation in the heart. Male cardioGRKO mice had a median survival age of 6 months. In contrast, females had a median survival age of 10 months. Transthoracic echocardiography data showed phenotypic differences between male and female cardioGRKO hearts. By 3 months of age, male cardioGRKO mice exhibited left ventricular systolic dysfunction. Conversely, no significant functional deficits were observed in female cardioGRKO mice at the same time point. Functional sensitivity of male hearts to the loss of cardiomyocyte GR was reversed following gonadectomy. RNA-Seq analysis showed that deleting GR in the male hearts leads to a more profound dysregulation in the expression of genes implicated in heart rate regulation (calcium handling). In agreement with these gene expression data, cardiomyocytes isolated from male cardioGRKO hearts displayed altered intracellular calcium responses. In contrast, female GR-deficient cardiomyocytes presented a response comparable with controls. Conclusions These data suggest that GR regulates calcium responses in a sex-biased manner, leading to sexually distinct responses to stress in male and female mice hearts, which may contribute to sex differences in heart disease, including the development of ventricular arrhythmias that contribute to heart failure and sudden death.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/JAHA.118.011012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6761632PMC
August 2019

Cardiomyocyte glucocorticoid and mineralocorticoid receptors directly and antagonistically regulate heart disease in mice.

Sci Signal 2019 04 16;12(577). Epub 2019 Apr 16.

Signal Transduction Laboratory, NIEHS, NIH, DHHS, 111 T.W. Alexander Drive, Research Triangle Park, NC 27709, USA.

Stress is increasingly associated with heart dysfunction and is linked to higher mortality rates in patients with cardiometabolic disease. Glucocorticoids are primary stress hormones that regulate homeostasis through two nuclear receptors, the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR), both of which are present in cardiomyocytes. To examine the specific and coordinated roles that these receptors play in mediating the direct effects of stress on the heart, we generated mice with cardiomyocyte-specific deletion of GR (cardioGRKO), MR (cardioMRKO), or both GR and MR (cardioGRMRdKO). The cardioGRKO mice spontaneously developed cardiac hypertrophy and left ventricular systolic dysfunction and died prematurely from heart failure. In contrast, the cardioMRKO mice exhibited normal heart morphology and function. Despite the presence of myocardial stress, the cardioGRMRdKO mice were resistant to the cardiac remodeling, left ventricular dysfunction, and early death observed in the cardioGRKO mice. Gene expression analysis revealed the loss of gene changes associated with impaired Ca handling, increased oxidative stress, and enhanced cell death and the presence of gene changes that limited the hypertrophic response and promoted cardiomyocyte survival in the double knockout hearts. Reexpression of MR in cardioGRMRdKO hearts reversed many of the cardioprotective gene changes and resulted in cardiac failure. These findings reveal a critical role for balanced cardiomyocyte GR and MR stress signaling in cardiovascular health. Therapies that shift stress signaling in the heart to favor more GR and less MR activity may provide an improved approach for treating heart disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/scisignal.aau9685DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7082727PMC
April 2019

Silencing of maternal hepatic glucocorticoid receptor is essential for normal fetal development in mice.

Commun Biol 2019 15;2:104. Epub 2019 Mar 15.

Signal Transduction Laboratory, Research Triangle Park, North Carolina USA.

Excessive or chronic stress can lead to a variety of diseases due to aberrant activation of the glucocorticoid receptor (GR), a ligand activated transcription factor. Pregnancy represents a particular window of sensitivity in which excessive stress can have adverse outcomes, particularly on the developing fetus. Here we show maternal hepatic stress hormone responsiveness is diminished via epigenetic silencing of the glucocorticoid receptor during pregnancy. Provocatively, reinstallation of GR to hepatocytes during pregnancy by adeno-associated viral transduction dysregulates genes involved in proliferation, resulting in impaired pregnancy-induced hepatomegaly. Disruption of the maternal hepatic adaptation to pregnancy results in in utero growth restriction (IUGR). These data demonstrate pregnancy antagonizes the liver-specific effects of stress hormone signaling in the maternal compartment to ultimately support the healthy development of embryos.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s42003-019-0344-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6420645PMC
April 2020

DNA methylation in mice is influenced by genetics as well as sex and life experience.

