bluuebunny/crossref_metadata_2025_split huggingface dataset:
The NAD Metabolome is Functionally Depressed in Patients Undergoing Liver Transplantation for Alcohol-related Liver Disease
Authors: Parker Richard , Schmidt Mark S. , Cain Owen , Gunson Bridget , Brenner Charles 
Published: March 2020

AbstractNicotinamide adenine dinucleotide (NAD+) and related coenzymes play critical roles in liver function. Though hepatic alcohol metabolism depresses NAD+, current understanding of the NAD+metabolome in alcohol-related liver disease (ArLD) is based on animal models. We used human liver samples to quantify the NAD+metabolome in ArLD with samples obtained at the time of liver transplantation or resection at University Hospitals Birmingham NHS Foundation Trust (UHB). The severity of steatohepatitis in liver from patients with ArLD was assessed with standard liver function tests (LFT) and histology. NAD-targeted quantitative metabolomic analysis of liver tissue was performed by liquid chromatography-tandem mass spectrometry (LC-MS). Seventy-two human liver specimens were analyzed including 43 with ArLD. The NAD+metabolome differed significantly between different types of liver disease (two-way ANOVA p = 0.001). ArLD liver tissue showed markedly depressed concentrations of NAD+(432 μM vs. 616 μM in NL) and precursor molecules nicotinic acid and nicotinamide riboside. There was a significant overall difference in the NAD+metabolome between ArLD samples with and without steatohepatitis (two-way ANOVA p = 0.018). After correcting for multiple comparisons, a significant difference for individual components of the metabolome was observed for the concentration of NAD+(mean 451 μM vs. 381 μM, p = 0.045). NAD+concentration was inversely related to serum bilirubin concentration (r2−0.127, p = 0.04) and positively correlated with myeloperoxidase activity (r20.31, p = 0.003). The concentration of NAD+and its precursor molecules are significantly reduced in ArLD and are associated with disease activity. Conclusion: Liver samples from people with ArLD show depressed NAD+and precursor levels as well as depressed myeloperoxidase activity.
Computational Design of Peptides to Block Binding of the SARS-CoV-2 Spike Protein to Human ACE2
Authors: Huang Xiaoqiang , Pearce Robin , Zhang Yang 
Published: March 2020

ABSTRACTThe outbreak of COVID-19 has now become a global pandemic and it continues to spread rapidly worldwide, severely threatening lives and economic stability. Making the problem worse, there is no specific antiviral drug that can be used to treat COVID-19 to date. SARS-CoV-2 initiates its entry into human cells by binding to angiotensin-converting enzyme 2 (hACE2) via the receptor binding domain (RBD) of its spike protein. Therefore, molecules that can block SARS-CoV-2 from binding to hACE2 may potentially prevent the virus from entering human cells and serve as an effective antiviral drug. Based on this idea, we designed a series of peptides that can strongly bind to SARS-CoV-2 RBD in computational experiments. Specifically, we first constructed a 31-mer peptidic scaffold by linking two fragments grafted from hACE2 (a.a. 22-44 and 351-357) with a linker glycine, and then redesigned the peptide sequence to enhance its binding affinity to SARS-CoV-2 RBD. Compared with several computational studies that failed to identify that SARS-CoV-2 shows higher binding affinity for hACE2 than SARS-CoV, our protein design scoring function, EvoEF2, makes a correct identification, which is consistent with the recently reported experimental data, implying its high accuracy. The top designed peptide binders exhibited much stronger binding potency to hACE2 than the wild-type (−53.35 vs. −46.46 EvoEF2 energy unit for design and wild-type, respectively). The extensive and detailed computational analyses support the high reasonability of the designed binders, which not only recapitulated the critical native binding interactions but also introduced new favorable interactions to enhance binding. Due to the urgent situation created by COVID-19, we share these computational data to the community, which should be helpful to develop potential antiviral peptide drugs to combat this pandemic.
No Evidence for Temperature-Dependence of the COVID-19 Epidemic
Authors: Jamil Tahira , Alam Intikhab , Gojobori Takashi , Duarte Carlos M. 
Published: March 2020

