An Accurate Data Preparation Approach for the Prediction of Mortality in ACLF Patients using the CANONIC Dataset

The incidence of chronic liver disease has increased in Europe and can lead to Acute on Chronic Liver Failure (ACLF) which is associated with high levels of mortality due to multisystem organ failure. The characteristics of the ACLF patients can change very rapidly within a short period of time. Continuous assessment of their recovery status is critical for clinicians to adjust and deliver effective treatment. The aim of this paper is to validate the usefulness of a data preparation approach by combining different criteria to replace missing values, balance target-class variables, select useful patient characteristics and optimise hyperparameters of machine learning models for the prediction of ACLF associated mortality rates. A key step in the data preparation is a feature selection Mutual Information (MI) based multivariate approach to build smaller, and yet equally and in some cases more informative, subsets of patient characteristics than those frequently proposed for the prediction of mortality, from patients with ACLF in the CANONIC dataset. The usefulness of the data preparation approach proposed to predict mortality was evaluated by training the XGBoost and Logistic Regression models with the prepared data. Evaluations of the models trained using a test set provided evidence of an overall high accuracy in the prediction of the mortality rates of patients for days after their diagnosis, and in some cases even higher when reduced and more informative subsets of patient characteristics were found

Phenomenological Consequences of sub-leading Terms in See-Saw Formulas

Several aspects of next-to-leading (NLO) order corrections to see-saw formulas are discussed and phenomenologically relevant situations are identified. We generalize the formalism to calculate the NLO terms developed for the type I see-saw to variants like the inverse, double or linear see-saw, i.e., to cases in which more than two mass scales are present. In the standard type I case with very heavy fermion singlets the sub-leading terms are negligible. However, effects in the percent regime are possible when sub-matrices of the complete neutral fermion mass matrix obey a moderate hierarchy, e.g. weak scale and TeV scale. Examples are cancellations of large terms leading to small neutrino masses, or inverse see-saw scenarios. We furthermore identify situations in which no NLO corrections to certain observables arise, namely for mu-tau symmetry and cases with a vanishing neutrino mass. Finally, we emphasize that the unavoidable unitarity violation in see-saw scenarios with extra fermions can be calculated with the formalism in a straightforward manner.Comment: 22 pages, matches published versio

Optimizing the diagnostic power with gastric emptying scintigraphy at multiple time points

<p>Abstract</p> <p>Background</p> <p>Gastric Emptying Scintigraphy (GES) at intervals over 4 hours after a standardized radio-labeled meal is commonly regarded as the gold standard for diagnosing gastroparesis. The objectives of this study were: 1) to investigate the best time point and the best combination of multiple time points for diagnosing gastroparesis with repeated GES measures, and 2) to contrast and cross-validate Fisher's Linear Discriminant Analysis (LDA), a rank based Distribution Free (DF) approach, and the Classification And Regression Tree (CART) model.</p> <p>Methods</p> <p>A total of 320 patients with GES measures at 1, 2, 3, and 4 hour (h) after a standard meal using a standardized method were retrospectively collected. Area under the Receiver Operating Characteristic (ROC) curve and the rate of false classification through jackknife cross-validation were used for model comparison.</p> <p>Results</p> <p>Due to strong correlation and an abnormality in data distribution, no substantial improvement in diagnostic power was found with the best linear combination by LDA approach even with data transformation. With DF method, the linear combination of 4-h and 3-h increased the Area Under the Curve (AUC) and decreased the number of false classifications (0.87; 15.0%) over individual time points (0.83, 0.82; 15.6%, 25.3%, for 4-h and 3-h, respectively) at a higher sensitivity level (sensitivity = 0.9). The CART model using 4 hourly GES measurements along with patient's age was the most accurate diagnostic tool (AUC = 0.88, false classification = 13.8%). Patients having a 4-h gastric retention value >10% were 5 times more likely to have gastroparesis (179/207 = 86.5%) than those with ≤10% (18/113 = 15.9%).</p> <p>Conclusions</p> <p>With a mixed group of patients either referred with suspected gastroparesis or investigated for other reasons, the CART model is more robust than the LDA and DF approaches, capable of accommodating covariate effects and can be generalized for cross institutional applications, but could be unstable if sample size is limited.</p

Non-standard interactions versus non-unitary lepton flavor mixing at a neutrino factory

The impact of heavy mediators on neutrino oscillations is typically described by non-standard four-fermion interactions (NSIs) or non-unitarity (NU). We focus on leptonic dimension-six effective operators which do not produce charged lepton flavor violation. These operators lead to particular correlations among neutrino production, propagation, and detection non-standard effects. We point out that these NSIs and NU phenomenologically lead, in fact, to very similar effects for a neutrino factory, for completely different fundamental reasons. We discuss how the parameters and probabilities are related in this case, and compare the sensitivities. We demonstrate that the NSIs and NU can, in principle, be distinguished for large enough effects at the example of non-standard effects in the $\mu$-$\tau$-sector, which basically corresponds to differentiating between scalars and fermions as heavy mediators as leading order effect. However, we find that a near detector at superbeams could provide very synergistic information, since the correlation between source and matter NSIs is broken for hadronic neutrino production, while NU is a fundamental effect present at any experiment.Comment: 32 pages, 5 figures. Final version published in JHEP. v3: Typo in Eq. (27) correcte