Nat Commun 2019 01 18;10(1):305. Epub 2019 Jan 18.

Division of Intramural Research, NIEHS, 111 TW Alexander Drive, Research Triangle Park, NC, 27709, USA.

DNA methylation is an essential epigenetic process in mammals, intimately involved in gene regulation. Here we address the extent to which genetics, sex, and pregnancy influence genomic DNA methylation by intercrossing 2 inbred mouse strains, C57BL/6N and C3H/HeN, and analyzing DNA methylation in parents and offspring using whole-genome bisulfite sequencing. Differential methylation across genotype is detected at thousands of loci and is preserved on parental alleles in offspring. In comparison of autosomal DNA methylation patterns across sex, hundreds of differentially methylated regions are detected. Comparison of animals with different histories of pregnancy within our study reveals a CpG methylation pattern that is restricted to female animals that had borne offspring. Collectively, our results demonstrate the stability of CpG methylation across generations, clarify the interplay of epigenetics with genetics and sex, and suggest that CpG methylation may serve as an epigenetic record of life events in somatic tissues at loci whose expression is linked to the relevant biology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-018-08067-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6338756PMC
January 2019

Endogenous glucocorticoids prevent gastric metaplasia by suppressing spontaneous inflammation.

J Clin Invest 2019 03 18;129(3):1345-1358. Epub 2019 Feb 18.

Molecular Endocrinology Group, Signal Transduction Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA.

In the stomach, chronic inflammation causes metaplasia and creates a favorable environment for the evolution of gastric cancer. Glucocorticoids are steroid hormones that repress proinflammatory stimuli, but their role in the stomach is unknown. In this study, we show that endogenous glucocorticoids are required to maintain gastric homeostasis. Removal of circulating glucocorticoids in mice by adrenalectomy resulted in the rapid onset of spontaneous gastric inflammation, oxyntic atrophy, and spasmolytic polypeptide-expressing metaplasia (SPEM), a putative precursor of gastric cancer. SPEM and oxyntic atrophy occurred independently of lymphocytes. However, depletion of monocytes and macrophages by clodronate treatment or inhibition of gastric monocyte infiltration using the Cx3cr1 knockout mouse model prevented SPEM development. Our results highlight the requirement for endogenous glucocorticoid signaling within the stomach to prevent spontaneous gastric inflammation and metaplasia, and suggest that glucocorticoid deficiency may lead to gastric cancer development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/JCI123233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391099PMC
March 2019

A retrospective analysis of 1,231 patients with anemia after surgical treatment of hyperthyroidism.

Exp Ther Med 2018 Dec 14;16(6):4664-4668. Epub 2018 Sep 14.

Department of Neck and Thoracic Surgery, 187th Hospital of People's Liberation Army, Haikou, Hainan 571100, P.R. China.

This study retrospectively analyzed the clinical and pathological data of 1,231 patients affected by anemia after surgical treatment of hyperthyroidism to explore the influencing factors of anemia after surgical treatment of hyperthyroidism. The clinical data of 1,231 patients affected by anemia after surgical treatment of hyperthyroidism from 1987 to 2017 were analyzed. Clinical data included the surgery methods, sex, age and pathological types. SPSS 22.0 statistical software was used for all statistical analyses. Correlation analyses were performed by using logistic regression analysis, and other enumeration data were subjected to χ test. p<0.05 was considered to be statistically significant. The occurrence of anemia after surgical treatment of hyperthyroidism was significantly correlated with age and pathological types (p<0.05). Correlation analysis also showed that age and pathological types were significantly correlated with the occurrence of anemia after surgical treatment of hyperthyroidism. Age and pathological types may be the risk factors for anemia in patients with surgical treatment of hyperthyroidism. Age and pathological type were significantly correlated with the occurrence of anemia after surgical treatment of hyperthyroidism, and may be risk factors for this disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3892/etm.2018.6738DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6257823PMC
December 2018

A new look at survival times during cold water immersion.

