54 research outputs found
Continuous and Discontinuous Phase Transitions in the evolution of a polygenic trait under stabilizing selective pressure
The presence of phenomena analogous to phase transition in Statistical
Mechanics, has been suggested in the evolution of a polygenic trait under
stabilizing selection, mutation and genetic drift.
By using numerical simulations of a model system, we analyze the evolution of
a population of diploid hermaphrodites in random mating regime. The
population evolves under the effect of drift, selective pressure in form of
viability on an additive polygenic trait, and mutation. The analysis allows to
determine a phase diagram in the plane of mutation rate and strength of
selection. The involved pattern of phase transitions is characterized by a line
of critical points for weak selective pressure (smaller than a threshold),
whereas discontinuous phase transitions, characterized by metastable
hysteresis, are observed for strong selective pressure. A finite size scaling
analysis suggests the analogy between our system and the mean field Ising model
for selective pressure approaching the threshold from weaker values. In this
framework, the mutation rate, which allows the system to explore the accessible
microscopic states, is the parameter controlling the transition from large
heterozygosity (disordered phase) to small heterozygosity (ordered one).Comment: 8 pages, 7 figures, 1 tabl
An ecofriendly lipophilization of hydroxytyrosol present in industrial Olea europaea L. fractions obtained from olive oil by-products
Mitotic cell death induction by targeting the mitotic spindle with tubulin-inhibitory indole derivative molecules
Tubulin-targeting molecules are widely used cancer therapeutic agents. They inhibit microtubule-based structures, including the mitotic spindle, ultimately preventing cell division. The final fates of microtubule-inhibited cells are however often heterogeneous and difficult to predict. While recent work has provided insight into the cell response to inhibitors of microtubule dynamics (taxanes), the cell response to tubulin polymerization inhibitors remains less well characterized. Arylthioindoles (ATIs) are recently developed tubulin inhibitors. We previously identified ATI members that effectively inhibit tubulin polymerization in vitro and cancer cell growth in bulk cell viability assays. Here we characterise in depth the response of cancer cell lines to five selected ATIs. We find that all ATIs arrest mitotic progression, yet subsequently yield distinct cell fate profiles in time-lapse recording assays, indicating that molecules endowed with similar tubulin polymerization inhibitory activity in vitro can in fact display differential efficacy in living cells. Individual ATIs induce cytological phenotypes of increasing severity in terms of damage to the mitotic apparatus. That differentially triggers MCL-1 down-regulation and caspase-3 activation, and underlies the terminal fate of treated cells. Collectively, these results contribute to define the cell response to tubulin inhibitors and pinpoint potentially valuable molecules that can increase the molecular diversity of tubulin-targeting agents
Low-cost multi-channel synchronous data acquisition system based on compressive sampling approach
Peer Reviewe
AIforCOVID: predicting the clinical outcomes in patients with COVID-19 applying AI to chest-X-rays. An Italian multicentre study
Recent epidemiological data report that worldwide more than 53 million people
have been infected by SARS-CoV-2, resulting in 1.3 million deaths. The disease
has been spreading very rapidly and few months after the identification of the
first infected, shortage of hospital resources quickly became a problem. In
this work we investigate whether chest X-ray (CXR) can be used as a possible
tool for the early identification of patients at risk of severe outcome, like
intensive care or death. CXR is a radiological technique that compared to
computed tomography (CT) it is simpler, faster, more widespread and it induces
lower radiation dose. We present a dataset including data collected from 820
patients by six Italian hospitals in spring 2020 during the first COVID-19
emergency. The dataset includes CXR images, several clinical attributes and
clinical outcomes. We investigate the potential of artificial intelligence to
predict the prognosis of such patients, distinguishing between severe and mild
cases, thus offering a baseline reference for other researchers and
practitioners. To this goal, we present three approaches that use features
extracted from CXR images, either handcrafted or automatically by convolutional
neuronal networks, which are then integrated with the clinical data. Exhaustive
evaluation shows promising performance both in 10-fold and leave-one-centre-out
cross-validation, implying that clinical data and images have the potential to
provide useful information for the management of patients and hospital
