bluuebunny/crossref_metadata_2025_split huggingface dataset:
SeqRepo: A system for managing local collections biological sequences
Authors: Hart Reece K. , Prlić Andreas 
Published: September 2020

AbstractMotivationAccess to biological sequence data, such as genome, transcript, or protein sequence, is at the core of many bioinformatics analysis workflows. The National Center for Biotechnology Information (NCBI), Ensembl, and other sequence database maintainers provide methods to access sequences through network connections. For many users, the convenience and currency of remotely managed data are compelling, and the network latency is non-consequential. However, for high-throughput and clinical applications, local sequence collections are essential for performance, stability, privacy, and reproducibility.ResultsHere we describe SeqRepo, a novel system for building a local, high-performance, non-redundant collection of biological sequences. SeqRepo enables clients to use primary database identifiers and several digests to identify sequences and sequence alises. SeqRepo provides a native Python interface and a REST interface, which can run locally and enables access from other programming languages. SeqRepo also provides an alternative REST interface based on the GA4GH refget protocol.SeqRepo provides fast random access to sequence slices. We provide results that demonstrate that a local SeqRepo sequence collection yields significant performance benefits of up to 1300-fold over remote sequence collections. In our use case for a variant validation and normalization pipeline, SeqRepo improved throughput 50-fold relative to use with remote sequences. SeqRepo may be used with any species or sequence type. Regular snapshots of Human sequence collections are available.It is often convenient or necessary to use a computed digest as a sequence identifier. For example, a digest-based identifier may be used to refer to proprietary reference genomes or segments of a graph genome, for which conventional identifiers will not be available. Here we also introduce a convention for the application of the SHA-512 hashing algorithm with Base64 encoding to generate URL-safe identifiers. This convention,sha512t24u, combines a fast digest mechanism with a space-efficient representation that can be used for any object. Our report includes an analysis of timing and collision probabilities forsha512t24u. SeqRepo enables clients to use sha512t24u as identifiers, thereby seamlessly integrating public and private sequence sets.AvailabilitySeqRepo is released under the Apache License 2.0 and is available on github and PyPi. Docker images and database snapshots are also available. Seehttps://github.com/biocommons/biocommons.seqrepo.
AlphaImpute2: Fast and accurate pedigree and population based imputation for hundreds of thousands of individuals in livestock populations
Authors: Whalen Andrew , Hickey John M 
Published: September 2020

AbstractIn this paper we present a new imputation algorithm, AlphaImpute2, which performs fast and accurate pedigree and population based imputation for livestock populations of hundreds of thousands of individuals. Genetic imputation is a tool used in genetics to decrease the cost of genotyping a population, by genotyping a small number of individuals at high-density and the remaining individuals at low-density. Shared haplotype segments between the high-density and low-density individuals can then be used to fill in the missing genotypes of the low-density individuals. As the size of genetics datasets have grown, the computational cost of performing imputation has increased, particularly in agricultural breeding programs where there might be hundreds of thousands of genotyped individuals. To address this issue, we present a new imputation algorithm, AlphaImpute2, which performs population imputation by using a particle based approximation to the Li and Stephens which exploits the Positional Burrows Wheeler Transform, and performs pedigree imputation using an approximate version of multi-locus iterative peeling. We tested AlphaImpute2 on four simulated datasets designed to mimic the pedigrees found in a real pig breeding program. We compared AlphaImpute2 to AlphaImpute, AlphaPeel, findhap version 4, and Beagle 5.1. We found that AlphaImpute2 had the highest accuracy, with an accuracy of 0.993 for low-density individuals on the pedigree with 107,000 individuals, compared to an accuracy of 0.942 for Beagle 5.1, 0.940 for AlphaImpute, and 0.801 for findhap. AlphaImpute2 was also the fastest software tested, with a runtime of 105 minutes a pedigree of 107,000 individuals and 5,000 markers was 105 minutes, compared to 190 minutes for Beagle 5.1, 395 minutes for findhap, and 7,859 minutes AlphaImpute. We believe that AlphaImpute2 will enable fast and accurate large scale imputation for agricultural populations as they scale to hundreds of thousands or millions of genotyped individuals.
Transcriptome analysis of EPO and GFP HEK293 Cell-lines Reveal Shifts in Energy and ER Capacity Support Improved Erythropoietin Production in HEK293F Cells
Authors: Saghaleyni Rasool , Malm Magdalena , Zrimec Jan , Razavi Ronia , Wistbacka Num , Chotteau Veronique , Hatton Diane , Grassi Luigi , Zelezniak Aleksej , Svensson Thomas , Nielsen Jens , Robinson Jonathan L. , Rockberg Johan 
Published: September 2020

