bluuebunny/crossref_metadata_2025_split huggingface dataset:
Resource conflicts leading to moral distress: A longitudinal study among physicians in Norway
Authors: Miljeteig Ingrid , Førde Reidun , Rø Karin Isaksson , Bååthe Fredrik , Bringedal Berit 
Published: September 2023

AbstractBackgroundThe scarcity of resources represents ethical challenges and involves moral distress for health professionals. There are no longitudinal studies of moral distress among representative samples of physicians.MethodSurveys of the Norwegian Physician Panel (NPP) compared the extent of moral distress in 2004 and 2021. Descriptive statistics and regression analysis were used in the study.ResultsResponse rates were 67% (1004/1499) in 2004 and 70% (1639/2316) in 2021. That patient care is deprived due to time constraints is the most severe dimension of moral distress among physicians, and it has increased comparing 2021 with 2004 (68.3% in 2004 to 75.1% in 2021 reported “somewhat” or “very morally distressing”). Moral distress also increased concerning patients who “cry the loudest” get better and faster treatment than others. Moral distress was reduced on statements about long waiting times, treatment not provided due to economic limitations, deprioritisation of older patients, and acting against one’s conscience. Women reported higher moral distress than men in both years, and there were significant gender differences for six statements in 2021 and one in 2004. Though not consistently, the physicians’ age and workplace influenced the reported moral distress.ConclusionIn both years, moral distress among physicians related to scarcity of or unfair distribution of resources was high. Moral distress associated with resource scarcity and acting against one’s conscience decreased, which might indicate improvements in the healthcare system. On the other hand, it might suggest that physicians have reduced their ideals or expectations or are morally fatigued.
PROxAb Shuttle: A non-covalent plug-and-play platform for the rapid generation of tumor-targeting antibody-PROTAC conjugates
Authors: Schneider Hendrik , Jäger Sebastian , Könning Doreen , Rasche Nicolas , Schröter Christian , Elter Desislava , Evers Andreas , Lecomte Marc , Sirtori Federico Riccardi , Schwarz Daniel , Wegener Ansgar , Hartung Ingo , Rieker Marcel 
Published: September 2023

AbstractProteolysis-targeting chimeras (PROTACs) have evolved in recent years from an academic idea to a therapeutic modality with more than 25 active clinical programs. However, achieving oral bioavailability and cell-type specificity remains a challenge, especially for PROTACs recruiting the von Hippel-Lindau (VHL) E3 ligase. Herein, we present an unprecedented, plug- and-play platform for VHL-recruiting PROTACs to overcome these limitations. Our platform allows for the generation of non-covalent antibody-PROTAC complexes within minutes and obviates the need for prior PROTAC modification, antibody-drug linker chemistry optimization or bioconjugation. Our technology relies on camelid-derived antibody domains (VHHs) which can easily be engineered into existing therapeutic antibody scaffolds. The resulting targeted, bispecific fusion proteins can be complexed with PROTACs at defined PROTAC-to-antibody ratios and have been termed PROxAb Shuttles. PROxAb Shuttles can prolong the half-life of PROTACs from hours to days, demonstrate anti-tumor efficacyin vivoand have the potential for reloadingin vivoto further boost efficacy.
Voluntary wheel running mitigates disease in an Orai1 gain-of-function mouse model of tubular aggregate myopathy
Authors: O’Connor Thomas N. , Zhao Nan , Orciuoli Haley M. , Brasile Alice , Pietrangelo Laura , He Miao , Groom Linda , Leigh Jennifer , Mahamed Zahra , Liang Chen , Malik Sundeep , Protasi Feliciano , Dirksen Robert T. 
Published: September 2023

