Age-related degenerative and malignant diseases represent major challenges for health care systems. Elucidation of the molecular mechanisms underlying carcinogenesis and age-associated pathologies is ...thus of growing biomedical relevance. We identified biallelic germline mutations in SPRTN (also called C1orf124 or DVC1) in three patients from two unrelated families. All three patients are affected by a new segmental progeroid syndrome characterized by genomic instability and susceptibility toward early onset hepatocellular carcinoma. SPRTN was recently proposed to have a function in translesional DNA synthesis and the prevention of mutagenesis. Our in vivo and in vitro characterization of identified mutations has uncovered an essential role for SPRTN in the prevention of DNA replication stress during general DNA replication and in replication-related G2/M-checkpoint regulation. In addition to demonstrating the pathogenicity of identified SPRTN mutations, our findings provide a molecular explanation of how SPRTN dysfunction causes accelerated aging and susceptibility toward carcinoma.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The COVID-19 pandemic has the potential to affect the human microbiome in infected and uninfected individuals, having a substantial impact on human health over the long term. This pandemic intersects ...with a decades-long decline in microbial diversity and ancestral microbes due to hygiene, antibiotics, and urban living (the hygiene hypothesis). High-risk groups succumbing to COVID-19 include those with preexisting conditions, such as diabetes and obesity, which are also associated with microbiome abnormalities. Current pandemic control measures and practices will have broad, uneven, and potentially long-term effects for the human microbiome across the planet, given the implementation of physical separation, extensive hygiene, travel barriers, and other measures that influence overall microbial loss and inability for reinoculation. Although much remains uncertain or unknown about the virus and its consequences, implementing pandemic control practices could significantly affect the microbiome. In this Perspective, we explore many facets of COVID-19-induced societal changes and their possible effects on the microbiome, and discuss current and future challenges regarding the interplay between this pandemic and the microbiome. Recent recognition of the microbiome's influence on human health makes it critical to consider both how the microbiome, shaped by biosocial processes, affects susceptibility to the coronavirus and, conversely, how COVID-19 disease and prevention measures may affect the microbiome. This knowledge may prove key in prevention and treatment, and long-term biological and social outcomes of this pandemic.
Genomic technologies such as next-generation sequencing (NGS) are revolutionizing molecular diagnostics and clinical medicine. However, these approaches have proven inefficient at identifying ...pathogenic repeat expansions. Here, we apply a collection of bioinformatics tools that can be utilized to identify either known or novel expanded repeat sequences in NGS data. We performed genetic studies of a cohort of 35 individuals from 22 families with a clinical diagnosis of cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS). Analysis of whole-genome sequence (WGS) data with five independent algorithms identified a recessively inherited intronic repeat expansion (AAGGG)exp in the gene encoding Replication Factor C1 (RFC1). This motif, not reported in the reference sequence, localized to an Alu element and replaced the reference (AAAAG)11 short tandem repeat. Genetic analyses confirmed the pathogenic expansion in 18 of 22 CANVAS-affected families and identified a core ancestral haplotype, estimated to have arisen in Europe more than twenty-five thousand years ago. WGS of the four RFC1-negative CANVAS-affected families identified plausible variants in three, with genomic re-diagnosis of SCA3, spastic ataxia of the Charlevoix-Saguenay type, and SCA45. This study identified the genetic basis of CANVAS and demonstrated that these improved bioinformatics tools increase the diagnostic utility of WGS to determine the genetic basis of a heterogeneous group of clinically overlapping neurogenetic disorders.
•Granulocyte colony stimulating factor (G-CSF) is a key regulator of neutrophils.•G-CSF contributes to protecting the host against infection.•Conversely, G-CSF can play a deleterious role in ...inflammatory diseases.•The G-CSF pathway may provide novel therapeutic targets in inflammatory diseases.
Neutrophils are vital for the innate immune system’s control of pathogens and neutrophil deficiency can render the host susceptible to life-threatening infections. Neutrophil responses must also be tightly regulated because excessive production, recruitment or activation of neutrophils can cause tissue damage in both acute and chronic inflammatory diseases. Granulocyte colony stimulating factor (G-CSF) is a key regulator of neutrophil biology, from production, differentiation, and release of neutrophil precursors in the bone marrow (BM) to modulating the function of mature neutrophils outside of the BM, particularly at sites of inflammation. G-CSF acts by binding to its cognate cell surface receptor on target cells, causing the activation of intracellular signalling pathways mediating the proliferation, differentiation, function, and survival of cells in the neutrophil lineage. Studies in humans and mice demonstrate that G-CSF contributes to protecting the host against infection, but conversely, it can play a deleterious role in inflammatory diseases. As such, neutrophils and the G-CSF pathway may provide novel therapeutic targets. This review will focus on understanding the role G-CSF plays in the balance between effective neutrophil mediated host defence versus neutrophil-mediated inflammation and tissue damage in various inflammatory and infectious diseases.