J Therm Biol 2018 Dec 18;78:100-105. Epub 2018 Sep 18.

Laboratory for Exercise and Environmental Medicine, 108 Frank Kennedy, Faculty of Kinesiology and Recreation Management, University of Manitoba, Winnipeg, Manitoba, Canada R3T 2N2.

This paper presents an expanded dataset for survival times during cold water immersion. In 1946, the first set of human data for cold water survival was derived from the US Navy medical reports during WWII. Although this is the largest and most widely used data source, it has only 23 data points and immersion times are less than 5.5 h for water temperature below 20 °C. For the new dataset, data (i.e., immersion times, water temperatures, clothing worn, and in some cases, body masses, heights, and survival times for the deaths witnessed by survivors) was retrieved from 12 well-documented incidents of accidental immersions which involved 22 survivors and 21 deaths. These data were combined with the 1946 dataset to create the expanded dataset which included 122 data points. Analysis of the dataset revealed critical details pertinent to cold water survival: 1) immersion times, up to 75 h, at water temperatures below 20 °C, were longer than most immersion times documented in the 1946 dataset; 2) thermal protection (wetsuit or drysuit), high body mass, and partial immersion may significantly impact survival during immersion in cold water; 3) twenty-one actual survival times until witnessed death are added. A maximal survival time curve was derived to represent the survival limit which many victims are unlikely to approach and few can exceed except under unique circumstances.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtherbio.2018.08.022DOI Listing
December 2018

Effect of localized microclimate heating on peripheral skin temperatures and manual dexterity during cold exposure.

J Appl Physiol (1985) 2018 11 23;125(5):1498-1510. Epub 2018 Aug 23.

United States Army Research Institute of Environmental Medicine , Natick, Massachusetts.

Reduced dexterity is a major problem in cold weather, with a need for a countermeasure that increases hand (T) and finger (T) temperatures and improves dexterity. The purpose of this study was to determine whether electric heat (set point, 42°C) applied to the forearm (ARM, 82 W), face (FACE, 9.2 W), or combination of both (COMB, 91.2 W), either at the beginning of cold exposure (COLD; 0.5°C, 120 min; 2 clo insulation, seated, bare-handed) or after T fell to 10.5°C [delayed trials (D)], improves T, T, dexterity, and finger key pinch strength (S). Volunteers ( n = 8; 26 ± 9 yr) completed 7 experimental trials in COLD: ARM, ARM-D, FACE, FACE-D, COMB, COMB-D, and no heating (CON). Temperatures were measured before (BASE) and throughout COLD. Tests of dexterity [Purdue Pegboard assembly (PP) and magazine loading (MAGLOAD)] and S were measured at BASE and after 45 and 90 min of COLD. Data presented are at minute 90. T was warmer ( P < 0.001) during ARM (18.0 ± 2.6°C) and COMB (18.9 ± 2.0°C) versus CON (15.3 ± 1.5°C) and FACE (15.8 ± 1.5°C) for heating that was initiated at the beginning of COLD. T was higher ( P < 0.04) during COMB (12.7 ± 5.1°C) versus CON (9.7 ± 2.1°C) and FACE (8.9 ± 2.2°C). The change from BASE for PP (no. of pieces) was less ( P < 0.005) in COMB (-4.5 ± 3.3) and ARM (-5.0 ± 6.0) versus CON (-13.0 ± 7.3) and FACE (-10.0 ± 8.3), and for MAGLOAD, it tended ( P = 0.06) to be less in COMB (-8.9 ± 6.2 cartridges) versus CON (-14.8 ± 3.7 cartridges). There was no change in S from BASE (10.5 kg) to minute 90 in ARM or COMB (0.7 ± 1.4 and -0.2 ± 1.7 kg, respectively) but a decrease ( P < 0.01) in CON and FACE (-2.1 ± 2.0 and -1.6 ± 1.9 kg, respectively). There were no differences in T, T, dexterity, and S at minute 90 when comparing heating that was initiated at the beginning of COLD versus delayed heating. In conclusion, heating using either COMB or ARM, compared with CON and FACE, improved T and T and reduced the decline in dexterity by 20%-50% and S by 90%. Furthermore, delayed heating had no deleterious effect on T, T, dexterity, and S compared with heating that started at the beginning of cold exposure. NEW & NOTEWORTHY The present study demonstrated that, during sedentary cold air exposure, localized heating that was applied from the beginning of cold exposure on the forearm increases hand and finger temperatures and finger strength, leading to subsequent improvements in manual dexterity. In addition, localized heating that was delayed until finger temperatures cooled significantly also caused higher peripheral temperatures, leading to better strength and manual dexterity, compared with no heating.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1152/japplphysiol.00513.2018DOI Listing
November 2018