AbstractTubular aggregate myopathy (TAM) is an inherited skeletal muscle disease associated with progressive muscle weakness, cramps, and myalgia. Tubular aggregates (TAs) are regular arrays of highly ordered and densely packed SR straight-tubes in muscle biopsies; the extensive presence of TAs represent a key histopathological hallmark of this disease in TAM patients. TAM is caused by gain-of-function mutations in proteins that coordinate store-operated Ca2+entry (SOCE): STIM1 Ca2+sensor proteins in the sarcoplasmic reticulum (SR) and Ca2+-permeable ORAI1 channels in the surface membrane. We have previously shown that voluntary wheel running (VWR) prevents formation of TAs in aging mice. Here, we assessed the therapeutic potential of endurance exercise (in the form of VWR) in mitigating the functional and structural alterations in a knock-in mouse model of TAM (Orai1G100S/+or GS mice) based on a gain-of-function mutation in the ORAI1 pore. WT and GS mice were singly-housed for six months (from two to eight months of age) with either free-spinning or locked low profile wheels. Six months of VWR exercise significantly increased soleus peak tetanic specific force production, normalized FDB fiber Ca2+store content, and markedly reduced TAs in EDL muscle from GS mice. Six months of VWR exercise normalized the expression of mitochondrial proteins found to be altered in soleus muscle of sedentary GS mice in conjunction with a signature of increased protein translation and biosynthetic processes. Parallel proteomic analyses of EDL muscles from sedentary WT and GS mice revealed changes in a tight network of pathways involved in formation of supramolecular complexes, which were also normalized following six months of VWR. In summary, sustained voluntary endurance exercise improved slow twitch muscle function, reduced the presence of TAs in fast twitch muscle, and normalized the muscle proteome of GS mice consistent with protective adaptions in proteostasis, mitochondrial structure/function, and formation of supramolecular complexes.
Genetic diversity of domestic cat hepadnavirus in Taiwan
Authors: Ilagan Silva Benji Brayan , Chen Jin-Yang , Avanceña Villanueva Brian Harvey , Lu Zi-Ying , Zhen Hsing-Hua , Montecillo Andrew D. , Shofa Maya , Minh Hoang , Chuang Jen-Pin , Huang Huai-Ying , Saito Akatsuki , Chuang Kuo-Pin 
Published: September 2023

AbstractDomestic cat hepadnavirus (DCH) is an infectious disease associated with chronic hepatitis in cats, suggesting a similarity with hepatitis B virus infection in humans. Since its first identification in Australia in 2018, DCH has been reported in several countries with varying prevalence rates, but its prevalence in Taiwan has not yet been investigated. Here, we aimed to identify the presence and prevalence of DCH infections in Taiwan. Among 71 samples tested, eight (11.27%) were positive for DCH. Of these positive cases, three cats had elevated levels of alanine transaminase (ALT) and aspartate transaminase (AST), suggesting an association between DCH infection and chronic hepatitis. Four DCH-positive samples were also tested for feline immunodeficiency virus (FIV) and feline leukemia virus (FeLV) co-infection, one (25%) was positive for FIV while none for FeLV (0%). In addition, we performed whole genome sequencing of six samples to determine the viral genome sequences. Phylogenetic analyses identified a distinct lineage compared with previously reported sequences. Considering the recent findings suggesting the potential risk of DCH for interspecies or zoonotic transmission, this study suggests the importance of continuous surveillance of DCH and further research to elucidate the pathophysiology and transmission route of DCH.
Temperature elevation synergises with and enhances the type-I IFN-mediated restriction of MPXV
Authors: Davis Chris , Epifano Ilaria , Dee Kieran , McFarlane Steven , Wojtus Joanna K. , Brennan Benjamin , Gu Quan , Sreenu Vattipally B. , Nomikou Kyriaki , Tong Lily , Orr Lauren , Filipe Ana Da Silva , Barr David A. , Ho Antonia , Thomson Emma C. , Boutell Chris 
Published: September 2023

