bluuebunny/crossref_metadata_2025_split huggingface dataset:
ARP2/3- and resection-coupled genome reorganization facilitates translocations
Authors: Zagelbaum Jennifer , Schooley Allana , Zhao Junfei , Schrank Benjamin R. , Callen Elsa , Zha Shan , Gottesman Max E. , Nussenzweig André , Rabadan Raul , Dekker Job , Gautier Jean 
Published: October 2021

SummaryDNA end-resection and nuclear actin-based movements orchestrate clustering of double-strand breaks (DSBs) into homology-directed repair (HDR) domains. Here, we analyze how actin nucleation by ARP2/3 affects damage-dependent and -independent 3D genome reorganization and facilitates pathologic repair. We observe that DNA damage, followed by ARP2/3-dependent establishment of repair domains enhances local chromatin insulation at a set of damage-proximal boundaries and affects compartment organization genome-wide. Nuclear actin polymerization also promotes interactions between DSBs, which in turn facilitates aberrant intra- and inter-chromosomal rearrangements. Notably, BRCA1 deficiency, which decreases end-resection, DSB mobility, and subsequent HDR, nearly abrogates recurrent translocations between AsiSI DSBs. In contrast, loss of functional BRCA1 yields unique translocations genome-wide, reflecting a critical role in preventing spontaneous genome instability and subsequent rearrangements. Our work establishes that the assembly of DSB repair domains is coordinated with multiscale alterations in genome architecture that enable HDR despite increased risk of translocations with pathologic potential.
A Biodegradable, Tacrolimus-releasing Nerve Wrap Promotes Peripheral Nerve Regeneration
Authors: Daeschler Simeon C. , Chan Katelyn , Feinberg Konstantin , Manoraj Marina , Cheung Jenny , Zhang Jennifer , Mirmoeini Kaveh , Santerre J. Paul , Gordon Tessa , Borschel Gregory H. 
Published: October 2021

AbstractAxonal regeneration following nerve repair is slow and often incomplete, resulting in poor functional recovery and sometimes lifelong disability. Yet, there are no FDA-approved therapies available to promote nerve regeneration. Tacrolimus accelerates axonal regeneration, but systemic side-effects presently outweigh its potential benefits for peripheral nerve surgery. We have developed a biodegradable drug delivery system for the sustained local release of tacrolimus at the nerve repair site, with suitable properties for large-scale manufacturing and clinical application, aiming to promote axonal regeneration and functional recovery with minimal systemic drug exposure. Tacrolimus is encapsulated in polycarbonate-urethane nanofibers and electrospun to generate an implantable nerve wrap that releases therapeutic doses of bioactive tacrolimus over 31 days. Size and drug loading are adjustable for applications in small and large caliber nerves, and the wrap degrades within 120 days into biocompatible byproducts. Tacrolimus released from the nerve wrap promotes axon elongation in vitro and accelerates nerve regeneration and functional recovery in preclinical nerve repair models while systemic drug exposure is reduced by 80% compared to systemic delivery. Given its surgical suitability and preclinical efficacy and safety, this system may provide a readily translatable approach to support axonal regeneration and recovery in patients undergoing nerve surgery.
Kinetic and data-driven modeling of pancreatic β-cell central carbon metabolism and insulin secretion
Authors: Gelbach Patrick E. , Zheng Dongqing , Fraser Scott E. , White Kate , Graham Nicholas A. , Finley Stacey D. 
Published: October 2021

