Brain invasion by glioblastoma determines prognosis, recurrence, and lethality in patients, but no master factor coordinating the invasive properties of glioblastoma has been identified. Here we ...report evidence favoring such a role for the noncanonical WNT family member Wnt5a. We found the most invasive gliomas to be characterized by Wnt5a overexpression, which correlated with poor prognosis and also discriminated infiltrating mesenchymal glioblastoma from poorly motile proneural and classical glioblastoma. Indeed, Wnt5a overexpression associated with tumor-promoting stem-like characteristics (TPC) in defining the character of highly infiltrating mesenchymal glioblastoma cells (Wnt5a
). Inhibiting Wnt5a in mesenchymal glioblastoma TPC suppressed their infiltrating capability. Conversely, enforcing high levels of Wnt5a activated an infiltrative, mesenchymal-like program in classical glioblastoma TPC and Wnt5a
mesenchymal TPC. In intracranial mouse xenograft models of glioblastoma, inhibiting Wnt5a activity blocked brain invasion and increased host survival. Overall, our results highlight Wnt5a as a master regulator of brain invasion, specifically TPC, and they provide a therapeutic rationale to target it in patients with glioblastoma.
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Non-alcoholic fatty liver disease (NAFLD) is the most frequent hepatic pathology in the Western world and may evolve into steatohepatitis (NASH), increasing the risk of cirrhosis, portal hypertension ...and hepatocellular carcinoma. NAFLD derives from the accumulation of hepatic fat due to discrepant free fatty acid metabolism. Other factors contributing to this are deranged nutrients and bile acids fluxes as well as alterations in nuclear receptors, hormones, and intermediary metabolites, which impact on signaling pathways involved in metabolism and inflammation. Autophagy and host gut-microbiota interplay are also relevant to NAFLD pathogenesis. Notably, liver metabolic pathways and bile acid synthesis as well as autophagic and immune/inflammatory processes all show circadian patterns driven by the biological clock. Gut microbiota impacts on the biological clock, at the same time as the appropriate timing of metabolic fluxes, hormone secretion, bile acid turnover, autophagy and inflammation with behavioural cycles of fasting/feeding and sleeping/waking is required to circumvent hepatosteatosis, indicating significant interactions of the gut and circadian processes in NAFLD pathophysiology. Several time-related factors and processes interplay in NAFLD development, with the biological clock proposed to act as a network level hub. Deranged physiological rhythms (chronodisruption) may also play a role in liver steatosis pathogenesis. The current article reviews how the circadian clock circuitry intimately interacts with several mechanisms involved in the onset of hepatosteatosis and its progression to NASH, thereby contributing to the global NAFLD epidemic.
Abstract
Numerous lines of evidence have shown that the interaction between the nuclear and mitochondrial genomes ensures the efficient functioning of the OXPHOS complexes, with substantial ...implications in bioenergetics, adaptation, and disease. Their interaction is a fascinating and complex trait of the eukaryotic cell that MitImpact explores with its third major release. MitImpact expands its collection of genomic, clinical, and functional annotations of all non-synonymous substitutions of the human mitochondrial genome with new information on putative Compensated Pathogenic Deviations and co-varying amino acid sites of the Respiratory Chain subunits. It further provides evidence of energetic and structural residue compensation by techniques of molecular dynamics simulation. MitImpact is freely accessible at http://mitimpact.css-mendel.it.
24,189 are all the possible non-synonymous amino acid changes potentially affecting the human mitochondrial DNA. Only a tiny subset was functionally evaluated with certainty so far, while the ...pathogenicity of the vast majority was only assessed in-silico by software predictors. Since these tools proved to be rather incongruent, we have designed and implemented APOGEE, a machine-learning algorithm that outperforms all existing prediction methods in estimating the harmfulness of mitochondrial non-synonymous genome variations. We provide a detailed description of the underlying algorithm, of the selected and manually curated training and test sets of variants, as well as of its classification ability.
