bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization and identification of antimicrobial peptides with different functional activities
Authors: Chung Chia-Ru , Kuo Ting-Rung , Wu Li-Ching , Lee Tzong-Yi , Horng Jorng-Tzong 
Published: March 2019

Abstract
In recent years, antimicrobial peptides (AMPs) have become an emerging area of focus when developing therapeutics hot spot residues of proteins are dominant against infections. Importantly, AMPs are produced by virtually all known living organisms and are able to target a wide range of pathogenic microorganisms, including viruses, parasites, bacteria and fungi. Although several studies have proposed different machine learning methods to predict peptides as being AMPs, most do not consider the diversity of AMP activities. On this basis, we specifically investigated the sequence features of AMPs with a range of functional activities, including anti-parasitic, anti-viral, anti-cancer and anti-fungal activities and those that target mammals, Gram-positive and Gram-negative bacteria. A new scheme is proposed to systematically characterize and identify AMPs and their functional activities. The 1st stage of the proposed approach is to identify the AMPs, while the 2nd involves further characterization of their functional activities. Sequential forward selection was employed to extract potentially informative features that are possibly associated with the functional activities of the AMPs. These features include hydrophobicity, the normalized van der Waals volume, polarity, charge and solvent accessibility—all of which are essential attributes in classifying between AMPs and non-AMPs. The results revealed the 1st stage AMP classifier was able to achieve an area under the receiver operating characteristic curve (AUC) value of 0.9894. During the 2nd stage, we found pseudo amino acid composition to be an informative attribute when differentiating between AMPs in terms of their functional activities. The independent testing results demonstrated that the AUCs of the multi-class models were 0.7773, 0.9404, 0.8231, 0.8578, 0.8648, 0.8745 and 0.8672 for anti-parasitic, anti-viral, anti-cancer, anti-fungal AMPs and those that target mammals, Gram-positive and Gram-negative bacteria, respectively. The proposed scheme helps facilitate biological experiments related to the functional analysis of AMPs. Additionally, it was implemented as a user-friendly web server (AMPfun, http://fdblab.csie.ncu.edu.tw/AMPfun/index.html) that allows individuals to explore the antimicrobial functions of peptides of interest.
SummaryAUC: a tool for evaluating the performance of polygenic risk prediction models in validation datasets with only summary level statistics
Authors: Song Lei , Liu Aiyi , Shi Jianxin ,   Molecular Genetics of Schizophrenia Consortium, Gejman P V , Sanders A R , Duan J , Cloninger C R , Svrakic D M , Buccola N G , Levinson D F , Mowry B J , Freedman R , Olincy A , Amin F , Black D W , Silverman J M , Byerley W F 
Published: March 2019

AbstractMotivationPolygenic risk score (PRS) methods based on genome-wide association studies (GWAS) have a potential for predicting the risk of developing complex diseases and are expected to become more accurate with larger training datasets and innovative statistical methods. The area under the ROC curve (AUC) is often used to evaluate the performance of PRSs, which requires individual genotypic and phenotypic data in an independent GWAS validation dataset. We are motivated to develop methods for approximating AUC of PRSs based on the summary level data of the validation dataset, which will greatly facilitate the development of PRS models for complex diseases.ResultsWe develop statistical methods and an R package SummaryAUC for approximating the AUC and its variance of a PRS when only the summary level data of the validation dataset are available. SummaryAUC can be applied to PRSs with SNPs either genotyped or imputed in the validation dataset. We examined the performance of SummaryAUC using a large-scale GWAS of schizophrenia. SummaryAUC provides accurate approximations to AUCs and their variances. The bias of AUC is typically &lt;0.5% in most analyses. SummaryAUC cannot be applied to PRSs that use all SNPs in the genome because it is computationally prohibitive.Availability and implementationhttps://github.com/lsncibb/SummaryAUC.Supplementary informationSupplementary data are available at Bioinformatics online.
Simulation-assisted machine learning
Authors: Deist Timo M , Patti Andrew , Wang Zhaoqi , Krane David , Sorenson Taylor , Craft David 
Published: March 2019

Abstract

Motivation
In a predictive modeling setting, if sufficient details of the system behavior are known, one can build and use a simulation for making predictions. When sufficient system details are not known, one typically turns to machine learning, which builds a black-box model of the system using a large dataset of input sample features and outputs. We consider a setting which is between these two extremes: some details of the system mechanics are known but not enough for creating simulations that can be used to make high quality predictions. In this context we propose using approximate simulations to build a kernel for use in kernelized machine learning methods, such as support vector machines. The results of multiple simulations (under various uncertainty scenarios) are used to compute similarity measures between every pair of samples: sample pairs are given a high similarity score if they behave similarly under a wide range of simulation parameters. These similarity values, rather than the original high dimensional feature data, are used to build the kernel.