AbstractPancreatic β-cells respond to increased extracellular glucose levels by initiating a metabolic shift. That change in metabolism is part of the process of glucose-stimulated insulin secretion and is of particular interest in the context of diabetes. However, we do not fully understand how the coordinated changes in metabolic pathways and metabolite products influence insulin secretion. In this work, we apply systems biology approaches to develop a detailed kinetic model of the intracellular central carbon metabolic pathways in pancreatic β-cells upon stimulation with high levels of glucose. The model is calibrated to published metabolomics datasets for the INS1 823/13 cell line, accurately capturing the measured metabolite fold-changes. We first employed the calibrated mechanistic model to estimate the stimulated cell’s fluxome. We then used the predicted network fluxes in a data-driven approach to build a partial least squares regression model. By developing the combined kinetic and data-driven modeling framework, we gain insights into the link between β-cell metabolism and glucose-stimulated insulin secretion. The combined modeling framework was used to predict the effects of common anti-diabetic pharmacological interventions on metabolite levels, flux through the metabolic network, and insulin secretion. Our simulations reveal targets that can be modulated to enhance insulin secretion. The model is a promising tool to contextualize and extend the usefulness of metabolomics data and to predict dynamics and metabolite levels that are difficult to measure in vitro. In addition, the modeling framework can be applied to identify, explain, and assess novel and clinically-relevant interventions that may be particularly valuable in diabetes treatment.Author SummaryDiabetes is among the most common chronic illnesses, occurring when the β-cells in the pancreas are unable to produce enough insulin to properly manage the body’s blood sugar levels. β-cells metabolize nutrients to produce energy needed for insulin secretion in response to high glucose, and there is a potential to harness β-cell metabolism for treating diabetes. However, β-cell metabolism is not fully characterized. We have developed a computational modeling framework to better understand the relationship between cellular metabolism and insulin production in the pancreatic β-cell. With this modeling framework, we are able to simulate metabolic perturbations, such as the knockdown of the activity of a metabolic enzyme, and predict the effect on the metabolic network and on insulin production. This work can therefore be applied to investigate, in a time- and cost-efficient manner, β-cell metabolism and predict effective therapies that target the cell’s metabolic network.
Discovery and biosynthesis of persiathiacins: Unusual polyglycosylated thiopeptides active against multi-drug resistant tuberculosis
Authors: Dashti Yousef , Mohammadipanah Fatemeh , Belousoff Matthew , Vocat Anthony , Zabala Daniel , Fage Christopher D , Romero-Canelon Isolda , Bunk Boyke , Spröer Cathrin , Overmann Jörg , Cole Stewart T , Challis Gregory L 
Published: October 2021

AbstractThiopeptides are ribosomally biosynthesized and post-translationally modified peptides (RiPPs) that potently inhibit the growth of Gram-positive bacteria by targeting multiple steps in protein biosynthesis. The poor pharmacological properties of thiopeptides, in particular their low aqueous solubility, has hindered their development into clinically useful antibiotics. Antimicrobial activity screens of a library of Actinobacterial extracts led to discovery of the novel polyglycosylated thiopeptides persiathiacins A and B from Actinokineospora sp. UTMC 2475 and Actinokineospora sp. UTMC 2448. Persiathiacin A is active against methicillin-resistant Staphylococcus aureus (MRSA) and several Mycobacterium tuberculosis strains, including drug-resistant and multidrug-resistant clinical isolates, and does not significantly affect the growth of ovarian cancer cells at concentrations up to 400 μM. In vitro translation assays showed that, like other thiopeptide antibiotics, persiathiacin A targets protein biosynthesis. Polyglycosylated thiopeptides are extremely rare and nothing is known about their biosynthesis. Sequencing and analysis of the Actinokineospora sp. UTMC 2448 genome enabled identification of the putative persiathiacin biosynthetic gene cluster. A cytochrome P450 encoded by this gene cluster catalyses the hydroxylation of nosiheptide in vitro and in vivo, consistent with the proposal that the cluster directs persiathiacin biosynthesis. Several genes in the cluster encode homologues of enzymes known to catalyse the assembly and attachment of deoxysugars during the biosynthesis of other classes of glycosylated natural products. The discovery of the persiathiacins and their biosynthetic gene cluster thus provides the basis for the development of biosynthetic engineering approaches to the creation of novel (poly)glycosylated thiopeptide derivatives with enhanced pharmacological properties.
Experimental microevolution of Trypanosoma cruzi reveals hybridization and clonal mechanisms driving rapid diversification of genome sequence and structure
Authors: Matos Gabriel M. , Lewis Michael D. , Talavera-López Carlos , Yeo Matthew , Grisard Edmundo C. , Messenger Louisa A. , Miles Michael A. , Andersson Björn 
Published: October 2021

