Friedrichsengustavsen4809
We provide recommendations for practitioners and suggest ways that these results can foster improvements to the quality and defensibility of risk and impact assessments.DNA replication is dramatically slowed down under replication stress. The regulation of replication speed is a conserved response in eukaryotes and, in fission yeast, requires the checkpoint kinases Rad3ATR and Cds1Chk2 However, the underlying mechanism of this checkpoint regulation remains unresolved. Here, we report that the Rad3ATR-Cds1Chk2 checkpoint directly targets the Cdc45-MCM-GINS (CMG) replicative helicase under replication stress. When replication forks stall, the Cds1Chk2 kinase directly phosphorylates Cdc45 on the S275, S322, and S397 residues, which significantly reduces CMG helicase activity. Furthermore, in cds1 Chk2 -mutated cells, the CMG helicase and DNA polymerases are physically separated, potentially disrupting replisomes and collapsing replication forks. This study demonstrates that the intra-S phase checkpoint directly regulates replication elongation, reduces CMG helicase processivity, prevents CMG helicase delinking from DNA polymerases, and therefore helps preserve the integrity of stalled replisomes and replication forks.Global cooling and glacial-interglacial cycles since Antarctica's isolation have been responsible for the diversification of the region's marine fauna. BAY-985 concentration By contrast, these same Earth system processes are thought to have played little role terrestrially, other than driving widespread extinctions. Here, we show that on islands along the Antarctic Polar Front, paleoclimatic processes have been key to diversification of one of the world's most geographically isolated and unique groups of herbivorous beetles-Ectemnorhinini weevils. Combining phylogenomic, phylogenetic, and phylogeographic approaches, we demonstrate that these weevils colonized the sub-Antarctic islands from Africa at least 50 Ma ago and repeatedly dispersed among them. As the climate cooled from the mid-Miocene, diversification of the beetles accelerated, resulting in two species-rich clades. One of these clades specialized to feed on cryptogams, typical of the polar habitats that came to prevail under Miocene conditions yet remarkable as a food source for any beetle. This clade's most unusual representative is a marine weevil currently undergoing further speciation. The other clade retained the more common weevil habit of feeding on angiosperms, which likely survived glaciation in isolated refugia. Diversification of Ectemnorhinini weevils occurred in synchrony with many other Antarctic radiations, including penguins and notothenioid fishes, and coincided with major environmental changes. Our results thus indicate that geo-climatically driven diversification has progressed similarly for Antarctic marine and terrestrial organisms since the Miocene, potentially constituting a general biodiversity paradigm that should be sought broadly for the region's taxa.Galanin receptor1 (GalR1) transcript levels are elevated in the rat ventral periaqueductal gray (vPAG) after chronic mild stress (CMS) and are related to depression-like behavior. To explore the mechanisms underlying the elevated GalR1 expression, we carried out molecular biological experiments in vitro and in animal behavioral experiments in vivo. It was found that a restricted upstream region of the GalR1 gene, from -250 to -220, harbors an E-box and plays a negative role in the GalR1 promoter activity. The transcription factor Scratch2 bound to the E-box to down-regulate GalR1 promoter activity and lower expression levels of the GalR1 gene. The expression of Scratch2 was significantly decreased in the vPAG of CMS rats. Importantly, local knockdown of Scratch2 in the vPAG caused elevated expression of GalR1 in the same region, as well as depression-like behaviors. RNAscope analysis revealed that GalR1 mRNA is expressed together with Scratch2 in both GABA and glutamate neurons. Taking these data together, our study further supports the involvement of GalR1 in mood control and suggests a role for Scratch2 as a regulator of depression-like behavior by repressing the GalR1 gene in the vPAG.
To investigate the abundance and the prevalence of
J115
, a novel butyrate-producing bacterium isolated from the human gut both in the general population and in subjects with metabolic syndrome. To study the impact of this bacterium on host metabolism using diet-induced obese and diabetic mice.
We analysed the presence and abundance of the bacterium in 11 984 subjects using four human cohorts (ie, Human Microbiome Project, American Gut Project, Flemish Gut Flora Project and Microbes4U). Then, we tested the effects of daily oral gavages with live
J115
on metabolism and several hallmarks of obesity, diabetes, inflammation and lipid metabolism in obese/diabetic mice.
This newly identified bacterium was detected in 62.7%-69.8% of the healthy population. Strikingly, in obese humans with a metabolic syndrome, the abundance of
genus correlates negatively with body mass index, fasting glucose and glycated haemoglobin. In mice, supplementation with live
J115
, but not with the pasteurised bacteria, partially counteracted diet-induced obesity development, fat mass gain, insulin resistance and white adipose tissue hypertrophy and inflammation. In addition, live
J115
administration protected the mice from brown adipose tissue inflammation in association with increased mitochondria number and non-shivering thermogenesis. These effects occurred with minor impact on the mouse intestinal microbiota composition.
These results suggest that
J115
directly and beneficially influences host metabolism and is a strong candidate for the development of next-generation beneficial bacteria targeting obesity and associated metabolic diseases.
These results suggest that D. welbionis J115T directly and beneficially influences host metabolism and is a strong candidate for the development of next-generation beneficial bacteria targeting obesity and associated metabolic diseases.