Results
We demonstrate and explore the simulation-based kernel (SimKern) concept using four synthetic complex systems—three biologically inspired models and one network flow optimization model. We show that, when the number of training samples is small compared to the number of features, the SimKern approach dominates over no-prior-knowledge methods. This approach should be applicable in all disciplines where predictive models are sought and informative yet approximate simulations are available.

Availability and implementation
The Python SimKern software, the demonstration models (in MATLAB, R), and the datasets are available at https://github.com/davidcraft/SimKern.

Supplementary information
Supplementary data are available at Bioinformatics online.
Incidence and Trends in Immune Reconstitution Inflammatory Syndrome Associated With Histoplasma capsulatum Among People Living With Human Immunodeficiency Virus: A 20-Year Case Series and Literature Review
Authors: Melzani Alessia , de Reynal de Saint Michel Regis , Ntab Balthazar , Djossou Felix , Epelboin Loic , Nacher Mathieu , Blanchet Denis , Demar Magalie , Couppie Pierre , Adenis Antoine 
Published: March 2019

Abstract

Background
Histoplasmosis is among the main acquired immunodeficiency syndrome (AIDS)–defining conditions in endemic areas. Although histoplasmosis has a worldwide distribution, histoplasmosis-associated immune reconstitution inflammatory syndrome (IRIS) in people living with human immunodeficiency virus (PLHIV) is rarely reported.
This study aimed to describe the incidence and features of histoplasmosis-associated IRIS in a cohort of PLHIV.

Methods
A retrospective multicenter study was conducted in French Guiana from 1 January 1997 to 30 September 2017. The target population was represented by PLHIV who presented an episode of histoplasmosis within 6 months after antiretroviral therapy initiation. We used a consensual IRIS case definition, submitted to the agreement of 2 experts. Each case was described using a standardized questionnaire, and all patients gave informed consent.

Results
Twenty-two cases of histoplasmosis-associated IRIS were included (14 infectious/unmasking and 8 paradoxical), with an overall incidence rate of 0.74 cases per 1000 HIV-infected person-years (95% confidence interval, 0.43–1.05). Mean age was 40.5 years. The ratio of males to females was 1:4. Median time to IRIS was 11 days (interquartile range 7–40 days) after antiretroviral therapy initiation. The main clinical presentation was fever, without any specific pattern, and disseminated disease. We reported 2 severe cases and partial or complete recovery at 1 month was the rule. Twenty-two cases were identified in the literature with similar characteristics.

Conclusions
Histoplasmosis-associated IRIS incidence was low but generated significant morbidity in PLHIV. In endemic areas, screening for latent or subclinical histoplasmosis should be implemented before antiretroviral therapy initiation.
Butyrate Does Not Protect Against Inflammation-induced Loss of Epithelial Barrier Function and Cytokine Production in Primary Cell Monolayers From Patients With Ulcerative Colitis
Authors: Vancamelbeke Maaike , Laeremans Thessa , Vanhove Wiebe , Arnauts Kaline , Ramalho Anabela Santo , Farré Ricard , Cleynen Isabelle , Ferrante Marc , Vermeire Séverine 
Published: March 2019