AbstractProtozoa and fungi are known to have extraordinarily diverse mechanisms of genetic exchange. However, the presence and epidemiological relevance of genetic exchange in Trypanosoma cruzi, the agent of Chagas disease, has been controversial and debated for many years. Field studies have identified both predominantly clonal and sexually recombining natural populations. Two of six natural T. cruzi lineages (TcV and TcVI) show hybrid mosaicism, using analysis of single-gene locus markers. The formation of hybrid strains in vitro has been achieved and this provides a framework to study the mechanisms and adaptive significance of genetic exchange. Using whole genome sequencing of a set of experimental hybrids strains, we have confirmed that hybrid formation initially results in tetraploid parasites. The hybrid progeny showed novel mutations that were not attributable to either (diploid) parent showing an increase in amino acid changes. In long-term culture, up to 800 generations, there was progressive, gradual erosion of progeny genomes towards triploidy, yet retention of elevated copy number was observed at several core housekeeping loci. Our findings indicate hybrid formation by fusion of diploid T. cruzi, followed by sporadic genome erosion, but with substantial potential for adaptive evolution, as has been described as a genetic feature of other organisms, such as some fungi.
Diverse group effectiveness: co-occurrence of task and relationship conflict, and transformational leadership
Authors: Dahlan Mohanad , Al-Atwi Amer Ali , Alshaibani Elham , Bakir Ali , Maher Kevin 
Published: October 2021

PurposeThis study aims to develop a theoretical integrated model examining the role of the co-occurrence of task and relationship conflict (CTRC) as a mediator in the relationship between diversity and group effectiveness. The model also examines transformational leadership (TFL) as a moderator in this relationship.Design/methodology/approachData were collected using a questionnaire survey from 354 faculty in 56 workgroups from three private universities in the Middle East. SEM and hierarchical regression analysis were used to test the suitability of the model and its hypotheses.FindingsThe results revealed that TFL moderated diversity's direct effect on CTRC as well as the indirect effect linking diversity, CTRC, and group effectiveness. Specifically, diversity had an inverted U-shaped relationship with CTRC in groups with low TFL, but a negative linear relationship in those with high TFL.Originality/valueThe findings expand understanding of how, and under what conditions, diversity influences group effectiveness by: offering a fresh treatment of this relationship, introducing CTRC as a bivariate construct and bringing into focus the centrality of its harmful effect on this association, and highlighting the influence of TFL in ameliorating this harmful effect.
A model to evaluate the acceptance and usefulness of enterprise architecture for digitalization of cities
Authors: Anthony Jnr Bokolo , Petersen Sobah Abbas , Krogstie John 
Published: October 2021

PurposeEnterprise architecture (EA) is usually adopted as an approach for managing enterprise complexities and aligning business and information technology (IT) capabilities. Although IT practitioners and researchers agree about the potential applicability and benefits of EA in smart cities, little is known about the factors that influence the acceptance and usefulness of EA in smart cities. Thus, EA acceptance and usage remains a central concern of urban research and practice. Similarly, there are fewer studies that explored EA adoption from the context of enterprises that provide digital services in cities grounded on empirical evidence. Therefore, this study assesses the acceptance and usefulness of EA in smart cities context by developing an EA adoption model drawing on the DeLone and McLean Information System (IS) success model.Design/methodology/approachBased on the identified factors survey questionnaire was designed and sent out to participants which includes IT professionals, senior managers and consultants from 18 organizations in Norway and Ireland involved in a smart city project (+CityxChange) (https://cityxchange.eu/). Statistical Package for Social Science (SPSS) and structural equation modelling using partial least square was applied for data analysis.FindingsThe results suggest that service quality and system quality positively impact user satisfaction of EA and user's intention to use EA. More importantly, information quality does not influence user satisfaction of EA, and the user satisfaction of EA and user's intention to use EA significantly influences the net benefit of EA.Originality/valueThis study provides a complete understanding for academicians and IT practitioners regarding the factors and impacts on EA acceptance and use in smart cities. Finally, this study discusses the implications of this research and provides recommendations for future research.
The experiences of adults with learning disabilities in the UK during the COVID-19 pandemic: qualitative results from Wave 1 of the Coronavirus and people with learning disabilities study
Authors: Flynn Samantha , Caton Sue , Gillooly Amanda , Bradshaw Jill , Hastings Richard P. , Hatton Chris , Jahoda Andrew , Mulhall Peter , Todd Stuart , Beyer Stephen , Taggart Laurence 
Published: October 2021