AbstractFever is an evolutionary conserved host pro-inflammatory immune response that governs the regulation of multiple biological processes to control the outcome of infection. In January 2022, the World Health Organization (WHO) reported a global outbreak in mpox cases with a high incidence of human-to-human transmission. A frequent prodromal symptom of monkeypox virus (MPXV) infection is fever, with a febrile temperature range of 38.3 to 40.5 °C. However, the outcome of temperature elevation on MPXV infection remains poorly defined. Here, we isolated a circulating strain of MPXV from a patient who presented with fever (38.5 °C) and rash from the 2022 outbreak. Genomic sequencing identified this isolate to belong to the epidemic Clade IIb.B1. Transcriptomic analysis of infected cells demonstrated this virus to induce a strong IL6 pro-inflammatory immune response, consistent with a role for this pyrogen in the regulation of fever. We identify host-cell temperature at both physiological skin (33 °C) and clinical febrile temperatures (38.5 and 40 °C) to be a key determinant in the outcome of infection through the differential regulation of MPXV transcription and associated amplitude of host cytokine response to infection. Incubation of infected cells at 38.5 or 40 °C led to a restriction or ablation in MPXV replication, respectively. Importantly, this thermal inhibition was reversible upon temperature downshift to 37 °C without detriment to viral replication fitness. Co-stimulation of the type-I interferon (IFN) response led to a dose- and temperature-dependent inhibition in MPXV replication that restricted the re-establishment of infection upon temperature downshift and withdrawal of IFN as an immune stimulus. Our data identify febrile temperatures associated with mpox disease to be a critical component of the host pro-inflammatory immune response to infection which can synergise with the type-I IFN response to enhance the host-cell mediated restriction of MPXV.
Reversible conjugation of a CBASS nucleotide cyclase regulates immune response to phage infection
Authors: Krüger Larissa , Gaskell-Mew Laura , Graham Shirley , Shirran Sally , Hertel Robert , White Malcolm F 
Published: September 2023

AbstractAntiviral defence systems build the prokaryotic immune system and their proper regulation is vital for survival and fitness. While it is important that they are readily available in case of infection, they need to be tightly controlled to prevent activation of an unnecessary cellular response. Here we describe how the bacterial cyclic oligonucleotide-based antiphage signalling system (CBASS) uses its intrinsic protein modification system to regulate the nucleotide cyclase. By integrating a Type II CBASS system fromBacillus cereusinto the cognate hostBacillus subtilis, we show that the Cap2 protein conjugates the cyclase exclusively to the conserved phage shock protein A (PspA) in the absence of phage. This cyclase-PspA conjugation is reversed after infection by the isopeptidase Cap3. Finally, we propose a model in which the cyclase is held in an inactive state by conjugation to PspA in the absence of phage and that this conjugation is released upon infection, priming the cyclase for activation.
Discovery of First-in-Class PROTAC Degraders of SARS-CoV-2 Main Protease
Authors: Alugubelli Yugendar R. , Xiao Jing , Khatua Kaustav , Kumar Sathish , Ma Yuying , Ma Xinyu R. , Vulupala Veerabhadra R. , Atla Sandeep R. , Blankenship Lauren , Coleman Demonta , Neuman Benjamin W. , Liu Wenshe Ray , Xu Shiqing 
Published: September 2023

ABSTRACTWe have witnessed three coronavirus (CoV) outbreaks in the past two decades, including the COVID-19 pandemic caused by SARS-CoV-2. Main protease (MPro) is a highly conserved and essential protease that plays key roles in viral replication and pathogenesis among various CoVs, representing one of the most attractive drug targets for antiviral drug development. Traditional antiviral drug development strategies focus on the pursuit of high-affinity binding inhibitors against MPro. However, this approach often suffers from issues such as toxicity, drug resistance, and a lack of broad-spectrum efficacy. Targeted protein degradation represents a promising strategy for developing next-generation antiviral drugs to combat infectious diseases. Here we leverage the proteolysis targeting chimera (PROTAC) technology to develop a new class of small-molecule antivirals that induce the degradation of SARS-CoV-2 MPro. Our previously developed MProinhibitors MPI8 and MPI29 were used as MProligands to conjugate a CRBN E3 ligand, leading to compounds that can both inhibit and degrade SARS-CoV-2 MPro. Among them, MDP2 was demonstrated to effectively reduce MProprotein levels in 293T cells (DC50= 296 nM), relying on a time-dependent, CRBN-mediated, and proteasome-driven mechanism. Furthermore, MPD2 exhibited remarkable efficacy in diminishing MProprotein levels in SARS-CoV-2-infected A549-ACE2 cells, concurrently demonstrating potent anti-SARS-CoV-2 activity (EC50= 492 nM). This proof-of-concept study highlights the potential of PROTAC-mediated targeted protein degradation of MProas an innovative and promising approach for COVID-19 drug discovery.
Disease-specific selective vulnerability and neuroimmune pathways in dementia revealed by single cell genomics
Authors: Rexach Jessica E. , Cheng Yuyan , Chen Lawrence , Polioudakis Damon , Lin Li-Chun , Mitri Vivianne , Elkins Andrew , Yin Anna , Calini Daniela , Kawaguchi Riki , Ou Jing , Huang Jerry , Williams Christopher , Robinson John , Gaus Stephanie E. , Spina Salvatore , Lee Edward B. , Grinberg Lea T. , Vinters Harry , Trojanowski John Q. , Seeley William W. , Malhotra Dheeraj , Geschwind Daniel H. 
Published: September 2023