Implementation of faecal immunochemical tests (FIT) as a triage test in primary healthcare may improve the efficiency of referrals without missing cases of colorectal cancer (CRC). We aim to summarise the performance characteristics of FITs for CRC in symptomatic patients presenting to primary healthcare.
We performed a systematic literature review of Medline and EMBASE databases from May 2018 to November 2020. Previous related systematic searches were also adapted to this aim and completed with reference screening. We identified studies performed on adult patients consulting for abdominal symptoms in primary care which reported data such that the FIT diagnostic performance parameters for CRC could be obtained. Bivariate models were used to synthesise available evidence. Meta-regression analysis was performed to evaluate the causes of heterogeneity.
Twenty-three studies (69 536 participants) were included (CRC prevalence 0.3%-6.2%). Six studies (n=34 691) assessed FIT as rule in test (threshold of ≥150 µg Hb/g faeces) showing a sensitivity of 64.1% (95% CI 57.8% to 69.9%) and a specificity of 95.0% (95% CI 91.2% to 97.2%). A threshold of 10 µg/g (15 studies; n=48 872) resulted in a sensitivity of 87.2% (95% CI 81.0% to 91.6%) and a specificity of 84.4% (95% CI 79.4% to 88.3%) for CRC. At a 20 µg Hb/g faeces threshold (five studies; n=24 187) less than one additional CRC would be missed per 1000 patients investigated compared with 10 µg Hb/g faeces threshold (CRC prevalence 2%).
FIT is the test of choice to evaluate patients with new-onset lower gastrointestinal symptoms in primary healthcare.
FIT is the test of choice to evaluate patients with new-onset lower gastrointestinal symptoms in primary healthcare.
In the management of juvenile idiopathic arthritis (JIA), there is a lack of diagnostic and prognostic biomarkers. This study assesses the use of serum calprotectin (sCal) as a marker to monitor disease activity, and as a classification and prognosis tool of response to treatment or risk of flares in patients with JIA.
Eighty-one patients with JIA from the CAP48 multicentric cohort were included in this study, as well as 11 non-paediatric healthy controls. An ELISA method was used to quantify sCal with a commercial kit.
Patients with an active disease compared with healthy controls and with patients with inactive disease showed an eightfold and a twofold increased level of sCal, respectively. sCal was found to be correlated with the C-reactive protein (CRP) and even more strongly with the erythrocyte sedimentation rate. Evolution of DAS28 scores correlated well with evolution of sCal, as opposed to evolution of CRP. With regard to CRP, sCal could differentiate forms with active oligoarthritis from polyarthritis and systemic forms. However, sCal brought an added value compared with the CRP as a prognosis marker. Indeed, patients with active disease and reaching minimal disease activity (according to Juvenile Arthritis Disease Activity Score) at 6 months following the test had higher sCal levels, while patients with inactive disease had higher sCal levels if a flare was observed up to 3-9 months following the test.
This study confirms the potential uses of sCal as a biomarker in the diagnosis and follow-up of JIA.
This study confirms the potential uses of sCal as a biomarker in the diagnosis and follow-up of JIA.Ischemia reperfusion injury (IRI) is the most common cause of in-hospital AKI and is associated with increased morbidity and mortality. IRI is associated with an early phase of inflammation primarily regulated by the canonical NFκB signaling pathway. Despite recent advances in our understanding of the pathogenesis of IRI, few therapeutic strategies have emerged. The purpose of this manuscript is to review interventions targeting NFκB after IRI.TNRC6 is a scaffolding protein that bridges interactions between small RNAs, argonaute (AGO) protein, and effector proteins to control gene expression. There are three paralogs in mammalian cells, TNRC6A, TNRC6B, and TNRC6C. These paralogs have ~40% sequence identity and the extent of their unique or redundant functions is unclear. Here, we use knockout cell lines, enhanced crosslinking immunoprecipitation (eCLIP), and high-throughput RNA sequencing (RNAseq) to explore the roles of TNRC6 paralogs in RNA-mediated control of gene expression. We find that that the paralogs are largely functionally redundant and changes in levels of gene expression are well-correlated with those observed in AGO knockout cell lines. Splicing changes observed in AGO knockout cell lines are observed in TNRC6 knockout cells. These data further define the roles of the TNRC6 isoforms as part of the RNA interference (RNAi) machinery.Mammalian RNA interference (RNAi) is often linked to the regulation of gene expression in the cytoplasm. Synthetic RNAs, however, can also act through the RNAi pathway to regulate transcription and splicing. While nuclear regulation by synthetic RNAs can be robust, a critical unanswered question is whether endogenous functions for nuclear RNAi exist in mammalian cells. Using enhanced crosslinking immunoprecipitation (eCLIP), we mapped AGO2 binding sites within nuclear RNA. The strongest AGO2 binding sites were mapped to micro RNAs (miRNAs). The most abundant miRNAs were distributed similarly between cytoplasm and nucleus, providing no evidence for mechanisms that facilitate localization of miRNAs in one compartment versus the other. Beyond miRNAs, most statistically-significant AGO2 binding was within introns. Splicing changes were confirmed by RT-PCR and were recapitulated by synthetic duplex RNAs and miRNA mimics complementary to the sites of AGO2 binding. These data support the hypothesis that miRNAs can control gene splicing.