Mitochondrial dysfunction has pleiotropic effects and is frequently caused by mitochondrial DNA mutations. However, factors such as significant variability in clinical manifestations make ...interpreting the pathogenicity of variants in the mitochondrial genome challenging. Here, we present APOGEE 2, a mitochondrially-centered ensemble method designed to improve the accuracy of pathogenicity predictions for interpreting missense mitochondrial variants. Built on the joint consensus recommendations by the American College of Medical Genetics and Genomics/Association for Molecular Pathology, APOGEE 2 features an improved machine learning method and a curated training set for enhanced performance metrics. It offers region-wise assessments of genome fragility and mechanistic analyses of specific amino acids that cause perceptible long-range effects on protein structure. With clinical and research use in mind, APOGEE 2 scores and pathogenicity probabilities are precompiled and available in MitImpact. APOGEE 2's ability to address challenges in interpreting mitochondrial missense variants makes it an essential tool in the field of mitochondrial genetics.
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•Paper discusses the relevance of the adoption of ad-hoc vaccination strategies.•Paper shows how to evaluate the impact of different vaccination strategy by considering network-based ...models.•Tailored interventions, e.g., vaccination, applied on central nodes of these networks may efficiently stop the propagation of an infection.•The way node "centrality" is defined is the key to curb infection spreading.
The mitigation of an infectious disease spreading has recently gained considerable attention from the research community. It may be obtained by adopting sanitary measurements (e.g., vaccination, wearing masks), social rules (e.g., social distancing), together with an extensive vaccination campaign. Vaccination is currently the primary way for mitigating the Coronavirus Disease (COVID-19) outbreak without severe lockdown. Its effectiveness also depends on the number and timeliness of administrations and thus demands strict prioritization criteria. Almost all countries have prioritized similar classes of exposed workers: healthcare professionals and the elderly, obtaining to maximize the survival of patients and years of life saved. Nevertheless, the virus is currently spreading at high rates, and any prioritization criterion so far adopted did not account for the structural organization of the contact networks.
We reckon that a network where nodes are people while the edges represent their social contacts may efficiently model the virus’s spreading. It is known that tailored interventions (e.g., vaccination) on central nodes may efficiently stop the propagation, thereby eliminating the “bridge edges.” We then introduce such a model and consider both synthetic and real datasets. We present the benefits of a topology-aware versus an age-based vaccination strategy to mitigate the spreading of the virus. The code is available athttps://github.com/mazzalab/playgrounds.
Contained-reflected beds deposited by fully-ponded or partially-reflected turbidity currents are important because their correct evaluation can give important indications on the degree of basin ...confinement and on the type, size and orientation of the morphological obstacle. Through a detailed facies analysis of various significant megabeds in the Marnoso-arenacea Formation, including the Contessa key bed, in the helminthoid flysches in the northern Apennines (Italy) and in the Pyrenees (megaturbidite MT5), this work proposes a depositional model that is well consistent with the recent experimental data available in the literature, discussing their strengths and limits. The Contessa and flysch megabeds fit very well with the experimental conditions because they are deposited in narrow and elongated confined basins characterized by axial flows. Indeed, in the proposed model, it is possible to recognize facies deposited by: 1) a basal underflow directed towards the bounding slope (Facies A), 2) an intermediate part of the flow characterized by lateral deflections (facies B1), 3) an upper well-developed reversing flow (facies B2) and 4) an uppermost residual reversing flow recording the final collapse of the fine-grained suspended load forming a poorly-sorted slurry facies C and a very thick mudstone unit D. Facies A, B1 and B2 are usually separated by very thin fine-grained muddy drapes rich in carbonaceous matter, which can be traced throughout the basin. These drapes - very common in contained and confined beds in these settings - can be related to internal density surfaces, along which decoupling processes, separating underflows from reversing overflows, can easily occur. Conversely, as the MT5 is characterized by a source transversal to an elongated narrow basin, the large flow volume versus basin capacity hinders the generation of reversing flows and rebound layers favoring the formation of fully-ponded pulsating overflows able to deposit alternations of laminated and massive units. This facies type can be observed in the basins that are characterized by axial flows only near the basin margins where the pulsating collapse of the reversing flow can dominate. This study shows that the integration of detailed field studies are essential to validate experimental data from an applicative point of view.
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