Search

Background: Burgeoning evidence highlights seminal roles for microglia in the pathogenesis of neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). The receptor for advanced glycation end products (RAGE) binds ligands relevant to ALS that accumulate in the diseased spinal cord and RAGE has been previously implicated in the progression of ALS pathology.Methods: We generated a novel mouse model to temporally delete Ager from microglia in the murine SOD1G93A model of ALS. Microglia Ager deficient SOD1G93A mice and controls were examined for changes in survival, motor function, gliosis, motor neuron numbers, and transcriptomic analyses of lumbar spinal cord. Furthermore, we examined bulk-RNA-sequencing transcriptomic analyses of human ALS cervical spinal cord.Results: Transcriptomic analysis of human cervical spinal cord reveals a range of AGER expression in ALS patients, which was negatively correlated with age at disease onset and death or tracheostomy. The degree of AGER expression related to differential expression of pathways involved in extracellular matrix, lipid metabolism, and intercellular communication. Microglia display increased RAGE immunoreactivity in the spinal cords of high AGER expressing patients and in the SOD1G93A murine model of ALS vs. respective controls. We demonstrate that microglia Ager deletion at the age of symptomatic onset, day 90, in SOD1G93A mice extends survival in male but not female mice. Critically, many of the pathways identified in human ALS patients that accompanied increased AGER expression were significantly ameliorated by microglia Ager deletion in male SOD1G93A mice.Conclusions: Our results indicate that microglia RAGE disrupts communications with cell types including astrocytes and neurons, intercellular communication pathways that divert microglia from a homeostatic to an inflammatory and tissue-injurious program. In totality, microglia RAGE contributes to the progression of SOD1G93A murine pathology in male mice and may be relevant in human disease. [ABSTRACT FROM AUTHOR]

Background: Vitamin D deficiency is widespread in China, particularly among older adults. Factors associated with suboptimal vitamin D levels are not well defined. The present study was a population-based study that included 10 urban and suburban communities in Shanghai, to evaluate vitamin D status and its correlates among older adults.Method: This cross-sectional study was based on study data for 3924 healthy men and women aged 65-95 years. Anthropometric and socioeconomic data were collected in June-July 2014. Serum 25(OH)D levels were detected using a chemiluminescence immunoassay. The following socioeconomic data were obtained through self-administered questionnaires: education level, lifestyle, residency, and dietary habits. A logistic regression model was used to assess associations between anthropometric factors, socioeconomic factors and serum 25(OH)D levels.Results: Median levels of serum 25(OH)D in men and women were 22.73 and 19.99 ng/mL, respectively. Vitamin D deficiency was common in subjects, even though data collection was conducted during summer. The general prevalence of serum 25(OH)D levels <20 ng/mL were 35.4% and 50.5% for men and women respectively. The general prevalence of serum 25(OH)D levels <10 ng/mL were 2.73% and 5.9% for men and women respectively. A multivariable model indicated serum 25(OH)D levels ≥20 ng/mL were significantly and positively correlated with male sex, calcium or vitamin D supplementation, and residency in suburban communities. The model also indicated that high level of physical activity was protective factors of vitamin D deficiency for men and milk consumption for women, respectively. By contrast, deficient serum 25(OH)D levels were significantly correlated with education level (lower than primary school) or obesity [body mass index (BMI) ≥ 26.06 kg/m2] for men or women, respectively.Conclusion: This cross-sectional study of older adults in communities in Shanghai demonstrates that key factors positively correlated with serum 25(OH)D levels ≥20 ng/mL include male sex, residency in suburban communities, calcium or vitamin D supplementation, high physical activity and education level (for men), and dairy consumption and maintenance of normal BMI (for women). [ABSTRACT FROM AUTHOR]

