MicroRNAs and extracellular vesicles in the gut::New host modulators of the microbiome?

The gut microbiota plays an integral role in human health and its dysbiosis is associated with many chronic diseases. There are still large gaps in understanding the host and environmental factors that directly regulate the gut microbiota, and few effective strategies exist to modulate the microbiota in therapeutic applications. Recent reports suggest that certain microRNAs (miRNAs) released by mammalian cells can regulate bacterial gene expression to influence the microbiome composition and propose extracellular vesicles as one natural mechanism for miRNA transport in the gut. These new findings interface with a burgeoning body of data showing that miRNAs are present in a stable form in extracellular environments and can mediate cell-to-cell communication in mammals. Here, we review the literature on RNA-mediated modulation of the microbiome to bring cross-disciplinary perspective to this new type of interaction and its potential implications in biology and medicine

Weight Gain Trajectories Associated With Elevated C‐Reactive Protein Levels in Chinese Adults

BACKGROUND: Recent longitudinal work suggests that weight change is an important risk factor for inflammation across the full range of BMI. However, few studies have examined whether the risk of inflammation differs by patterns of weight gain over time. Using latent class trajectory analysis, we test whether patterns of weight gain are associated with elevated high-sensitivity C-reactive protein (hs-CRP 2-10 mg/L). METHODS AND RESULTS: Data come from China Health and Nutrition Survey (CHNS) participants (n=5536), aged 18 at baseline to 66 years in 2009, with measured weight over 18 years. Latent class trajectory analysis was used to identify weight-change trajectories in 6 age and sex strata. Multivariable general linear mixed-effects models fit with a logit link were used to assess the risk of elevated hs-CRP across weight trajectory classes. Models were fit within age and sex strata, controlling for baseline weight, adult height, and smoking, and included random intercepts to account for community-level correlation. Steeper weight-gain trajectories were associated with greater risk of elevated hs-CRP compared to more moderate weight-gain trajectories in men and women. Initially high weight gain followed by weight loss was associated with lower risk of elevated hs-CRP in women aged 18 to 40. CONCLUSIONS: Latent class trajectory analysis identified heterogeneity in adult weight change associated with differential risk of inflammation independently of baseline weight and smoking. These results suggest that trajectories of weight gain are an important clinical concern and may identify those at risk for inflammation and the development of cardiometabolic disease

Longitudinal T1 relaxation rate (R1) captures changes in short-term Mn exposure in welders

We demonstrated recently that the T1 relaxation rate (R1) captured short-term Mn exposure in welders with chronic, relatively low exposure levels in a cross-sectional study. In the current study, we used a longitudinal design to examine whether R1 values reflect the short-term dynamics of Mn exposure

Associations between age, cohort, and urbanization with SBP and DBP in China: a population-based study across 18 years

Little is known about whether large-scale environmental changes, such as those seen with urbanization, are differentially associated with systolic versus diastolic blood pressure, and whether those changes vary by birth cohort

Genetic containment in vegetatively propagated forest trees : CRISPR disruption of LEAFY function in Eucalyptus gives sterile indeterminate inflorescences and normal juvenile development

Eucalyptus is among the most widely planted taxa of forest trees worldwide. However, its spread as an exotic or genetically engineered form can create ecological and social problems. To mitigate gene flow via pollen and seeds, we mutated the Eucalyptus orthologue of LEAFY (LFY) by transforming a Eucalyptus grandis 9 urophylla wild-type hybrid and two Flowering Locus T (FT) overexpressing (and flowering) lines with CRISPR Cas9 targeting its LFY orthologue, ELFY. We achieved high rates of elfy biallelic knockouts, often approaching 100% of transgene insertion events. Frameshift mutations and deletions removing conserved amino acids caused strong floral alterations, including indeterminacy in floral development and an absence of male and female gametes. These mutants were otherwise visibly normal and did not differ statistically from transgenic controls in juvenile vegetative growth rate or leaf morphology in greenhouse trials. Genes upstream or near to ELFY in the floral development pathway were overexpressed, whereas floral organ identity genes downstream of ELFY were severely depressed. We conclude that disruption of ELFY function appears to be a useful tool for sexual containment, without causing statistically significant or large adverse effects on juvenile vegetative growth or leaf morphology.http://onlinelibrary.wiley.com/journal/10.1111/(ISSN)1467-7652pm2022BiochemistryForestry and Agricultural Biotechnology Institute (FABI)GeneticsMicrobiology and Plant PathologyZoology and Entomolog

Quantifying the Detrimental Impacts of Land-Use and Management Change on European Forest Bird Populations

The ecological impacts of changing forest management practices in Europe are poorly understood despite European forests being highly managed. Furthermore, the effects of potential drivers of forest biodiversity decline are rarely considered in concert, thus limiting effective conservation or sustainable forest management. We present a trait-based framework that we use to assess the detrimental impact of multiple land-use and management changes in forests on bird populations across Europe. Major changes to forest habitats occurring in recent decades, and their impact on resource availability for birds were identified. Risk associated with these changes for 52 species of forest birds, defined as the proportion of each species' key resources detrimentally affected through changes in abundance and/or availability, was quantified and compared to their pan-European population growth rates between 1980 and 2009. Relationships between risk and population growth were found to be significantly negative, indicating that resource loss in European forests is an important driver of decline for both resident and migrant birds. Our results demonstrate that coarse quantification of resource use and ecological change can be valuable in understanding causes of biodiversity decline, and thus in informing conservation strategy and policy. Such an approach has good potential to be extended for predictive use in assessing the impact of possible future changes to forest management and to develop more precise indicators of forest health