Summary/AbstractThe development of successful therapeutics for dementias requires an understanding of their shared and distinct molecular features in the human brain. We performed single-nuclear RNAseq and ATACseq in Alzheimer disease (AD), Frontotemporal degeneration (FTD), and Progressive Supranuclear Palsy (PSP), analyzing 40 participants, yielding over 1.4M cells from three brain regions ranging in vulnerability and pathological burden. We identify 35 shared disease-associated cell types and 14 that are disease-specific, replicating those previously identified in AD. Disease-specific cell states represent molecular features of disease-specific glial-immune mechanisms and neuronal vulnerability in each disorder, layer 4/5 intra-telencephalic neurons in AD, layer 2/3 intra-telencephalic neurons in FTD, and layer 5/6 near-projection neurons in PSP. We infer intrinsic disease-associated gene regulatory networks, which we empirically validate by chromatin footprinting. We find that causal genetic risk acts in specific neuronal and glial cells that differ across disorders, primarily non-neuronal cells in AD and specific neuronal subtypes in FTD and PSP. These data illustrate the heterogeneous spectrum of glial and neuronal composition and gene expression alterations in different dementias and identify new therapeutic targets by revealing shared and disease-specific cell states.
Parameter estimation of Wiener-Hammerstein system based on multi-population self-adaptive differential evolution algorithm
Authors: Chu Jie , Li Junhong , Jiang Yizhe , Song Weicheng , Zong Tiancheng 
Published: September 2023

PurposeThe Wiener-Hammerstein nonlinear system is made up of two dynamic linear subsystems in series with a static nonlinear subsystem, and it is widely used in electrical, mechanical, aerospace and other fields. This paper considers the parameter estimation of the Wiener-Hammerstein output error moving average (OEMA) system.Design/methodology/approachThe idea of multi-population and parameter self-adaptive identification is introduced, and a multi-population self-adaptive differential evolution (MPSADE) algorithm is proposed. In order to confirm the feasibility of the above method, the differential evolution (DE), the self-adaptive differential evolution (SADE), the MPSADE and the gradient iterative (GI) algorithms are derived to identify the Wiener-Hammerstein OEMA system, respectively.FindingsFrom the simulation results, the authors find that the estimation errors under the four algorithms stabilize after 120, 30, 20 and 300 iterations, respectively, and the estimation errors of the four algorithms converge to 5.0%, 3.6%, 2.7% and 7.3%, which show that all four algorithms can identify the Wiener-Hammerstein OEMA system.Originality/valueCompared with DE, SADE and GI algorithm, the MPSADE algorithm not only has higher parameter estimation accuracy but also has a faster convergence speed. Finally, the input–output relationship of laser welding system is described and identified by the MPSADE algorithm. The simulation results show that the MPSADE algorithm can effectively identify parameters of the laser welding system.
Key policy mechanisms supporting the University–Industry collaboration in the Danube region: case study of academic HPC centres and SMEs
Authors: Besednjak Valič Tamara , Kolar Janez , Lamut Urša , Pandiloska Jurak Alenka 
Published: September 2023