Purpose
The purpose of this paper is to present data about the experiences of adults with learning disabilities during the COVID-19 pandemic across the UK.

Design/methodology/approach
Interviews were conducted with 609 adults with learning disabilities. Family carers and support staff of another 351 adults with learning disabilities completed a proxy online survey. The data were collected between December 2020 and February 2021 and concerned both worries/negatives and anything positive that had happened because of the COVID-19 pandemic.

Findings
Social isolation was the most commonly reported worry/negative for adults with learning disabilities, with other frequently reported worries/negatives including: changes to/loss of routine; loss of support/services; and decreased health/well-being/fitness. A large proportion of participants indicated that nothing positive had happened because of COVID-19, but some positives were reported, including: digital inclusion; more time spent with important people; improved health/well-being/fitness; and, a slower pace of life.

Practical implications
Future pandemic planning must ensure that adults with learning disabilities are supported to maintain social contact with the people who matter to them and to support their health and well-being (including maintaining access to essential services and activities). Some adults with learning disabilities may benefit from additional support to improve their digital confidence and access. This may in turn enable them to maintain contact with family, friends and support services/activities.

Originality/value
This is the largest study about the experiences of adults with learning disabilities during the COVID-19 pandemic in the UK. The authors primarily collected data directly from adults with learning disabilities and worked with partner organisations of people with learning disabilities throughout the study.
Revenue and distributional modelling for a UK wealth tax
Authors: Advani Arun , Hughson Helen , Tarrant Hannah 
Published: October 2021

AbstractIn this paper, we model the revenue that could be raised from an annual and a one‐off wealth tax of the design recommended by Advani, Chamberlain and Summers in the Wealth Tax Commission's Final Report (2020). We examine the distributional effects of the tax, in terms of both wealth and other characteristics. We also estimate the share of taxpayers who would face liquidity constraints in meeting their tax liability. We find that an annual wealth tax charging 0.17 per cent on wealth above £500,000 could generate £10 billion in revenue, before administrative costs. Alternatively, a one‐off tax charging 4.8 per cent (effectively 0.95 per cent per year, paid over a five‐year period) on wealth above the same threshold, would generate £250 billion in revenue. To put our revenue estimates into context, we present revenue estimates and costings for some commonly proposed reforms to the existing set of taxes on capital.
Initial experience with CytoSorb therapy in patients receiving left ventricular assist devices
Authors: Zhigalov Konstantin , Van den Eynde Jef , Zubarevich Alina , Chrosch Thomas , Goerdt Lukas , Arjomandi Rad Arian , Vardanyan Robert , Sá Michel Pompeu Barros Oliveira , Luedike Peter , Pizanis Nikolaus , Koch Achim , Schmack Bastian , Kamler Markus , Ruhparwar Arjang , Weymann Alexander 
Published: October 2021