Sphingosine 1-phosphate receptor 4 promotes nonalcoholic steatohepatitis by activating NLRP3 inflammasome

BACKGROUND & AIMS: Sphingosine 1-phosphate receptors (S1PRs) are a group of G-protein-coupled receptors that confer a broad range of functional effects in chronic inflammatory and metabolic diseases. S1PRs also may mediate the development of nonalcoholic steatohepatitis (NASH), but the specific subtypes involved and the mechanism of action are unclear. METHODS: We investigated which type of S1PR isoforms is activated in various murine models of NASH. The mechanism of action of S1PR4 was examined in hepatic macrophages isolated from high-fat, high-cholesterol diet (HFHCD)-fed mice. We developed a selective S1PR4 functional antagonist by screening the fingolimod (2-amino-2-[2-(4- n-octylphenyl)ethyl]-1,3-propanediol hydrochloride)-like sphingolipid-focused library. RESULTS: The livers of various mouse models of NASH as well as hepatic macrophages showed high expression of S1pr4. Moreover, in a cohort of NASH patients, expression of S1PR4 was 6-fold higher than those of healthy controls. S1pr4(++/-) mice were protected from HFHCD-induced NASH and hepatic fibrosis without changes in steatosis. S1pr4 depletion in hepatic macrophages inhibited lipopolysaccharide-mediated Ca++ release and deactivated the Nod-like receptor pyrin domaincontainning protein 3 (NLRP3) inflammasome. S1P increased the expression of S1pr4 in hepatic macrophages and activated NLRP3 inflammasome through inositol trisphosphate/inositol trisphosphate-receptor-dependent [Ca++] signaling. To further clarify the biological function of S1PR4, we developed SLB736, a novel selective functional antagonist of SIPR4. Similar to S1pr4(+/-) mice, administration of SLB736 to HFHCD-fed mice prevented the development of NASH and hepatic fibrosis, but not steatosis, by deactivating the NLRP3 inflammasome. CONCLUSIONS: S1PR4 may be a new therapeutic target for NASH that mediates the activation of NLRP3 inflammasome in hepatic macrophages

TAp73 is one of the genes responsible for the lack of response to chemotherapy depending on B-Raf mutational status

<p>Abstract</p> <p>Background</p> <p>Although there have been many studies on the p73 gene, some of its functions still remain unclear. There is little research on the relationship between p73 gene transcription and its protein expression and the response to certain drugs such as oxaliplatin and cetuximab, which are drugs currently used in colorectal cancer.</p> <p>The purpose of this study was to evaluate the impact of TAp73 expression on oxaliplatin and cetuximab-based chemotherapy in colorectal cancer cell lines with different K-Ras and B-Raf mutational status.</p> <p>Methods</p> <p>TAp73 was analyzed in three colorectal tumor cell lines HT-29, SW-480 and Caco-2. mRNA TAp73 was determined using Real time PCR; TAp73 protein by immunoblotting and cell viability was analyzed by the MTT method.</p> <p>Results</p> <p>We found that mRNA and TAp73 protein were decreased in cells treated with oxaliplatin (in monotherapy or combined with cetuximab) when B-Raf is mutated. This was statistically significant and was also associated with higher cell viability after the treatment.</p> <p>Conclusions</p> <p>Here, for the first time we report, that there is a signaling loop between B-Raf activation and p73 function.</p> <p>Low expression of TAp73 in colorectal cancer cell lines with mutated B-Raf may be involved in the lack of response to oxaliplatin in monotherapy or combined with cetuximab.</p

Interferon-β Pretreatment of Conventional and Plasmacytoid Human Dendritic Cells Enhances Their Activation by Influenza Virus

Influenza virus produces a protein, NS1, that inhibits infected cells from releasing type I interferon (IFN) and blocks maturation of conventional dendritic cells (DCs). As a result, influenza virus is a poor activator of both mouse and human DCs in vitro. However, in vivo a strong immune response to virus infection is generated in both species, suggesting that other factors may contribute to the maturation of DCs in vivo. It is likely that the environment in which a DC encounters a virus would contain multiple pro-inflammatory molecules, including type I IFN. Type I IFN is a critical component of the viral immune response that initiates an antiviral state in cells, primarily by triggering a broad transcriptional program that interferes with the ability of virus to establish infection in the cell. In this study, we have examined the activation profiles of both conventional and plasmacytoid dendritic cells (cDCs and pDCs) in response to an influenza virus infection in the context of a type I IFN-containing environment. We found that both cDCs and pDCs demonstrate a greater activation response to influenza virus when pre-exposed to IFN-β (IFN priming); although, the priming kinetics are different in these two cell types. This strongly suggests that type I IFN functions not only to reduce viral replication in these immune cells, but also to promote greater DC activation during influenza virus infections