SummaryHigher eukaryotic cell lines like HEK293 are the preferred hosts for production of therapeutic proteins requiring human post translational processing. However, recombinant protein production can result in severe stress on the cellular machinery, resulting in limited titre and product quality. To investigate the cellular and metabolic characteristics associated with these limitations, we compared erythropoietin (secretory) and GFP (non-secretory) protein producer HEK293 cell-lines using transcriptomics analysis. Despite the high demand for ATP in all protein producer clones, a significantly higher capacity for ATP production was observed with erythropoietin producers as evidenced by the enrichment of upregulated genes in the oxidative phosphorylation pathway. In addition, ribosomal genes exhibited specific patterns of expression depending on the recombinant protein and the production rate. In a clone displaying a dramatically increased erythropoietin secretion, we detected higher ER stress, including upregulation of the ATF6B gene. Our results are significant in recognizing key pathways for recombinant protein production and identifying potential target genes for further development of secretory power in mammalian cell factories.In BriefAlthough the protein secretion process has been widely studied, the complexity of it leaves many questions with regards to defining bottlenecks for successful protein secretion to be answered. By investigating the transcriptomic profiles of different HEK293 clones with varying translational rates producing either the secreted protein erythropoietin or the intracellular GFP, we reveal that high ATP production and improved capacity of specific post-translational pathways are key factors associated with boosting erythropoietin production.HighlightsTranscriptomics analysis of a panel of HEK293 stable cell lines expressing GFP or erythropoietin (EPO) at varying translational ratesExpression of mitochondrial ribosomal genes is positively correlated with EPO secretionExpression of different cytosolic ribosomal genes are correlated with productivity in a recombinant-protein specific mannerHigh EPO producing clones have significant upregulation of ATF6B, potentially enabling a beneficial ER stress response to cope with high protein secretionGraphical Abstract
Baricitinib treatment resolves lower airway inflammation and neutrophil recruitment in SARS-CoV-2-infected rhesus macaques
Authors: Hoang Timothy N. , Pino Maria , Boddapati Arun K. , Viox Elise G. , Starke Carly E. , Upadhyay Amit A. , Gumber Sanjeev , Busman-Sahay Kathleen , Strongin Zachary , Harper Justin L. , Tharp Gregory K. , Pellegrini Kathryn L. , Kirejczyk Shannon , Zandi Keivan , Tao Sijia , Horton Tristan R. , Beagle Elizabeth N. , Mahar Ernestine A. , Lee Michelle YH , Cohen Joyce , Jean Sherrie M. , Wood Jennifer S. , Connor-Stroud Fawn , Stammen Rachelle L. , Delmas Olivia M. , Wang Shelly , Cooney Kimberly A. , Sayegh Michael N. , Wang Lanfang , Weiskopf Daniela , Filev Peter D. , Waggoner Jesse , Piantadosi Anne , Kasturi Sudhir P. , Shakhshir Hilmi Al- , Ribeiro Susan P. , Sekaly Rafick P. , Levit Rebecca D. , Estes Jacob D. , Vanderford Thomas H. , Schinazi Raymond F. , Bosinger Steven E. , Paiardini Mirko 
Published: September 2020