MicroRNA Profiling and Bioinformatics Target Analysis in Dorsal Hippocampus of Chronically Stressed Rats: Relevance to Depression Pathophysiology.

Front Mol Neurosci 2018 6;11:251. Epub 2018 Aug 6.

Laboratory of Neuroplasticity and Neurogenetics, Faculty of Chemical and Pharmaceutical Sciences, Department of Biochemistry and Molecular Biology, Universidad de Chile, Santiago, Chile.

Studies conducted in rodents subjected to chronic stress and some observations in humans after psychosocial stress, have allowed to establish a link between stress and the susceptibility to many complex diseases, including mood disorders. The studies in rodents have revealed that chronic exposure to stress negatively affects synaptic plasticity by triggering changes in the production of trophic factors, subunit levels of glutamate ionotropic receptors, neuron morphology, and neurogenesis in the adult hippocampus. These modifications may account for the impairment in learning and memory processes observed in chronically stressed animals. It is plausible then, that stress modifies the interplay between signal transduction cascades and gene expression regulation in the hippocampus, therefore leading to altered neuroplasticity and functioning of neural circuits. Considering that miRNAs play an important role in post-transcriptional-regulation of gene expression and participate in several hippocampus-dependent functions; we evaluated the consequences of chronic stress on the expression of miRNAs in dorsal (anterior) portion of the hippocampus, which participates in memory formation in rodents. Here, we show that male rats exposed to daily restraint stress (2.5 h/day) during 7 and 14 days display a differential profile of miRNA levels in dorsal hippocampus and remarkably, we found that some of these miRNAs belong to the miR-379-410 cluster. We confirmed a rise in miR-92a and miR-485 levels after 14 days of stress by qPCR, an effect that was not mimicked by chronic administration of corticosterone (14 days). Our study identified the top-10 biological functions influenced by miR-92a, nine of which were shared with miR-485: Nervous system development and function, Tissue development, Behavior, Embryonic development, Organ development, Organismal development, Organismal survival, Tissue morphology, and Organ morphology. Furthermore, our study provided a landscape of potential miRNA-92a and miR-485 targets, along with relevant canonical pathways related to axonal guidance signaling and cAMP signaling, which may influence the functioning of several neuroplastic substrates in dorsal hippocampus. Additionally, the combined effect of miR-92a and miR-485 on transcription factors, along with histone-modifying enzymes, may have a functional relevance by producing changes in gene regulatory networks that modify the neuroplastic capacity of the adult dorsal hippocampus under stress.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fnmol.2018.00251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6088391PMC
August 2018

Glucocorticoids Impair Phagocytosis and Inflammatory Response Against Crohn's Disease-Associated Adherent-Invasive .