AbstractBackground and AimsIn vitro studies using immortalised cancer cell lines showed that butyrate has an overall positive effect on epithelial barrier integrity, but the physiological relevance of cancer cell lines is limited. We developed epithelial monolayers from human tissue samples of patients with ulcerative colitis [UC] to assess the effect of butyrate on epithelial barrier function.MethodsA protocol to establish monolayers from primary epithelial cells of UC patients [n = 10] and non-UC controls [n = 10] was optimised. The monolayers were treated with 8 mM sodium butyrate ± tumour necrosis factor alpha [TNFα] and type II interferon [IFNγ] for 48 h. Changes in transepithelial electrical resistance were monitored. Barrier gene expression levels were measured. Inflammatory proteins in the supernatant of the cells were quantified with OLINK.ResultsWe demonstrated that primary monolayer cultures can be grown within 1 week of culture with robust resistance values and polarised tight junction expression. Butyrate treatment of the cultures increased resistance but was detrimental in combination with TNFα and IFNγ. The combined treatment further induced even higher IL8 mRNA and inflammatory protein secretion than for the inflammatory mediators alone. The observed effects were similar in cultures from patients and non-UC controls, suggesting that there were no patient-specific responses responsible for these findings.ConclusionsWe found that butyrate does not protect against inflammation-induced barrier dysfunction and even worsens its effects in primary epithelial monolayers of UC patients and controls. The basic mechanisms of butyrate should therefore be reconsidered in future studies, in particular in patients with active inflammation and pre-existing barrier defects as is known for UC.
Mechanistic target of rapamycin signaling in mouse models of accelerated aging
Authors: Lee Jin Young , Kennedy Brian K , Liao Chen-Yu 
Published: March 2019

Abstract
The mechanistic target of rapamycin (mTOR) is an essential nutrient-sensing kinase that integrates and regulates a number of fundamental cellular processes required for cell growth, cell motility, translation, metabolism, and autophagy. mTOR signaling has been implicated in the progression of many human diseases, and its dysregulation has been reported in several pathological processes, especially in age-related human diseases and mouse models of accelerated aging. In addition, many studies have demonstrated that the regulation of mTOR activity has a beneficial effect on longevity in several mouse models of aging. However, not all mouse models of accelerated aging show positive effects on aging-associated phenotypes in response to targeting mTOR signaling. Here, we review the effects of interventions that modulate mTOR signaling on aging-related phenotypes in different mouse models of accelerated aging and discuss their implications with respect to aging and aging-related disorders.
Amyotrophic lateral sclerosis-associated TDP-43 mutation Q331K prevents nuclear translocation of XRCC4-DNA ligase 4 complex and is linked to genome damage-mediated neuronal apoptosis
Authors: Guerrero Erika N , Mitra Joy , Wang Haibo , Rangaswamy Suganya , Hegde Pavana M , Basu Priyadarshini , Rao K S , Hegde Muralidhar L 
Published: March 2019

Abstract
Dominant mutations in the RNA/DNA-binding protein TDP-43 have been linked to amyotrophic lateral sclerosis (ALS). Here, we screened genomic DNA extracted from spinal cord specimens of sporadic ALS patients for mutations in the TARDBP gene and identified a patient specimen with previously reported Q331K mutation. The patient spinal cord tissue with Q331K mutation showed accumulation of higher levels of DNA strand breaks and the DNA double-strand break (DSB) marker γH2AX, compared to age-matched controls, suggesting a role of the Q331K mutation in genome-damage accumulation. Using conditional SH-SY5Y lines ectopically expressing wild-type (WT) or Q331K-mutant TDP-43, we confirmed the increased cytosolic sequestration of the poly-ubiquitinated and aggregated form of mutant TDP-43, which correlated with increased genomic DNA strand breaks, activation of the DNA damage response factors phospho-ataxia-telangiectasia mutated (ATM), phospho-53BP1, γH2AX and neuronal apoptosis. We recently reported the involvement of WT TDP-43 in non-homologous end joining (NHEJ)-mediated DSB repair, where it acts as a scaffold for the recruitment of XRCC4-DNA ligase 4 complex. Here, the mutant TDP-43, due to its reduced interaction and enhanced cytosolic mislocalization, prevented the nuclear translocation of XRCC4-DNA ligase 4. Consistently, the mutant cells showed significantly reduced DNA strand break sealing activity and were sensitized to DNA-damaging drugs. In addition, the mutant cells showed elevated levels of reactive oxygen species, suggesting both dominant negative and loss-of-function effects of the mutation. Together, our study uncovered an association of sporadic Q331K mutation with persistent genome damage accumulation due to both damage induction and repair defects.
Rare variants in MYH15 modify amyotrophic lateral sclerosis risk
Authors: Kim Hyerim , Lim Junghwa , Bao Han , Jiao Bin , Canon Se Min , Epstein Michael P , Xu Keqin , Jiang Jie , Parameswaran Janani , Li Yingjie , Moberg Kenneth H , Landers John E , Fournier Christina , Allen Emily G , Glass Jonathan D , Wingo Thomas S , Jin Peng 
Published: March 2019

Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurological disorder characterized by progressive muscular atrophy and respiratory failure. The G4C2 repeat expansion in the C9orf72 gene is the most prevalent genetic risk for ALS. Mutation carriers (C9ALS) display variability in phenotypes such as age-at-onset and duration, suggesting the existence of additional genetic factors. Here we introduce a three-step gene discovery strategy to identify genetic factors modifying the risk of both C9ALS and sporadic ALS (sALS) using limited samples. We first identified 135 candidate genetic modifiers of C9ALS using whole-genome sequencing (WGS) of extreme C9ALS cases diagnosed ~30 years apart. We then performed an unbiased genetic screen using a Drosophila model of the G4C2 repeat expansion with the genes identified from WGS analysis. This genetic screen identified the novel genetic interaction between G4C2 repeat-associated toxicity and 18 genetic factors, suggesting their potential association with C9ALS risk. We went on to test if 14 out of the 18 genes, those which were not known to be risk factors for ALS previously, are also associated with ALS risk in sALS cases. Gene-based-statistical analyses of targeted resequencing and WGS were performed. These analyses together reveal that rare variants in MYH15 represent a likely genetic risk factor for ALS. Furthermore, we show that MYH15 could modulate the toxicity of dipeptides produced from expanded G4C2 repeat. Our study presented here demonstrates the power of combining WGS with fly genetics to facilitate the discovery of fundamental genetic components of complex traits with a limited number of samples.
Externalized conductor of a Kentrox lead and an unexpected insulation failure
Authors: Eulert-Grehn Jaime-Jürgen , Falk Volkmar , Nazari-Shafti Mir Timo , Starck Christoph 
Published: March 2019

Abstract
Cardiac resynchronization therapy-defibrillator device upgrades may represent a challenging scenario, especially because unexpected findings can increase procedure difficulty. One such unexpected finding represents insulation failure with unremarkable device interrogation. Insulation failure due to an externalized conductor of an implantable cardiac defibrillator-lead has been recently described for the Kentrox lead (Biotronik). Another challenging aspect of device upgrades is the presence of venous thrombosis as in this case. Here, we report an inside-out abrasion of a Kentrox lead, an unexpected second insulation failure found during pocket revision and the successful recanalization in a patient with known left subclavian vein thrombosis.
Infinite Geodesics of Sub-Finsler Distances in Heisenberg Groups
Authors: Balogh Zoltán M , Calogero Andrea 
Published: March 2019

Abstract
We consider Heisenberg groups equipped with a sub-Finsler metric. Using methods of optimal control theory we prove that in this geometric setting the infinite geodesics are horizontal lines under the assumption that the sub-Finsler metric is defined by a strictly convex norm. This answers a question posed in [8] and has applications in the characterization of isometric embeddings into Heisenberg groups.
Control of the HIV-1 Load Varies by Viral Subtype in a Large Cohort of African Adults With Incident HIV-1 Infection
Authors: Price Matt A , Rida Wasima , Kilembe William , Karita Etienne , Inambao Mubiana , Ruzagira Eugene , Kamali Anatoli , Sanders Eduard J , Anzala Omu , Hunter Eric , Allen Susan , Edward Vinodh A , Wall Kristin M , Tang Jianming , Fast Patricia E , Kaleebu Pontiano , Lakhi Shabir , Mutua Gaudensia , Bekker Linda Gail , Abu-Baker Ggayi , Tichacek Amanda , Chetty Paramesh , Latka Mary H , Maenetje Pholo , Makkan Heeran , Kibengo Freddie , Priddy Fran , Gilmour Jill 
Published: March 2019