AbstractEffective therapeutics aimed at mitigating COVID-19 symptoms are urgently needed. SARS-CoV-2 induced hypercytokinemia and systemic inflammation are associated with disease severity. Baricitinib, a clinically approved JAK1/2 inhibitor with potent anti-inflammatory properties is currently being investigated in COVID-19 human clinical trials. Recent reports suggest that baricitinib may also have antiviral activity in limiting viral endocytosis. Here, we investigated the immunologic and virologic efficacy of baricitinib in a rhesus macaque model of SARS-CoV-2 infection. Viral shedding measured from nasal and throat swabs, bronchoalveolar lavages and tissues was not reduced with baricitinib. Type I IFN antiviral responses and SARS-CoV-2 specific T cell responses remained similar between the two groups. Importantly, however, animals treated with baricitinib showed reduced immune activation, decreased infiltration of neutrophils into the lung, reduced NETosis activity, and more limited lung pathology. Moreover, baricitinib treated animals had a rapid and remarkably potent suppression of alveolar macrophage derived production of cytokines and chemokines responsible for inflammation and neutrophil recruitment. These data support a beneficial role for, and elucidate the immunological mechanisms underlying, the use of baricitinib as a frontline treatment for severe inflammation induced by SARS-CoV-2 infection.
The flexibility of ACE2 in the context of SARS-CoV-2 infection
Authors: Barros E. P. , Casalino L. , Gaieb Z. , Dommer A. C. , Wang Y. , Fallon L. , Raguette L. , Belfon K. , Simmerling C. , Amaro R. E. 
Published: September 2020

AbstractThe COVID-19 pandemic has swept over the world in the past months, causing significant loss of life and consequences to human health. Although numerous drug and vaccine developments efforts are underway, many questions remain outstanding on the mechanism of SARS-CoV-2 viral association to angiotensin-converting enzyme 2 (ACE2), its main host receptor, and entry in the cell. Structural and biophysical studies indicate some degree of flexibility in the viral extracellular Spike glycoprotein and at the receptor binding domain-receptor interface, suggesting a role in infection. Here, we perform all-atom molecular dynamics simulations of the glycosylated, full-length membrane-bound ACE2 receptor, in both an apo and spike receptor binding domain (RBD) bound state, in order to probe the intrinsic dynamics of the ACE2 receptor in the context of the cell surface. A large degree of fluctuation in the full length structure is observed, indicating hinge bending motions at the linker region connecting the head to the transmembrane helix, while still not disrupting the ACE2 homodimer or ACE2-RBD interfaces. This flexibility translates into an ensemble of ACE2 homodimer conformations that could sterically accommodate binding of the spike trimer to more than one ACE2 homodimer, and suggests a mechanical contribution of the host receptor towards the large spike conformational changes required for cell fusion. This work presents further structural and functional insights into the role of ACE2 in viral infection that can be exploited for the rational design of effective SARS-CoV-2 therapeutics.Statement of SignificanceAs the host receptor of SARS-CoV-2, ACE2 has been the subject of extensive structural and antibody design efforts in aims to curtail COVID-19 spread. Here, we perform molecular dynamics simulations of the homodimer ACE2 full-length structure to study the dynamics of this protein in the context of the cellular membrane. The simulations evidence exceptional plasticity in the protein structure due to flexible hinge motions in the head-transmembrane domain linker region and helix mobility in the membrane, resulting in a varied ensemble of conformations distinct from the experimental structures. Our findings suggest a dynamical contribution of ACE2 to the spike glycoprotein shedding required for infection, and contribute to the question of stoichiometry of the Spike-ACE2 complex.
Inhibition ofStreptococcus pneumoniaeautolysins highlight distinct differences between chemical and genetic inactivation
Authors: Haubrich Brad A , Nayyab Saman , Williams Caroline , Whitman Andrew , Zimmerman Tahl , Li Qiong , Chen Yuxing , Zhou Cong-Zhao , Basu Amit , Reid Christopher W 
Published: September 2020

AbstractDespite renewed interest, development of chemical biology methods to study peptidoglycan metabolism has lagged in comparison to the glycobiology field in general. To address this, a panel of diamides were screened against the Gram-positive pathogenStreptococcus pneumoniaeto identify inhibitors of bacterial growth. The screen identified the diamidefgkcas a narrow spectrum bacteriostatic inhibitor ofS. pneumoniaegrowth with an MIC of 7.8 μM. The diamide inhibited detergent-induced autolysis in a concentration dependent manner indicating peptidoglycan degradation as the mode-of-action. Genetic screening of autolysin mutants suggested LytB, an endo-N-acetylglucosaminidase, involved in cell division as the potential target. Surprisingly, biochemical, and phenotypic analysis contradicted the genetic screen results. Phenotypic studies with theΔlytbstrain illustrate the difference between genetic and chemical inactivation of autolysins. These findings suggest that meta-phenotypes including autolytic activity, cell morphology, and genetic screening can be the result of the complex interaction of one or more possible pathways that are connected to cell wall metabolism.
The Wnt effector TCF7l2 promotes oligodendroglial differentiation by repressing autocrine BMP4-mediated signaling
Authors: Zhang Sheng , Wang Yan , Zhu Xiaoqing , Song Lanying , Zhan Xinhua , Ma Edric , McDonough Jennifer , Fu Hui , Cambi Franca , Grinspan Judith , Guo Fuzheng 
Published: September 2020