1.AbstractThe pandemic of the COVID-19 disease extended from China across the north-temperate zone, and more recently to the tropics and southern hemisphere. We find no evidence that spread rates decline with temperatures above 20 °C, suggesting that the COVID-19 disease is unlikely to behave as a seasonal respiratory virus.
CD8+T-cell transcription and DNA methylation show age specific differences and lack correlation with clinical outcome in pediatric Inflammatory Bowel Disease
Authors: Gasparetto M , Payne F , Nayak K , Kraiczy J , Glemas C , Philip-McKenzie Y , Ross A , Edgar RD , Zerbino D , Salvestrini C , Torrente F , Sarkies P , Heuschkel R , Zilbauer M 
Published: March 2020

AbstractBackground & AimsCD8+T-cell gene expression has been implicated in the pathogenesis of Inflammatory Bowel Diseases (IBD) and has been shown to correlate with disease outcome in adult patients. Moreover, CD8+T-cell exhaustion was identified as a contributing mechanism that impacts on disease behaviour. We aimed to explore CD8+T-cell gene expression and DNA methylation in children newly diagnosed with IBD and test their correlation with disease outcome.MethodsWe prospectively recruited 112 children with IBD at the point of diagnosis and 19 non-IBD controls. Follow-up samples were obtained from a subset of patients at 3-month intervals (n=62). CD8+T-cells were purified from peripheral blood samples using magnetic bead sorting and genome-wide transcriptional (n=192) and DNA methylation (n=66) profiles were generated using Affymetrix and Illumina arrays respectively. Publicly available adult CD8+T-cell transcriptomes and DNA methylomes were included in data analyses to investigate age dependant differences.ResultsVariation amongst CD8+T-cell transcriptomes obtained from children showed association with disease, systemic inflammation, age and gender but lacked correlation with disease outcome in pediatric IBD. In contrast to CD8+T-cell transcriptomes in adult Crohn’s Disease (CD), samples from pediatric patients did not show variation within genes forming part of the previously reported prognostic expression or T-cell exhaustion signatures. Pediatric CD patient derived DNA methylation profiles also lacked correlation with disease outcome but in comparison to adult CD8+methylomes showed a higher predicted proportion of CD8+naïve T-cells.ConclusionsOur findings indicate age-related differences in IBD pathogenesis and highlight the importance of validating adult clinical biomarkers in pediatric cohorts.
Implicit modeling of the impact of adsorption on solid surfaces for protein mechanics and activity with a coarse-grain representation
Authors: Bourassin Nicolas , Baaden Marc , Lojou Elisabeth , Sacquin-Mora Sophie 
Published: March 2020

AbstractSurface immobilized enzymes play a key role in numerous biotechnological applications such as biosensors, biofuel cells or biocatalytic synthesis. As a consequence, the impact of adsorption on the enzyme structure, dynamics and function needs to be understood on the molecular level as it is critical for the improvement of these technologies. With this perspective in mind, we used a theoretical approach for investigating protein local flexibility on the residue scale that couples a simplified protein representation with an elastic network and Brownian Dynamics simulations. The protein adsorption on a solid surface is implicitly modeled via additional external constraints between the residues in contact with the surface. We first performed calculations on a redox enzyme, bilirubin oxidase (BOD) fromM. verrucaria, to study the impact of adsorption on its mechanical properties. The resulting rigidity profiles show that, in agreement with the available experimental data, the mechanical variations observed in the adsorbed BOD will depend on its orientation and its anchor residues (i.e. residues that are in contact with the functionalized surface). Additional calculations on ribonuclease A and nitroreductase shed light on how seemingly stable adsorbed enzymes can nonetheless display an important decrease in their catalytic activity resulting from a perturbation of their mechanics and internal dynamics.
Uptake of exogenous serine is important to maintain sphingolipid homeostasis inSaccharomyces cerevisiae
Authors: Esch Bianca M. , Limar Sergej , Bogdanowski André , Gournas Christos , More Tushar , Sundag Celine , Walter Stefan , Heinisch Jürgen J. , Ejsing Christer S. , André Bruno , Fröhlich Florian 
Published: March 2020