Abstract
Few human immunodeficiency virus (HIV)–infected persons can maintain low viral levels without therapeutic intervention. We evaluate predictors of spontaneous control of the viral load (hereafter, “viral control”) in a prospective cohort of African adults shortly after HIV infection. Viral control was defined as ≥2 consecutively measured viral loads (VLs) of ≤10 000 copies/mL after the estimated date of infection, followed by at least 4 subsequent measurements for which the VL in at least 75% was ≤10 000 copies/mL in the absence of ART. Multivariable logistic regression characterized predictors of viral control. Of 590 eligible volunteers, 107 (18.1%) experienced viral control, of whom 25 (4.2%) maintained a VL of 51–2000 copies/mL, and 5 (0.8%) sustained a VL of ≤50 copies/mL. The median ART-free follow-up time was 3.3 years (range, 0.3–9.7 years). Factors independently associated with control were HIV-1 subtype A (reference, subtype C; adjusted odds ratio [aOR], 2.1 [95% confidence interval {CI}, 1.3–3.5]), female sex (reference, male sex; aOR, 1.8 [95% CI, 1.1–2.8]), and having HLA class I variant allele B*57 (reference, not having this allele; aOR, 1.9 [95% CI, 1.0–3.6]) in a multivariable model that also controlled for age at the time of infection and baseline CD4+ T-cell count. We observed strong associations between infecting HIV-1 subtype, HLA type, and sex on viral control in this cohort. HIV-1 subtype is important to consider when testing and designing new therapeutic and prevention technologies, including vaccines.
Disrupting Membrane Adaptation Restores In Vivo Efficacy of Antibiotics Against Multidrug-Resistant Enterococci and Potentiates Killing by Human Neutrophils
Authors: Rincon Sandra , Panesso Diana , Miller William R , Singh Kavindra V , Cruz Melissa R , Khan Ayesha , Dinh An Q , Diaz Lorena , Rios Rafael , Shamoo Yousif , Reyes Jinnethe , Tran Truc T , Garsin Danielle A , Arias Cesar A 
Published: March 2019

AbstractDaptomycin resistance in enterococci is often mediated by the LiaFSR system, which orchestrates the cell membrane stress response. Activation of LiaFSR through the response regulator LiaR generates major changes in cell membrane function and architecture (membrane adaptive response), permitting the organism to survive the antibiotic attack. Here, using a laboratory strain of Enterococcus faecalis, we developed a novel Caenorhabditis elegans model of daptomycin therapy and showed that disrupting LiaR-mediated cell membrane adaptation restores the in vivo activity of daptomycin. The LiaR effect was also seen in a clinical strain of daptomycin-resistant Enterococcus faecium, using a murine model of peritonitis. Furthermore, alteration of the cell membrane response increased the ability of human polymorphonuclear neutrophils to readily clear both E. faecalis and multidrug-resistant E. faecium. Our results provide proof of concept that targeting the cell membrane adaptive response restores the in vivo activity of antibiotics, prevents resistance, and enhances the ability of the innate immune system to kill infecting bacteria.
Population pharmacokinetic meta-analysis of individual data to design the first randomized efficacy trial of vancomycin in neonates and young infants
Authors: Jacqz-Aigrain Evelyne , Leroux Stéphanie , Thomson Alison H , Allegaert Karel , Capparelli Edmund V , Biran Valérie , Simon Nicolas , Meibohm Bernd , Lo Yoke-Lin , Marques Remedios , Peris José-Esteban , Lutsar Irja , Saito Jumpei , Nakamura Hidefumi , van den Anker Johannes N , Sharland Mike , Zhao Wei 
Published: March 2019

Abstract

Objectives
In the absence of consensus, the present meta-analysis was performed to determine an optimal dosing regimen of vancomycin for neonates.

Methods
A ‘meta-model’ with 4894 concentrations from 1631 neonates was built using NONMEM, and Monte Carlo simulations were performed to design an optimal intermittent infusion, aiming to reach a target AUC0–24 of 400 mg·h/L at steady-state in at least 80% of neonates.

Results
A two-compartment model best fitted the data. Current weight, postmenstrual age (PMA) and serum creatinine were the significant covariates for CL. After model validation, simulations showed that a loading dose (25 mg/kg) and a maintenance dose (15 mg/kg q12h if <35 weeks PMA and 15 mg/kg q8h if ≥35 weeks PMA) achieved the AUC0–24 target earlier than a standard ‘Blue Book’ dosage regimen in >89% of the treated patients.

Conclusions
The results of a population meta-analysis of vancomycin data have been used to develop a new dosing regimen for neonatal use and to assist in the design of the model-based, multinational European trial, NeoVanc.