ABSTRACTPromoting oligodendrocyte differentiation represents a promising option for remyelination therapy for treating the demyelinating disease multiple sclerosis (MS). The Wnt effector TCF7l2 was upregulated in MS lesions and had been proposed to inhibit oligodendrocyte differentiation. Recent data suggest the opposite yet underlying mechanisms remain elusive. Here we unravel a previously unappreciated function of TCF7l2 in controlling autocrine bone morphogenetic protein (BMP4)-mediated signaling. Disrupting TCF7l2 results in oligodendroglial-specific BMP4 upregulation and canonical BMP4 signaling activationin vivo. Mechanistically, TCF7l2 binds toBmp4gene regulatory element and directly represses its transcriptional activity. Functionally, enforced TCF7l2 expression promotes oligodendrocyte differentiation by reducing autocrine BMP4 secretion and dampening BMP4 signaling. Importantly, compound genetic disruption demonstrates that oligodendroglial-specific BMP4 deletion rescues arrested oligodendrocyte differentiation elicited by TCF7l2 disruptionin vivo. Collectively, our study reveals a novel connection between TCF7l2 and BMP4 in oligodendroglial lineage and provides new insights into augmenting TCF7l2 for promoting remyelination in demyelinating disorders such as MS.Significance StatementIncomplete or failed myelin repairs, primarily resulting from the arrested differentiation of myelin-forming oligodendrocytes from oligodendroglial progenitor cells, is one of the major reasons for neurological progression in people affected by multiple sclerosis (MS). Usingin vitroculture systems andin vivoanimal models, this study unraveled a previously unrecognized autocrine regulation of BMP4-mediated signaling by the Wnt effector TCF7l2. We showed for the first time that TCF7l2 promotes oligodendroglial differentiation by repressing BMP4-mediated activity, which is dysregulated in MS lesions. Our study suggests that elevating TCF7l2 expression may be possible in overcoming arrested oligodendroglial differentiation as observed in MS patients.
Workfare redux? Pandemic unemployment, labour activation and the lessons of post-crisis welfare reform in Ireland
Authors: McGann Michael , Murphy Mary P. , Whelan Nuala 
Published: September 2020

PurposeThis paper addresses the labour market impacts of Covid-19, the necessity of active labour policy reform in response to this pandemic unemployment crisis and what trajectory this reform is likely to take as countries shift attention from emergency income supports to stimulating employment recovery.Design/methodology/approachThe study draws on Ireland’s experience, as an illustrative case. This is motivated by the scale of Covid-related unemployment in Ireland, which is partly a function of strict lockdown measures but also the policy choices made in relation to the architecture of income supports. Also, Ireland was one of the countries most impacted by the Great Recession leading it to introduce sweeping reforms of its active labour policy architecture.FindingsThe analysis shows that the Covid unemployment crisis has far exceeded that of the last financial and banking crisis in Ireland. Moreover, Covid has also exposed the fragility of Ireland's recovery from the Great Recession and the fault-lines of poor public services, which intensify precarity in the context of low-paid employment growth precipitated by workfare policies implemented since 2010. While these policies had some short-term success in reducing the numbers on the Live Register, many cohorts were left behind by the reforms and these employment gains have now been almost entirely eroded.Originality/valueThe lessons from Ireland's experience of post-crisis activation reform speak to the challenges countries now face in adapting their welfare systems to facilitate a post-Covid recovery, and the risks of returning to “workfare” as usual.
Investigating design targets for effective performance management system: an application of balance scorecard using QFD
Authors: Agarwal Alpana 
Published: September 2020