Front Immunol 2018 16;9:1026. Epub 2018 May 16.

Innate Immunity Laboratory, Immunology Program, Faculty of Medicine, Biomedical Sciences Institute, Universidad de Chile, Santiago, Chile.

Crohn's disease (CD) is a chronic inflammatory bowel disorder characterized by deregulated inflammation triggered by environmental factors. Notably, adherent-invasive (AIEC), a bacterium with the ability to survive within macrophages is believed to be one of such factors. Glucocorticoids are the first line treatment for CD and to date, it is unknown how they affect bactericidal and inflammatory properties of macrophages against AIEC. The aim of this study was to evaluate the impact of glucocorticoid treatment on AIEC infected macrophages. First, THP-1 cell-derived macrophages were infected with a CD2-a AIEC strain, in the presence or absence of the glucocorticoid dexamethasone (Dex) and mRNA microarray analysis was performed. Differentially expressed mRNAs were confirmed by TaqMan-qPCR. In addition, an amikacin protection assay was used to evaluate the phagocytic and bactericidal activity of Dex-treated macrophages infected with strains (CD2-a, HM605, NRG857c, and HB101). Finally, cytokine secretion and the inflammatory phenotype of macrophages were evaluated by ELISA and flow cytometry, respectively. The microarray analysis showed that CD2-a, Dex, and CD2-a + Dex-treated macrophages have differential inflammatory gene profiles. Also, canonical pathway analysis revealed decreased phagocytosis signaling by Dex and anti-inflammatory polarization on CD2-a + Dex macrophages. Moreover, amikacin protection assay showed reduced phagocytosis upon Dex treatment and TaqMan-qPCR confirmed Dex inhibition of three phagocytosis-associated genes. All bacteria strains induced TNF-α, IL-6, IL-23, CD40, and CD80, which was inhibited by Dex. Thus, our data demonstrate that glucocorticoids impair phagocytosis and induce anti-inflammatory polarization after AIEC infection, possibly contributing to the survival of AIEC in infected CD patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2018.01026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5964128PMC
July 2019

Estimation of core body temperature from skin temperature, heat flux, and heart rate using a Kalman filter.

Comput Biol Med 2018 08 18;99:1-6. Epub 2018 May 18.

Biophysics and Biomedical Modeling Division, U.S. Army Research Institute of Environmental Medicine, 10 General Greene Avenue, Natick, MA, 01760-5007, USA. Electronic address:

Core body temperature (T) is a key physiological metric of thermal heat-strain yet it remains difficult to measure non-invasively in the field. This work used combinations of observations of skin temperature (T), heat flux (HF), and heart rate (HR) to accurately estimate T using a Kalman Filter (KF). Data were collected from eight volunteers (age 22 ± 4 yr, height 1.75 ± 0.10 m, body mass 76.4 ± 10.7 kg, and body fat 23.4 ± 5.8%, mean ± standard deviation) while walking at two different metabolic rates (∼350 and ∼550 W) under three conditions (warm: 25 °C, 50% relative humidity (RH); hot-humid: 35 °C, 70% RH; and hot-dry: 40 °C, 20% RH). Skin temperature and HF data were collected from six locations: pectoralis, inner thigh, scapula, sternum, rib cage, and forehead. Kalman filter variables were learned via linear regression and covariance calculations between T and T, HF, and HR. Root mean square error (RMSE) and bias were calculated to identify the best performing models. The pectoralis (RMSE 0.18 ± 0.04 °C; bias -0.01 ± 0.09 °C), rib (RMSE 0.18 ± 0.09 °C; bias -0.03 ± 0.09 °C), and sternum (RMSE 0.20 ± 0.10 °C; bias -0.04 ± 0.13 °C) were found to have the lowest error values when using T, HF, and HR but, using only two of these measures provided similar accuracy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.compbiomed.2018.05.021DOI Listing
August 2018
-->