Background: Bi-potential hepatic progenitor cells can give rise to both hepatocytes and cholangiocytes, which is the last phase and critical juncture in terms of sequentially hepatic lineage restriction from any kind of stem cells. If their differentiation can be controlled, it might access to functional hepatocytes to develop pharmaceutical and biotechnology industries as well as cell therapies for end-stage liver diseases., Methods: In this study, we investigated the influence of Cx32 and Cx43 on hepatocyte differentiation of WB-F344 cells by in vitro gain and loss of function analyses. An inhibitor of Cx32 was also used to make further clarification. To reveal p38 MAPK pathway is closely related to Cxs, rats with 70% partial hepatectomy were injected intraperitoneally with a p38 inhibitor, SB203580. Besides, the effects of p38 MAPK pathway on differentiation of hepatoblasts isolated from fetal rat livers were evaluated by addition of SB203580 in culture medium., Results: In vitro gain and loss of function analyses showed overexpression of Connexin 32 and knockdown of Connexin 43 promoted hepatocytes differentiation from hepatic progenitor cells. In addition, in vitro and ex vivo research revealed inhibition of p38 mitogen-activated protein kinase pathway can improve hepatocytes differentiation correlating with upregulation of Connexin 32 expression and downregulation of Connexin 43 expression., Conclusions: Here we demonstrate that Connexins play crucial roles in facilitating differentiation of hepatic progenitors. Our work further implicates that regulators of Connexins and their related pathways might provide new insights to improve lineage restriction of stem cells to mature hepatocytes.

Background: Vitamin D deficiency is widespread in China, particularly among older adults. Factors associated with suboptimal vitamin D levels are not well defined. The present study was a population-based study that included 10 urban and suburban communities in Shanghai, to evaluate vitamin D status and its correlates among older adults., Method: This cross-sectional study was based on study data for 3924 healthy men and women aged 65-95 years. Anthropometric and socioeconomic data were collected in June-July 2014. Serum 25(OH)D levels were detected using a chemiluminescence immunoassay. The following socioeconomic data were obtained through self-administered questionnaires: education level, lifestyle, residency, and dietary habits. A logistic regression model was used to assess associations between anthropometric factors, socioeconomic factors and serum 25(OH)D levels., Results: Median levels of serum 25(OH)D in men and women were 22.73 and 19.99 ng/mL, respectively. Vitamin D deficiency was common in subjects, even though data collection was conducted during summer. The general prevalence of serum 25(OH)D levels <20 ng/mL were 35.4% and 50.5% for men and women respectively. The general prevalence of serum 25(OH)D levels <10 ng/mL were 2.73% and 5.9% for men and women respectively. A multivariable model indicated serum 25(OH)D levels ≥20 ng/mL were significantly and positively correlated with male sex, calcium or vitamin D supplementation, and residency in suburban communities. The model also indicated that high level of physical activity was protective factors of vitamin D deficiency for men and milk consumption for women, respectively. By contrast, deficient serum 25(OH)D levels were significantly correlated with education level (lower than primary school) or obesity [body mass index (BMI) ≥ 26.06 kg/m 2 ] for men or women, respectively., Conclusion: This cross-sectional study of older adults in communities in Shanghai demonstrates that key factors positively correlated with serum 25(OH)D levels ≥20 ng/mL include male sex, residency in suburban communities, calcium or vitamin D supplementation, high physical activity and education level (for men), and dairy consumption and maintenance of normal BMI (for women).

Background: Increasing evidence shows the importance of the commensal microbe Oxalobacter formigenes in regulating host oxalate homeostasis, with effects against calcium oxalate kidney stone formation, and other oxalate-associated pathological conditions. However, limited understanding of O. formigenes in humans poses difficulties for designing targeted experiments to assess its definitive effects and sustainable interventions in clinical settings. We exploited the large-scale dataset from the American Gut Project (AGP) to study O. formigenes colonization in the human gastrointestinal (GI) tract and to explore O. formigenes-associated ecology and the underlying host-microbe relationships., Results: In >8000 AGP samples, we detected two dominant, co-colonizing O. formigenes operational taxonomic units (OTUs) in fecal specimens. Multivariate analysis suggested that O. formigenes abundance was associated with particular host demographic and clinical features, including age, sex, race, geographical location, BMI, and antibiotic history. Furthermore, we found that O. formigenes presence was an indicator of altered host gut microbiota structure, including higher community diversity, global network connectivity, and stronger resilience to simulated disturbances., Conclusions: Through this study, we identified O. formigenes colonizing patterns in the human GI tract, potential underlying host-microbe relationships, and associated microbial community structures. These insights suggest hypotheses to be tested in future experiments. Additionally, we proposed a systematic framework to study any bacterial taxa of interest to computational biologists, using large-scale public data to yield novel biological insights.