Increased R2* in the Caudate Nucleus of Asymptomatic Welders

Welding has been associated with neurobehavioral disorders. Welding fumes contain several metals including copper (Cu), manganese (Mn), and iron (Fe) that may interact to influence welding-related neurotoxicity. Although welding-related airborne Fe levels are about 10-fold higher than Mn, previous studies have focused on Mn and its accumulation in the basal ganglia. This study examined differences in the apparent transverse relaxation rates [R2* (1/T2*), estimate of Fe accumulation] in the basal ganglia (caudate nucleus, putamen, and globus pallidus) between welders and controls, and the dose–response relationship between estimated Fe exposure and R2* values. Occupational questionnaires estimated recent and lifetime Fe exposure, and blood Fe levels and brain magnetic resonance imaging (MRI) were obtained. Complete exposure and MRI R2* and R1 (1/T1: measure to estimate Mn accumulation) data from 42 subjects with welding exposure and 29 controls were analyzed. Welders had significantly greater exposure metrics and higher whole-blood Fe levels compared with controls. R2* in the caudate nucleus was significantly higher in welders after controlling for age, body mass index, respirator use, caudate R1, and blood metals of Cu and Mn, whereas there was no difference in R1 values in the basal ganglia between groups. The R2* in the caudate nucleus was positively correlated with whole-blood Fe concentration. This study provides the first evidence of higher R2* in the caudate nucleus of welders, which is suggestive of increased Fe accumulation in this area. Further studies are needed to replicate the findings and determine the neurobehavioral relevance

Paternal obesity is associated with IGF2 hypomethylation in newborns: results from a Newborn Epigenetics Study (NEST) cohort

Data from epidemiological and animal model studies suggest that nutrition during pregnancy may affect the health status of subsequent generations. These transgenerational effects are now being explained by disruptions at the level of the epigenetic machinery. Besides in vitro environmental exposures, the possible impact on the reprogramming of methylation profiles at imprinted genes at a much earlier time point, such as during spermatogenesis or oogenesis, has not previously been considered. In this study, our aim was to determine associations between preconceptional obesity and DNA methylation profiles in the offspring, particularly at the differentially methylated regions (DMRs) of the imprinted Insulin-like Growth Factor 2 (IGF2) gene

DiffSplice: The Genome-Wide Detection of Differential Splicing Events with RNA-Seq

The RNA transcriptome varies in response to cellular differentiation as well as environmental factors, and can be characterized by the diversity and abundance of transcript isoforms. Differential transcription analysis, the detection of differences between the transcriptomes of different cells, may improve understanding of cell differentiation and development and enable the identification of biomarkers that classify disease types. The availability of high-throughput short-read RNA sequencing technologies provides in-depth sampling of the transcriptome, making it possible to accurately detect the differences between transcriptomes. In this article, we present a new method for the detection and visualization of differential transcription. Our approach does not depend on transcript or gene annotations. It also circumvents the need for full transcript inference and quantification, which is a challenging problem because of short read lengths, as well as various sampling biases. Instead, our method takes a divide-and-conquer approach to localize the difference between transcriptomes in the form of alternative splicing modules (ASMs), where transcript isoforms diverge. Our approach starts with the identification of ASMs from the splice graph, constructed directly from the exons and introns predicted from RNA-seq read alignments. The abundance of alternative splicing isoforms residing in each ASM is estimated for each sample and is compared across sample groups. A non-parametric statistical test is applied to each ASM to detect significant differential transcription with a controlled false discovery rate. The sensitivity and specificity of the method have been assessed using simulated data sets and compared with other state-of-the-art approaches. Experimental validation using qRT-PCR confirmed a selected set of genes that are differentially expressed in a lung differentiation study and a breast cancer data set, demonstrating the utility of the approach applied on experimental biological data sets. The software of DiffSplice is available at http://www.netlab.uky.edu/p/bioinfo/DiffSplice

Targeting PI3Kδ function for amelioration of murine chronic graft-versus-host disease.

Chronic graft-versus-host disease (cGVHD) is a leading cause of morbidity and mortality following allotransplant. Activated donor effector T cells can differentiate into pathogenic T helper (Th)-17 cells and germinal center (GC)-promoting T follicular helper (Tfh) cells, resulting in cGVHD. Phosphoinositide-3-kinase-δ (PI3Kδ), a lipid kinase, is critical for activated T cell survival, proliferation, differentiation, and metabolism. We demonstrate PI3Kδ activity in donor T cells that become Tfh cells is required for cGVHD in a nonsclerodermatous multiorgan system disease model that includes bronchiolitis obliterans (BO), dependent upon GC B cells, Tfhs, and counterbalanced by T follicular regulatory cells, each requiring PI3Kδ signaling for function and survival. Although B cells rely on PI3Kδ pathway signaling and GC formation is disrupted resulting in a substantial decrease in Ig production, PI3Kδ kinase-dead mutant donor bone marrow-derived GC B cells still supported BO cGVHD generation. A PI3Kδ-specific inhibitor, compound GS-649443, that has superior potency to idelalisib while maintaining selectivity, reduced cGVHD in mice with active disease. In a Th1-dependent and Th17-associated scleroderma model, GS-649443 effectively treated mice with active cGVHD. These data provide a foundation for clinical trials of US Food and Drug Administration (FDA)-approved PI3Kδ inhibitors for cGVHD therapy in patients