AbstractSphingolipids are abundant and essential molecules in eukaryotes that have crucial functions as signaling molecules and as membrane components. Sphingolipid biosynthesis starts in the endoplasmic reticulum with the condensation of serine and palmitoyl-CoA. Sphingolipid biosynthesis is highly regulated to maintain sphingolipid homeostasis. Even though, serine is an essential component of the sphingolipid biosynthesis pathway, its role in maintaining sphingolipid homeostasis has not been precisely studied. Here we show that serine uptake is an important factor for the regulation of sphingolipid biosynthesis inSaccharomyces cerevisiae. Using genetic experiments, we find the broad-specificity amino acid permease Gnp1 to be important for serine uptake. We confirm these results with serine uptake assays ingnp1Δcells. We further show that uptake of exogenous serine by Gnp1 is important to maintain cellular serine levels and observe a specific connection between serine uptake and the first step of sphingolipid biosynthesis. Using mass spectrometry-based flux analysis, we further observed imported serine as the main source forde novosphingolipid biosynthesis. Our results demonstrate that yeast cells preferentially use the uptake of exogenous serine to regulate sphingolipid biosynthesis. Our study can also be a starting point to analyze the role of serine uptake in mammalian sphingolipid metabolism.Author SummarySphingolipids (SPs) are membrane lipids globally required for eukaryotic life. In contrast to other lipid classes, SPs cannot be stored in the cell and therefore their levels have to be tightly regulated. Failure to maintain sphingolipid homeostasis can result in pathologies including neurodegeneration, childhood asthma and cancer. However, we are only starting to understand how SP biosynthesis is adjusted according to need. In this study, we use genetic and biochemical methods to show that the uptake of exogenous serine is necessary to maintain SP homeostasis inSaccharomyces cerevisiae. Serine is one of the precursors of long chain bases in cells, the first intermediate of SP metabolism. Our results suggest that the uptake of serine is directly coupled to SP biosynthesis at ER-plasma membrane contact sites. Overall, our study identifies serine uptake as a novel regulatory factor of SP homeostasis. While we use yeast as a discovery tool, these results also provide valuable insights into mammalian SP biology especially under pathological conditions.
The E3/E4 ubiquitin conjugation factor UBE4B interacts with and ubiquitinates the HTLV-1 Tax oncoprotein to promote NF-κB activation
Authors: Mohanty Suchitra , Han Teng , Choi Young Bong , Lavorgna Alfonso , Zhang Jiawen , Harhaj Edward W. 
Published: March 2020

AbstractHuman T-cell leukemia virus type 1 (HTLV-1) is the etiological agent of adult T-cell leukemia/lymphoma (ATLL), and the neurological disease HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). The HTLV-1 Tax protein persistently activates the NF-κB pathway to enhance the proliferation and survival of HTLV-1 infected T cells. Lysine 63 (K63)-linked polyubiquitination of Tax provides an important regulatory mechanism that promotes Tax-mediated interaction with the IKK complex and activation of NF-κB; however, the host proteins regulating Tax ubiquitination are largely unknown. To identify novel Tax interacting proteins that may regulate its ubiquitination we conducted a yeast two-hybrid screen using Tax as bait. This screen yielded the E3/E4 ubiquitin conjugation factor UBE4B as a novel binding partner for Tax. Here, we confirmed the interaction between Tax and UBE4B in mammalian cells by co-immunoprecipitation assays and demonstrated colocalization by proximity ligation assay and confocal microscopy. Overexpression of UBE4B specifically enhanced Tax-induced NF-κB activation, whereas knockdown of UBE4B impaired Tax-induced NF-κB activation and the induction of NF-κB target genes in T cells and ATLL cell lines. Furthermore, depletion of UBE4B with shRNA resulted in apoptotic cell death and diminished the proliferation of ATLL cell lines. Finally, overexpression of UBE4B enhanced Tax polyubiquitination, and knockdown or CRISPR/Cas9-mediated knockout of UBE4B attenuated both K48- and K63-linked polyubiquitination of Tax. Collectively, these results implicate UBE4B in HTLV-1 Tax polyubiquitination and downstream NF-κB activation.Author SummaryInfection with the retrovirus HTLV-1 leads to the development of either CD4+CD25+ leukemia/lymphoma (ATLL) or a demyelinating neuroinflammatory disease (HAM/TSP) in a subset of infected individuals. The HTLV-1 Tax protein is a regulatory protein which regulates viral gene expression and persistently activates cellular signaling pathways such as NF-κB to drive the clonal expansion and longevity of HTLV-1 infected CD4+ T cells. Polyubiquitination of Tax is a key mechanism of NF-κB activation by assembling and activating IκB kinase (IKK) signaling complexes; however, the host factors regulating Tax ubiquitination have remained elusive. Here, we have identified the E3/E4 ubiquitin conjugation factor UBE4B as a novel Tax binding protein that promotes both K48- and K63-linked polyubiquitination of Tax. Knockdown or knockout of UBE4B impairs Tax-induced NF-κB activation and triggers apoptosis of HTLV-1 transformed cells. Therefore, UBE4B is an integral host factor that supports HTLV-1 Tax polyubiquitination, NF-κB activation and cell survival.
High-quality chromosome-level genomes of two tilapia species reveal their evolution of repeat sequences and sex chromosomes
Authors: Tao Wenjing , Xu Luohao , Zhao Lin , Zhu Zexian , Wu Xin , Min Qianwen , Wang Deshou , Zhou Qi 
Published: March 2020