PurposeAn effective performance management must track level of employee engagement, ensure employee feedback on all aspects and ensure that the people act on that information. Also, it must ensure accessibility of essential conditions to perform. Considering the challenges associated with existing performance management system, present study attempts to discover factual expectations from the employees. The paper also establishes required conditions for fulfilling such expectations.Design/methodology/approachPresent study attempts to discover factual expectations from the employees using the Balance Scorecard approach (BSC). Furthermore, using Quality Function Deployment (QFD), relation between employers' expectation and requirements necessary to fulfill such expectations has also been determined.FindingsThe suggested model has been developed as House Of Performance Management (HOPM) outlining potential leveraging points for enhancing the performance, based on which immediate actionable measures for effective and efficient performance management can also been advocated. The HOQ suggested in this paper can be source of reference while developing performance management system for an organization. Besides, it can help the Human Resource team to discover strategic opportunities and set targets.Originality/valueEffective goal setting, pooled with a method to track progress and identify obstacles, contribute to attainment of bottom to top line results. However, designing and implementing such performance management system has been associated with many challenges like lack of top management support, perception of the process as time-consuming, failure to communicate clear and specific goals and expectations, lack of consistency, etc. (Managing employee performance, 2019). Hence most organizations have been increasingly looking for effective ways of assessing employee performance that can promote stakeholders' satisfaction, employee engagement and continuous improvement.
Driving sustainability in SMEs’ performance: the effect of strategic flexibility
Authors: Gorondutse Abdullahi Hassan , Arshad Darwina , Alshuaibi Ahmad Said 
Published: September 2020

PurposeAlthough the significance of small and medium enterprises (SMEs) in influencing economic growth is recognized, the performance of SMEs all over the world including Nigeria is unanticipated. Thus, this research aims to investigate the effect of strategic flexibility by moderating the effects of sustainability strategy on the SMEs' performance in Nigeria from a business strategy perspective.Design/methodology/approachThe hypotheses of the study were tested using personally administered survey questionnaires; the study obtained 486 valid questionnaires, which were evaluated using SmartPLS algorithm and bootstrapping functions.FindingsThe research findings were established using SmartPLS algorithm and bootstrapping functions. According to the results, the research constructs have a satisfactory convergent and discriminant validity. Equally, the overall model has a very high predictive relevance. The study established a strong positive influence of strategic flexibility on the SMEs’ performance. In addition, the study also established the moderating influence of sustainability strategy on the constructs.Research limitations/implicationsThe research is explorative and designed to yield results and to be generalizable. Future research is thus encouraged to confirm or contradict the results of this study in a different context.Practical implicationsThe research findings may be beneficial to policymakers and academics. It can particularly be useful in understanding strategic flexibility, its influence on the performance of SMEs and whether it can fit between the sustainability and strategic direction of a business enterprise.Originality/valueThis study fulfils an identified need to study strategic flexibility and its influence on the performance of SMEs using a dynamic perspective specifically in the context of emerging economies such as Nigeria.
Responsiveness to i.v. immunoglobulin therapy in patients with toxic epidermal necrolysis: A novel pharmaco‐immunogenetic concept
Authors: Borilova Linhartova Petra , Gachova Daniela , Lipovy Bretislav 
Published: September 2020

AbstractToxic epidermal necrolysis (TEN) represents a rare drug‐induced autoimmune reaction with delayed‐type hypersensitivity that initiates the process of developing massive keratinocyte apoptosis, dominantly in the dermoepidermal junction. Although the etiopathophysiology has not yet been fully elucidated, the binding of Fas ligand (FasL, CD95L) to the Fas receptor (CD95) was shown to play a key role in the induction of apoptosis in this syndrome. The knowledge of the role of immunoglobulin G (IgG) in inhibition of Fas‐mediated apoptosis contributed to the introduction of i.v. Ig (IVIg) in the therapy of TEN patients. Despite great enthusiasm for this therapy at the end of the 1990s, subsequent studies in various populations and meta‐analyses could not unequivocally confirm the efficacy of the IVIg‐based treatment concept. Today, therefore, we are faced with the dilemmas of how to adjust therapy of TEN patients most effectively, which patients could benefit from IVIg therapy and what dose of the preparation should be administrated. The ground‐breaking question is: do the host genetic profiles influence the responsiveness and side‐effects of IVIg therapy in TEN patients? Based on recent pharmacological, immunological and genetic findings, we suggest that the variability of IVIg therapy outcomes in TEN patients may be related to functional variants in Fas, FasL and Fc‐γ receptor genes. This novel concept could lead to improved quality of care for patients with TEN, facilitating personalized therapy to reduce mortality.