Metformin is widely used in the treatment of type 2 diabetes (T2D), but its mechanism of action is poorly defined. Recent evidence implicates the gut microbiota as a site of metformin action. In a ...double-blind study, we randomized individuals with treatment-naive T2D to placebo or metformin for 4 months and showed that metformin had strong effects on the gut microbiome. These results were verified in a subset of the placebo group that switched to metformin 6 months after the start of the trial. Transfer of fecal samples (obtained before and 4 months after treatment) from metformin-treated donors to germ-free mice showed that glucose tolerance was improved in mice that received metformin-altered microbiota. By directly investigating metformin-microbiota interactions in a gut simulator, we showed that metformin affected pathways with common biological functions in species from two different phyla, and many of the metformin-regulated genes in these species encoded metalloproteins or metal transporters. Our findings provide support for the notion that altered gut microbiota mediates some of metformin's antidiabetic effects.
There is a limited understanding about the impact of rare protein-truncating variants across multiple phenotypes. We explore the impact of this class of variants on 13 quantitative traits and 10 ...diseases using whole-exome sequencing data from 100,296 individuals. Protein-truncating variants in genes intolerant to this class of mutations increased risk of autism, schizophrenia, bipolar disorder, intellectual disability, and ADHD. In individuals without these disorders, there was an association with shorter height, lower education, increased hospitalization, and reduced age at enrollment. Gene sets implicated from GWASs did not show a significant protein-truncating variants burden beyond what was captured by established Mendelian genes. In conclusion, we provide a thorough investigation of the impact of rare deleterious coding variants on complex traits, suggesting widespread pleiotropic risk.
The antioxidant activity of resveratrol in the absence and presence of increasing concentrations of HP-β-CDs was determined using three different methods: ORAC, ABTS and DPPH. The three methods were ...validated and compared for their linearity, precision and accuracy in measuring resveratrol antioxidant activity. The results indicated that the most sensitive method is the ORAC assay, which can measure the lowest resveratrol concentration (0.15–2μM) with the highest precision. In the presence of increasing concentrations of HP-β-CDs, the antioxidant activity of resveratrol was seen to increase when it was measured by the ORAC and ABTS assays. However, no increase was observed when the DPPH assay was used. With the ORAC assay, the antioxidant activity increased until all the resveratrol had been included in HP-β-CDs (0.4mM CDs), whereas in the case of ABTS assay the plateau in antioxidant activity was reached after 2mM HP-β-CDs, suggesting that the CDs interferences in the measurement method. When the DPPH assay was used, no effect was observed when increasing concentrations of HP-β-CDs, indicating that in a methanolic medium resveratrol is free. Therefore, so this method cannot be used to measure the effect of resveratrol complexation with CDs on its antioxidant activity.
Development of methodologies to quantify airborne micro-organisms is needed for the prevention and control of infections. It is difficult to conclude which is the most efficient and sensitive ...strategy to assess airborne SARS-CoV-2 RNA levels due to the disparity of results reported in clinical settings.
To improve our previously reported protocol of measuring SARS-CoV-2 RNA levels, which was based on bioaerosol collection with a liquid impinger and RNA quantification with droplet digital polymerase chain reaction (ddPCR).
Air samples were collected in COVID-19 patient rooms to assess efficiency and/or sensitivity of different air samplers, liquid collection media, and reverse transcriptases (RT).
Mineral oil retains airborne RNA better than does hydrophilic media without impairing integrity. SARS-CoV-2 ORF1ab target was detected in 80% of the air samples using BioSampler with mineral oil. No significant differences in effectiveness were obtained with MD8 sampler equipped with gelatine membrane filters, but the SARS-CoV-2 copies/m3 air obtained with the latter were lower (28.4 ± 6.1 vs 9 ± 1.7). SuperScript II RT allows the detection of a single SARS-CoV-2 genome RNA molecule by ddPCR with high efficiency. This was the only RT that allowed the detection of SARS-CoV-2 N1 target in air samples.
The collection efficiency and detection sensivity of a protocol to quantify SARS-CoV-2 RNA levels in indoor air has been improved in the present study. Such optimization is important to improve our understanding of the microbiological safety of indoor air.
Genome-wide association studies (GWAS) are not fully comprehensive, as current strategies typically test only the additive model, exclude the X chromosome, and use only one reference panel for ...genotype imputation. We implement an extensive GWAS strategy, GUIDANCE, which improves genotype imputation by using multiple reference panels and includes the analysis of the X chromosome and non-additive models to test for association. We apply this methodology to 62,281 subjects across 22 age-related diseases and identify 94 genome-wide associated loci, including 26 previously unreported. Moreover, we observe that 27.7% of the 94 loci are missed if we use standard imputation strategies with a single reference panel, such as HRC, and only test the additive model. Among the new findings, we identify three novel low-frequency recessive variants with odds ratios larger than 4, which need at least a three-fold larger sample size to be detected under the additive model. This study highlights the benefits of applying innovative strategies to better uncover the genetic architecture of complex diseases.
Genome-wide association studies (GWAS) have identified more than 80 susceptibility loci for type 2 diabetes (T2D), but most of its heritability still remains to be elucidated. In this study, we ...conducted a meta-analysis of GWAS for T2D in the Japanese population. Combined data from discovery and subsequent validation analyses (23,399 T2D cases and 31,722 controls) identify 7 new loci with genome-wide significance (P<5 × 10(-8)), rs1116357 near CCDC85A, rs147538848 in FAM60A, rs1575972 near DMRTA1, rs9309245 near ASB3, rs67156297 near ATP8B2, rs7107784 near MIR4686 and rs67839313 near INAFM2. Of these, the association of 4 loci with T2D is replicated in multi-ethnic populations other than Japanese (up to 65,936 T2Ds and 158,030 controls, P<0.007). These results indicate that expansion of single ethnic GWAS is still useful to identify novel susceptibility loci to complex traits not only for ethnicity-specific loci but also for common loci across different ethnicities.
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