resources
Rare ATG7 genetic variants predispose patients to severe fatty liver disease
Non-alcoholic fatty liver disease (NAFLD) is the leading cause of liver disorders and has a strong heritable component. The aim of this study was to identify new loci that contribute to severe NAFLD by examining rare variants
New Indole Tubulin Assembly Inhibitors Cause Stable Arrest of Mitotic Progression, Enhanced Stimulation of Natural Killer Cell Cytotoxic Activity, and Repression of Hedgehog-Dependent Cancer
We designed 39 new 2-phenylindole derivatives as potential anticancer agents bearing the 3,4,5-trimethoxyphenyl moiety with a sulfur, ketone, or methylene bridging group at position 3 of the indole and with halogen or methoxy substituent(s) at positions 4-7. Compounds 33 and 44 strongly inhibited the growth of the P-glycoprotein-overexpressing multi-drug-resistant cell lines NCI/ADR-RES and Messa/Dx5. At 10 nM, 33 and 44 stimulated the cytotoxic activity of NK cells. At 20-50 nM, 33 and 44 arrested >80% of HeLa cells in the G2/M phase of the cell cycle, with stable arrest of mitotic progression. Cell cycle arrest was followed by cell death. Indoles 33, 44, and 81 showed strong inhibition of the SAG-induced Hedgehog signaling activation in NIH3T3 Shh-Light II cells with IC50 values of 19, 72, and 38 nM, respectively. Compounds of this class potently inhibited tubulin polymerization and cancer cell growth, including stimulation of natural killer cell cytotoxic activity and repression of Hedgehog-dependent cancer
Tracking the evolution of epialleles during neural differentiation and brain development: D- aspartate oxidase as a model gene
Prolonged higher dose methylprednisolone vs. conventional dexamethasone in COVID-19 pneumonia: a randomised controlled trial (MEDEAS)
Dysregulated systemic inflammation is the primary driver of mortality in severe COVID-19 pneumonia. Current guidelines favor a 7-10-day course of any glucocorticoid equivalent to dexamethasone 6 mg·day-1. A comparative RCT with a higher dose and a longer duration of intervention was lacking
Performance of non-invasive tests and histology for the prediction of clinical outcomes in patients with non-alcoholic fatty liver disease: an individual participant data meta-analysis.
BACKGROUND
Histologically assessed liver fibrosis stage has prognostic significance in patients with non-alcoholic fatty liver disease (NAFLD) and is accepted as a surrogate endpoint in clinical trials for non-cirrhotic NAFLD. Our aim was to compare the prognostic performance of non-invasive tests with liver histology in patients with NAFLD.
METHODS
This was an individual participant data meta-analysis of the prognostic performance of histologically assessed fibrosis stage (F0-4), liver stiffness measured by vibration-controlled transient elastography (LSM-VCTE), fibrosis-4 index (FIB-4), and NAFLD fibrosis score (NFS) in patients with NAFLD. The literature was searched for a previously published systematic review on the diagnostic accuracy of imaging and simple non-invasive tests and updated to Jan 12, 2022 for this study. Studies were identified through PubMed/MEDLINE, EMBASE, and CENTRAL, and authors were contacted for individual participant data, including outcome data, with a minimum of 12 months of follow-up. The primary outcome was a composite endpoint of all-cause mortality, hepatocellular carcinoma, liver transplantation, or cirrhosis complications (ie, ascites, variceal bleeding, hepatic encephalopathy, or progression to a MELD score ≥15). We calculated aggregated survival curves for trichotomised groups and compared them using stratified log-rank tests (histology: F0-2 vs F3 vs F4; LSM: 2·67; NFS: 0·676), calculated areas under the time-dependent receiver operating characteristic curves (tAUC), and performed Cox proportional-hazards regression to adjust for confounding. This study was registered with PROSPERO, CRD42022312226.
FINDINGS
Of 65 eligible studies, we included data on 2518 patients with biopsy-proven NAFLD from 25 studies (1126 [44·7%] were female, median age was 54 years [IQR 44-63), and 1161 [46·1%] had type 2 diabetes). After a median follow-up of 57 months [IQR 33-91], the composite endpoint was observed in 145 (5·8%) patients. Stratified log-rank tests showed significant differences between the trichotomised patient groups (p<0·0001 for all comparisons). The tAUC at 5 years were 0·72 (95% CI 0·62-0·81) for histology, 0·76 (0·70-0·83) for LSM-VCTE, 0·74 (0·64-0·82) for FIB-4, and 0·70 (0·63-0·80) for NFS. All index tests were significant predictors of the primary outcome after adjustment for confounders in the Cox regression.
INTERPRETATION
Simple non-invasive tests performed as well as histologically assessed fibrosis in predicting clinical outcomes in patients with NAFLD and could be considered as alternatives to liver biopsy in some cases.
FUNDING
Innovative Medicines Initiative 2
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