The Cambrian and Ordovician radiations were the most important biodiversification events in the history of animal life, yet they were separated by intervals of recurrent anoxic sedimentation and ...regional biomere extinction events in the Late Cambrian and Early Ordovician. Recent work linked biomere extinction events to positive carbon isotopic excursions interpreted to represent enhanced organic matter burial under anoxic conditions. This led to the hypothesis that an increase in oceanic oxygenation following the last of the biomere extinctions paved the way for the rapid diversification of the Ordovician Radiation. Here we test the hypothesis of increasing ocean oxygenation using Th/U preserved in carbonate rocks from the Lower–Middle Ordovician succession near Ibex, Utah, USA. The global seawater uranium inventory is expected to vary inversely with the amount of deep-water anoxic deposition due to uranium sequestration in black shales. Therefore in shallow water carbonates higher Th/U ratios may reflect increased global ocean anoxia. Our data show that the highest Th/U values are coincident with the heaviest carbon isotopic values reported from the base of this succession, which is latest Tremadocian in age. Th/U then decreases and remains low through the Floian up through the contact with the Kanosh Formation, a shale-dominated unit with interspersed limestone units. The geochemistry of the carbonates within the Kanosh Formation likely represents local rather than global conditions in the marine environment. We interpret the overall decrease in Th/U ratios throughout the Tremadocian to Floian interval to represent an increase in global seawater uranium concentration. These data are consistent with the hypothesis that an increase in ocean oxygenation occurred prior to the major pulses of diversification associated with the Ordovician Radiation.
•Th/U can be used as a global redox proxy in carbonate rocks.•The Ordovician Radiation was likely delayed due to biomere extinctions.•An increase in oxygen follows the last Early Ordovician biomere extinction.•Increased oxygen likely suppressed further biomere extinction events.
Non-small cell lung cancers (NSCLCs) that harbor mutations within the epidermal growth factor receptor (EGFR) gene are sensitive to the tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib. ...Unfortunately, all patients treated with these drugs will acquire resistance, most commonly as a result of a secondary mutation within EGFR (T790M). Because both drugs were developed to target wild-type EGFR, we hypothesized that current dosing schedules were not optimized for mutant EGFR or to prevent resistance. To investigate this further, we developed isogenic TKI-sensitive and TKI-resistant pairs of cell lines that mimic the behavior of human tumors. We determined that the drug-sensitive and drug-resistant EGFR-mutant cells exhibited differential growth kinetics, with the drug-resistant cells showing slower growth. We incorporated these data into evolutionary mathematical cancer models with constraints derived from clinical data sets. This modeling predicted alternative therapeutic strategies that could prolong the clinical benefit of TKIs against EGFR-mutant NSCLCs by delaying the development of resistance.
Characterizing polymorphism at the major histocompatibility complex (MHC) genes is key to understanding the vertebrate immune response to disease. Despite being globally afflicted by the infectious ...tumour disease fibropapillomatosis (FP), immunogenetic variation in sea turtles is minimally explored. We sequenced the
peptide-binding region of MHC class I genes (162 bp) from 268 juvenile green (
) and 88 loggerhead (
) sea turtles in Florida, USA. We recovered extensive variation (116 alleles) and trans-species polymorphism. Supertyping analysis uncovered three functional MHC supertypes corresponding to the three well-supported clades in the phylogeny. We found significant evidence of positive selection at seven amino acid sites in the class I exon. Random forest modelling and risk ratio analysis of
alleles uncovered one allele weakly associated with smooth FP tumour texture, which may be associated with disease outcome. Our study represents the first characterization of MHC class I diversity in
and the largest sample of sea turtles used to date in any study of adaptive genetic variation, revealing tremendous genetic variation and high adaptive potential to viral pathogen threats. The novel associations we identified between MHC diversity and FP outcomes in sea turtles further highlight the importance of evaluating genetic predictors of disease, including MHC and other functional markers.
Acute ischemic stroke is a leading cause of death and disability worldwide. Several recent clinical trials have shown that endovascular treatment improves clinical outcomes among patients with acute ...ischemic stroke.
To provide an overall and precise estimate of the efficacy of endovascular treatment predominantly using second-generation mechanical thrombectomy devices (stent-retriever devices) compared to medical management on clinical and functional outcomes among patients with acute ischemic stroke.
MEDLINE, EMBASE, Cochrane Collaboration Central Register of Controlled Clinical Trials, Web of Science, and NIH ClinicalTrials.gov were searched through November 2015.
Searches returned 3,045 articles. After removal of duplicates, two authors independently screened titles and abstracts to assess eligibility of 2,495 potentially relevant publications. From these, 38 full-text publications were more closely assessed. Finally, 5 randomized controlled trials of endovascular treatment with predominant use of retrievable stents were selected.
Three authors independently extracted information on participant and trial characteristics and clinical events using a standardized protocol. Random effects models were used to pool endovascular treatment effects across outcomes.
The primary outcome was better functional outcome as measured on the modified Rankin Scale at 90 days of follow-up. Secondary outcomes included all-cause mortality and symptomatic intra-cerebral hemorrhage.
Five trials representing 1,287 patients were included. Overall, patients randomized to endovascular therapy experienced 2.22 times greater odds of better functional outcome compared to those randomized to medical management (95% CI, 1.66 to 2.98; P < 0.0001). Endovascular therapy was not associated with mortality OR (95% CI), 0.78 (0.54, 1.12); P = 0.1056 or symptomatic intracerebral hemorrhage OR (95% CI), 1.19 (0.69, 2.05); P = 0.5348. Meta-regression analysis suggested that shorter times from stroke onset to groin puncture and from stroke onset to reperfusion result in better functional outcomes in ischemic stroke patients (P = 0.0077 and P = 0.0089). There were no significant differences in the beneficial effects of endovascular treatment on functional outcomes across categories of gender, age, stroke severity, ischemic changes on computed tomography, or intravenous tissue plasminogen activator administration.
This meta-analysis demonstrated superior functional outcomes in subjects receiving endovascular treatment compared to medical management. Further, this analysis showed that acute ischemic stroke patients may receive enhanced functional benefit from earlier endovascular treatment.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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