AbstractBackgroundTilapias are one of the most farmed fishes that are coined as ‘aquatic chicken’ by the food industry. Like many other teleosts, Nile tilapia and blue tilapia exhibit very recent transition of sex chromosome systems since their divergence about 5 million years ago, making them a great model for elucidating the molecular and evolutionary mechanisms of sex chromosome turnovers. Studies into their sex-determining pathways are also critical for developing genetic sex control in aquaculture.ResultsWe report here the newly produced genomes of Nile tilapia and blue tilapia that integrate long-read sequencing and chromatin conformation data. The two nearly complete genomes have anchored over 97% of the sequences into linkage groups (LGs), and assembled majorities of complex repetitive regions including telomeres, centromeres and rDNA clusters. In particular, we inferred two episodes of repeat expansion at LG3 respectively in the ancestor of cichlids and that of tilapias. The consequential large heterochromatic region concentrated at one end of LG3 comprises tandem arrays of mRNA and small RNA genes, among which we have identified a candidate female determining genePaicsin blue tilapia.Paicsshow female-specific patterns of single-nucleotide variants, copy numbers and expression patterns in gonads during early gonadogenesis.ConclusionsOur work provide a very important genomic resource for functional studies of cichlids, and suggested that unequal distribution of repeat content that impacts the local recombination rate might make some chromosomes more likely to become sex chromosomes.
Optoregulated force application to cellular receptors using molecular motors
Authors: Zheng Yijun , Han Mitchell K.L. , Zhao Renping , Blass Johanna , Zhang Jingnan , Zhou Dennis W. , Colard-Itté Jean-Rémy , Dattler Damien , Hoth Markus , García Andrés J. , Qu Bin , Bennewitz Roland , Giuseppone Nicolas , del Campo Aránzazu 
Published: March 2020

AbstractMechanotransduction events in physiological environments are difficult to investigate, in part due to the lack of experimental tools to apply forces to mechanosensitive receptors remotely. Inspired by cellular mechanisms for force application (i.e. motor proteins pulling on cytoskeletal fibers), here we present a unique molecular machine that can apply forces at cell-matrix and cell-cell junctions using light as an energy source. The key actuator is a light-driven rotatory molecular motor linked to polymer chains, which is intercalated between a membrane receptor and an engineered biointerface. The light-driven actuation of the molecular motor is converted in mechanical twisting of the polymer chains, which will in turn effectively “pulls” on engaged cell membrane receptors (integrins, cadherins…) within the illuminated area. Applied forces have the adequate magnitude and occur at time scales within the relevant ranges for mechanotransduction at cell-friendly exposure conditions, as demonstrated in forcedependent focal adhesion maturation and T cell activation experiments. Our results reveal the potential of nanomotors for the manipulation of living cells at the molecular scale and demonstrate, for the first time, a functionality which at the moment cannot be achieved by any other means.
Longitudinal dynamics of mutant huntingtin and neurofilament light in Huntington’s disease: the prospective HD-CSF study
Authors: Rodrigues Filipe B. , Byrne Lauren M. , Tortelli Rosanna , Johnson Eileanoir B. , Wijeratne Peter A. , Arridge Marzena , De Vita Enrico , Ghazaleh Naghmeh , Houghton Richard , Furby Hannah , Alexander Daniel C. , Tabrizi Sarah J. , Schobel Scott , Scahill Rachael I. , Heslegrave Amanda , Zetterberg Henrik , Wild Edward J. 
Published: March 2020