AbstractBackgroundThe use of left ventricular assist devices (LVAD) in patients with advance heart failure is still associated with an important risk of immune dysregulation and infections. The aim of this study was to determine whether extracorporeal blood purification using the CytoSorb device benefits patients after LVAD implantation in terms of complications and overall survival.Materials and MethodsBetween August 2010 and January 2020, 207 consecutive patients underwent LVAD implantation, of whom 72 underwent CytoSorb therapy and 135 did not. Overall survival, major adverse events, and laboratory parameters were compared between 112 propensity score‐matched patients (CytoSorb: 72 patients; non‐CytoSorb: 40 patients).ResultsWBC (p = .033), CRP (p = .001), and IL‐6 (p < .001), significantly increased with LVAD implantation, while CytoSorb did not influence this response. In‐hospital mortality and overall survival during follow‐up were similar with CytoSorb. However, patients treated with CytoSorb were more likely to develop respiratory failure (54.2% vs. 30.0%, p = .024), need mechanical ventilation for longer than 6 days post‐implant (50.0% vs. 27.5%, p = .035), and require tracheostomy during hospitalization (31.9% vs. 12.5%, p = .040). No other significant differences were observed with regard to major adverse events during follow‐up.ConclusionsOverall, our results showed that CytoSorb might not convey a significant morbidity or mortality benefit for patients undergoing LVAD implantation.
A case series of vaccine‐induced thrombotic thrombocytopenia in a London teaching hospital
Authors: Watts Isabella , Smith David , Mounter Sarah , Baker Emma H. , Hitchings Andrew W. , Gill Dipender 
Published: October 2021

The ChAdOx1 nCoV‐19 vaccine has been associated with increased risk of thrombosis. Understanding of the management of these rare events is evolving, and currently recommended treatments include human normal immunoglobulin and nonheparin anticoagulation such as direct oral anticoagulants. Our report describes three consecutive patients presenting to a London teaching hospital with vaccine‐induced thrombotic thrombocytopenia (VITT), also referred to as vaccine‐induced prothrombotic immune thrombocytopenia. The patients ranged in age from 40 to 54 years and two had no known previous medical comorbidities. Two patients had cerebral venous sinus thrombosis and one had a deep vein thrombosis. Two were treated with anticoagulation, one with oral rivaroxaban and the other with an intravenous argotraban infusion that was later converted to oral apixaban. One patient received three doses of human normal immunoglobulin and 5 days of therapeutic plasma exchange. This case series may be used to improve understanding of the clinical course and management of VITT.
Host specialization, genetic variability, and differentiation in three species of Tomoplagia from Brazilian rupestrian grasslands
Authors: Leal Camila Rabelo Oliveira , Souza Anete Pereira de , Silva‐Brandão Karina Lucas , Lewinsohn Thomas Michael 
Published: October 2021

AbstractIn this study, the geographic and host plant‐associated genetic structure of Tomoplagia spp. (Diptera: Tephritidae) was investigated. The study was developed in the rupestrian montane grasslands of the Espinhaço Mountain Range, Brazil, where these flies’ larvae develop within flower heads of Asteraceae. The three species of Tomoplagia investigated have different host spans within the subtribe Vernoniinae: one is strictly monophagous (Tomoplagia grandis Prado, Norrbom & Lewinsohn) and two are oligophagous [Tomoplagia incompleta (Williston) and Tomoplagia bicolor Prado, Norrbom & Lewinsohn]. The genetic variability and differentiation throughout their geographic distribution were investigated at the local scale (sympatric, between different host species in the same locality) and the regional scale (allopatric, on the same or different host species in different localities). Allele richness was greater for populations of the two oligophagous species. Moreover, population genetic structure was low in all species both on the local and regional scales, and the attribution of individuals of the three species to different genetic groups was not strongly associated with either locality or host plant. These results indicate the absence of simple geographic and host‐associated genetic structure in these specialized herbivores, suggesting that females of T. bicolor and T. incompleta have low host philopatry, using various host species indiscriminately within their distribution range. Therefore, the use of host plants by fruit flies of the genus Tomoplagia is a plastic character that can shift temporally and spatially among phylogenetically related and chemically similar plants. Contrary to expectations, given the specialized and intimate nature of their host association, the studied Tomoplagia species showed no clear host‐associated genetic differentiation; instead, genetic variation presents a mosaic pattern across hosts and localities.