Purpose This paper aims to explore the key anchors of the National Innovation System shaping the nature of collaboration between academic high-performance computing centres (academic HPC centres) and small- to medium-sized enterprises (SMEs) working in the automotive and electronics sectors of the Danube region. With two main research questions, it discusses the importance of knowledge transfer and technology transfer for collaboration between University and Industry (U-I collaboration) in three groups of developmentally distinct countries: competitively advanced, competitively intermediate and competitively lagging. As main anchors of the innovation system, stable legal environment, exciting innovation policies and strong R&D funding are recognised.Design/methodology/approachA qualitative empirical study in 14 Danube region countries included 92 focus group participants, expert representatives of academic HPC centres and SMEs. The data were audio recorded, transcribed and analysed.FindingsThe findings show the main prerequisites of the framework conditions for efficient U-I collaboration evolve through a goal-oriented National Innovation Policy and developed and functioning legal environment supporting labour market and intellectual property (IP) protection and enforcement. Additionally, skilled people are needed to be able to operate with HPC, where it seems all the countries lack such skilled workforce. In competitively lagging countries, the high levels of brain drain exhibit strong impact to U-I collaboration.Research limitations/implicationsResearch into relationships between academic HPC centres and SMEs conducted was qualitative; therefore, limitations in terms of generalisation arise from it. On the other hand, the research is promising in terms of offering the guidance for policy makers who can use the findings when delivering innovation policy mix, adjusted to developmental level of own innovation ecosystem.Originality/value The study is among the pioneering work in U-I collaboration between academic HPC centres and SMEs from automotive and electronics industries in the Danube region. The research addresses the dynamics of collaboration and offers policy implications to strengthen the particular U-I collaboration.
Moderating effect of Nigerian government policy support on the relationship between project management framework and emerging construction contractors' sustainability
Authors: Ebekozien Andrew , Aigbavboa Clinton , Samsurijan Mohamad Shaharudin , Amadi Godspower C. , Duru Okechukwu Dominic Saviour 
Published: September 2023

PurposeIn most developing countries, indigenous emerging construction contractors (ECCs) face severe problems of not adopting a project management framework (PMF) in their business activities. It has increased their business risk and threatened their sustainability. Studies showed that government policy support (GPS) helps mitigate business risks. Thus, there is a paucity of literature concerning GPS on emerging Nigerian construction contractors' business sustainability. Therefore, the paper aims to investigate the moderating effect of GPS on the relationship between PMF and ECCs in Nigeria.Design/methodology/approachSmartPLS was used to analyse the collected data from the useable 310 questionnaires retrieved from respondents in Abuja and Lagos, Nigeria. Systems Theory was used to support the developed framework.FindingsFindings show that government policy support significantly moderates the relationships between PMF and ECCs in the Nigerian construction sector. It implies that the study's results offer more understanding regarding issues affecting construction entrepreneurs' sustainable business cycle via applying PMF to mitigate business sustainable associated risks.Practical implicationsThe study will stir Nigeria's ECCs and policymakers to promote construction business sustainability for a new entrepreneur, emphasising business risk management via PMF and GPS to enhance the sustainable business cycle.Originality/valueThe research (PMF and GPS) is strategies to enhance ECCs business sustainability in the Nigerian construction sector and other developing countries with similar political and economic attributes. Besides the study guiding old and intending ECCs and policymakers in the developing countries industries, it would contribute to bridge the theoretical gap regarding PMF and ECC, especially ECCs in developing countries with similar business sustainability issues.
Job embeddedness and turnover intention in the public sector: the role of life satisfaction and ethical leadership
Authors: Nguyen Tuan Duong , Nguyen Thuy Thi , Nguyen Phuong Cam 
Published: September 2023

PurposeThis study aimed to investigate the impact of job embeddedness (JE) on the turnover intention (TI) of the public sector with the mediating effect of the individual factor (i.e. life satisfaction [LS]) and the moderating effect of the leadership style (i.e. ethical leadership [EL]).Design/methodology/approachThis study adopted a quantitative design to collect data from 236 employees working in the public sector in Vietnam through field research using structured questionnaires. Data were analysed using partial least squares structural equation modelling (PLS-SEM) to test the hypotheses.FindingsThe results show that JE negatively affects the TI of public sector employees through the mediation effect of LS. Additionally, this study indicates that EL moderates the relationship between JE and TI.Practical implicationsThis study implies that public sector stakeholders should consider both individual and contextual factors to manage and retain employees. In addition to addressing employees' embeddedness with the organisation and community and their LS, public organisations need to focus on hiring, training and promoting ethical leaders.Originality/valueThis study highlights the role of embeddedness within both the organisation and the community, along with the role of EL in the LS and TI of public sector employees.