AbstractThe longitudinal dynamics of the most promising biofluid biomarker candidates for Huntington’s disease (HD) – mutant huntingtin (mHTT) and neurofilament light (NfL) – are incompletely defined, but could help understand the natural history of the disease and how these biomarkers might help in therapeutic development and the clinic. In an 80-participant cohort over 24 months, mHTT in cerebrospinal fluid (CSF), and NfL in CSF and blood, had distinct longitudinal trajectories in HD mutation carriers compared with controls. Baseline analyte values predicted clinical disease status and subsequent clinical progression and brain atrophy, better than did the rate of change in analytes. Overall NfL was a stronger monitoring and prognostic biomarker for HD than mHTT. Nonetheless, mHTT possesses prognostic value and is a valuable pharmacodynamic marker for huntingtin-lowering trials.
Abstinence or controlled drinking – a five-year follow-up on Swedish clients reporting positive change after treatment for substance use disorders
Authors: von Greiff Ninive , Skogens Lisa 
Published: March 2020

Purpose
The purpose of this paper is to investigate how clients – five years after completing treatment interventions endorsing abstinence – view abstinence and the role of Alcoholics Anonymous (AA) in their recovery process.

Design/methodology/approach
Interviews with 40 clients were conducted shortly after them finishing treatment and five years later. All the interviewees had attended treatment programmes based on the 12-step philosophy, and they all described abstinence as crucial to their recovery process in an initial interview.

Findings
At follow-up, the majority remained abstinent. For many, attending AA meetings was still important – some described attending as a routine, whereas others stressed that the meetings were crucial for remaining abstinent. For those who reported controlled drinking (CD), this was described either as a natural step in their recovery process or as associated with worries and self-doubts.

Research limitations/implications
The results suggest the importance of offering interventions with various treatment goals and that clients choosing CD as part of their sustained recovery would benefit from support in this process, both from peers and professionals.

Originality/value
There are heterogeneous views on the possibilities of CD after recovery from substance use disorder both in research and in treatment systems. This study on client views on abstinence versus CD after treatment advocating total abstinence can contribute with perspectives on this ongoing discussion.
High-involvement HRM practices and innovative work behavior among production-line workers: mediating role of employee's functional flexibility
Authors: Yasir Muhammad , Majid Abdul 
Published: March 2020

PurposeFollowing “AMO” framework and resource-based theory (RBT), the current study empirically examines the relationships between high-involvement human resource management (HI HRM) practices, employee functional flexibility (FF) and innovative work behavior (IWB). Furthermore, the mediating effect of FF has also been tested.Design/methodology/approachDescriptive statistics, correlation, hierarchical regression analysis, baron and Kenny, PROCESS Macro and Sobel Test approach were used on a sample of 894 employees of manufacturing concerns.FindingsFindings revealed a direct effect of HI HRM practices on FF and IWB. In addition, the results confirm that FF positively mediates between HI HRM practices and IWB. Furthermore, three dimensions of HI HRM practices, i.e. ability-enhancing (AE), motivation-enhancing (ME) and opportunity-enhancing (OE) HRM practices also predicted FF and IWB.Practical implicationsThis study not only offers the empirical evidence to validate the findings of past researchers, but also provide insight how HI HRM practices flourish the mechanism of FF in manufacturing concerns. Furthermore, this study highlighted some interesting facts that should be meaningful options for HR managers to enhance the level of employees' FF and IWB.Originality/valueAlthough the empirical evidence is well established that HI HRM practices have a substantial contribution for organizational performance, however, there is lack of studies that empirically examine the associations among HI HRM practices, employee's competencies and behaviors, as well as the mechanism through which HI HRM practices affect work related innovative behavior. Finally, in distinguishing from the past studies, this study explores HI HRM practices as an important predictor of FF in addressing the IWB.