Genetic and Chemical Modifiers of a CUG Toxicity Model in Drosophila

Non-coding CUG repeat expansions interfere with the activity of human Muscleblind-like (MBNL) proteins contributing to myotonic dystrophy 1 (DM1). To understand this toxic RNA gain-of-function mechanism we developed a Drosophila model expressing 60 pure and 480 interrupted CUG repeats in the context of a non-translatable RNA. These flies reproduced aspects of the DM1 pathology, most notably nuclear accumulation of CUG transcripts, muscle degeneration, splicing misregulation, and diminished Muscleblind function in vivo. Reduced Muscleblind activity was evident from the sensitivity of CUG-induced phenotypes to a decrease in muscleblind genetic dosage and rescue by MBNL1 expression, and further supported by the co-localization of Muscleblind and CUG repeat RNA in ribonuclear foci. Targeted expression of CUG repeats to the developing eye and brain mushroom bodies was toxic leading to rough eyes and semilethality, respectively. These phenotypes were utilized to identify genetic and chemical modifiers of the CUG-induced toxicity. 15 genetic modifiers of the rough eye phenotype were isolated. These genes identify putative cellular processes unknown to be altered by CUG repeat RNA, and they include mRNA export factor Aly, apoptosis inhibitor Thread, chromatin remodelling factor Nurf-38, and extracellular matrix structural component Viking. Ten chemical compounds suppressed the semilethal phenotype. These compounds significantly improved viability of CUG expressing flies and included non-steroidal anti-inflammatory agents (ketoprofen), muscarinic, cholinergic and histamine receptor inhibitors (orphenadrine), and drugs that can affect sodium and calcium metabolism such as clenbuterol and spironolactone. These findings provide new insights into the DM1 phenotype, and suggest novel candidates for DM1 treatments

PDBe: improved accessibility of macromolecular structure data from PDB and EMDB

© 2015 The Authors. Published by OUP. This is an open access article available under a Creative Commons licence. The published version can be accessed at the following link on the publisher’s website: https://doi.org/10.1093/nar/gkv1047The Protein Data Bank in Europe (http://pdbe.org) accepts and annotates depositions of macromolecular structure data in the PDB and EMDB archives and enriches, integrates and disseminates structural information in a variety of ways. The PDBe website has been redesigned based on an analysis of user requirements, and now offers intuitive access to improved and value-added macromolecular structure information. Unique value-added information includes lists of reviews and research articles that cite or mention PDB entries as well as access to figures and legends from full-text open-access publications that describe PDB entries. A powerful new query system not only shows all the PDB entries that match a given query, but also shows the 'best structures' for a given macromolecule, ligand complex or sequence family using data-quality information from the wwPDB validation reports. A PDBe RESTful API has been developed to provide unified access to macromolecular structure data available in the PDB and EMDB archives as well as value-added annotations, e.g. regarding structure quality and up-to-date cross-reference information from the SIFTS resource. Taken together, these new developments facilitate unified access to macromolecular structure data in an intuitive way for non-expert users and support expert users in analysing macromolecular structure data.The Wellcome Trust [88944, 104948]; UK Biotechnology and Biological Sciences Research Council [BB/J007471/1, BB/K016970/1, BB/M013146/1, BB/M011674/1]; National Institutes of Health [GM079429]; UK Medical Research Council [MR/L007835/1]; European Union [284209]; CCP4; European Molecular Biology Laboratory (EMBL). Funding for open access charge: The Wellcome Trust.Published versio

Tuning fresh: radiation through rewiring of central metabolism in streamlined bacteria

Most free-living planktonic cells are streamlined and in spite of their limitations in functional flexibility, their vast populations have radiated into a wide range of aquatic habitats. Here we compared the metabolic potential of subgroups in the Alphaproteobacteria lineage SAR11 adapted to marine and freshwater habitats. Our results suggest that the successful leap from marine to freshwaters in SAR11 was accompanied by a loss of several carbon degradation pathways and a rewiring of the central metabolism. Examples for these are C1 and methylated compounds degradation pathways, the Entner–Doudouroff pathway, the glyoxylate shunt and anapleuretic carbon fixation being absent from the freshwater genomes. Evolutionary reconstructions further suggest that the metabolic modules making up these important freshwater metabolic traits were already present in the gene pool of ancestral marine SAR11 populations. The loss of the glyoxylate shunt had already occurred in the common ancestor of the freshwater subgroup and its closest marine relatives, suggesting that the adaptation to freshwater was a gradual process. Furthermore, our results indicate rapid evolution of TRAP transporters in the freshwater clade involved in the uptake of low molecular weight carboxylic acids. We propose that such gradual tuning of metabolic pathways and transporters toward locally available organic substrates is linked to the formation of subgroups within the SAR11 clade and that this process was critical for the freshwater clade to find and fix an adaptive phenotype.This work was supported by the Swedish Research Council (Grant Numbers 2012-4592 to AE and 2012-3892 to SB) and the Communiy Sequencing Programme of the US Department of Energy Joint Genome Institute. The work conducted by the US Department of Energy Joint Genome Institute, a DOE Office of Science User Facility, is supported under Contract No. DE-AC02-05CH11231