Background: The role of the microbiota in human health and disease has been increasingly studied, gathering momentum through the use of high-throughput technologies. Further identification of the roles of specific microbes is necessary to better understand the mechanisms involved in diseases related to microbiome perturbations., Methods: Here, we introduce a new microbiome-based group association testing method, optimal microbiome-based association test (OMiAT). OMiAT is a data-driven testing method which takes an optimal test throughout different tests from the sum of powered score tests (SPU) and microbiome regression-based kernel association test (MiRKAT). We illustrate that OMiAT efficiently discovers significant association signals arising from varying microbial abundances and different relative contributions from microbial abundance and phylogenetic information. We also propose a way to apply it to fine-mapping of diverse upper-level taxa at different taxonomic ranks (e.g., phylum, class, order, family, and genus), as well as the entire microbial community, within a newly introduced microbial taxa discovery framework, microbiome comprehensive association mapping (MiCAM)., Results: Our extensive simulations demonstrate that OMiAT is highly robust and powerful compared with other existing methods, while correctly controlling type I error rates. Our real data analyses also confirm that MiCAM is especially efficient for the assessment of upper-level taxa by integrating OMiAT as a group analytic method., Conclusions: OMiAT is attractive in practice due to the high complexity of microbiome data and the unknown true nature of the state. MiCAM also provides a hierarchical association map for numerous microbial taxa and can also be used as a guideline for further investigation on the roles of discovered taxa in human health and disease.

Background: Obesity, type 2 diabetes, and non-alcoholic fatty liver disease (NAFLD) are serious health concerns, especially in Western populations. Antibiotic exposure and high-fat diet (HFD) are important and modifiable factors that may contribute to these diseases., Methods: To investigate the relationship of antibiotic exposure with microbiome perturbations in a murine model of growth promotion, C57BL/6 mice received lifelong sub-therapeutic antibiotic treatment (STAT), or not (control), and were fed HFD starting at 13 weeks. To characterize microbiota changes caused by STAT, the V4 region of the 16S rRNA gene was examined from collected fecal samples and analyzed., Results: In this model, which included HFD, STAT mice developed increased weight and fat mass compared to controls. Although results in males and females were not identical, insulin resistance and NAFLD were more severe in the STAT mice. Fecal microbiota from STAT mice were distinct from controls. Compared with controls, STAT exposure led to early conserved diet-independent microbiota changes indicative of an immature microbial community. Key taxa were identified as STAT-specific and several were found to be predictive of disease. Inferred network models showed topological shifts concurrent with growth promotion and suggest the presence of keystone species., Conclusions: These studies form the basis for new models of type 2 diabetes and NAFLD that involve microbiome perturbation.

Background: Helicobacter pylori are successful colonizers of the human gastric mucosa. Colonization increases the risk of peptic ulcer disease and adenocarcinoma. However, potential benefits of H. pylori colonization include protection against early-onset asthma and against gastrointestinal infections. Campylobacter jejuni are a leading cause of bacterial diarrhea and complications include Guillain-Barré syndrome. Here, we describe the development of reliable serological assays to detect antibodies against those two bacteria in Rhesus macaques and investigated their distribution within a social group of monkeys., Methods: Two cohorts of monkeys were analyzed. The first cohort consisted of 30 monkeys and was used to establish an enzyme-linked immunosorbent assay (ELISA) for H. pylori antibodies detection. To evaluate colonization of those macaques, stomach biopsies were collected and analyzed for the presence of H. pylori by histology and culture. C. jejuni ELISAs were established using human serum with known C. jejuni antibody status. Next, plasma samples of the 89 macaques (Cohort 2) were assayed for antibodies and then statistically analyzed., Results: An H. pylori IgG ELISA, which was 100% specific and 93% sensitive, was established. In contrast, the IgA ELISA was only 82% specific and 61% sensitive. The CagA IgG assay was 100% sensitive and 61% of the macaques were positive. In cohort 2, 62% macaques were H. pylori sero-positive and 52% were CagA positive. The prevalence of H. pylori IgG and CagA IgG increased with monkey age as described for humans. Of the 89 macaques 52% showed IgG against C. jejuni but in contrast to H. pylori, the sero-prevalence was not associated with increasing age. However, there was a drop in the IgG (but not in IgA) mean values between infant and juvenile macaques, similar to trends described in humans., Conclusions: Rhesus macaques have widespread exposure to H. pylori and C. jejuni, reflecting their social conditions and implying that Rhesus macaques might provide a model to study effects of these two important human mucosal bacteria on a population.