bluuebunny/crossref_metadata_2025_split huggingface dataset:
Activation of Autoreactive Lymphocytes in the Lung by STING Gain-of-function Mutation Radioresistant Cells
Authors: Gao Kevin MingJie , Nündel Kerstin , Chiang Kristy , Yin Xihui , Utz Paul J. , Fitzgerald Kate , Marshak-Rothstein Ann 
Published: July 2023

AbstractGain-of-function mutations in the dsDNA sensing adaptor STING lead to a severe autoinflammatory syndrome known as STING-associated vasculopathy with onset in Infancy (SAVI). SAVI patients develop interstitial lung disease (ILD) and commonly produce anti-nuclear antibodies (ANAs), indicative of concomitant autoimmunity. Mice heterozygous for the most common SAVI mutation, V154M (VM), also develop ILD, triggered by nonhematopoietic VM cells, but exhibit severe peripheral lymphopenia, low serum Ig titers and fail to produce autoantibodies. In contrast, we now show that lethally irradiated VM mice reconstituted with WT stem cells (WT→VM chimeras) develop ANAs and lung-reactive autoantibodies associated with accumulation of activated lymphocytes and formation of germinal centers in lung tissues. Moreover, when splenocytes from WT→VM chimeras were adoptively transferred into unmanipulated Rag1-/-mice, donor T cells accumulated in the lung. Overall, these findings demonstrate that expression of the VM mutation in non-hematopoietic cells can promote the activation of immunocompetent autoreactive lymphocytes.SummaryChimeric mice expressing STING only in non-hematopoietic cells develop systemic and lung directed autoimmunity which recapitulates what is seen in pediatric patients with SAVI disease.
Targeted protein modification with an antibody-based system
Authors: Rimon Oded , Konc Juraj , Ali Montader , Roy Chowdhury Vaidehi , Černauskienė Inga , Sormanni Pietro , Bernardes Gonçalo J. L. , Vendruscolo Michele 
Published: July 2023

AbstractThe chemical modification of proteins is one of the major mechanisms used to regulate the properties and functions of these macromolecules in the cell. It is therefore of great interest to develop tools to exploit this type of modifications for applications in molecular biology, medicine and biotechnology. Here we present a method of using antibodies to perform post-translational covalent modifications of endogenous proteins in complex environments by exploiting proximity-driven chemistry. The method is based on the ability of antibodies to hold a weakly reactive group close to its intended site of reaction by binding the target protein on a nearby epitope. We characterise this approach by modifying the green fluorescent protein in increasingly complex environments, and illustrate its applicability by targeting the disease-associated protein beta-2 microglobulin.
A CRISPR screen of HIV dependency factors revealsCCNT1is non-essential in T cells but required for HIV-1 reactivation from latency
Authors: Hafer Terry L , Felton Abby , Delgado Yennifer , Srinivasan Harini , Emerman Michael 
Published: July 2023

AbstractWe sought to explore the hypothesis that host factors required for HIV-1 replication also play a role in latency reversal. Using a CRISPR gene library of putative HIV dependency factors, we performed a screen to identify genes required for latency reactivation. We identified several HIV-1 dependency factors that play a key role in HIV-1 latency reactivation includingELL,UBE2M,TBL1XR1,HDAC3,AMBRA1, andALYREF. Knockout of Cyclin T1 (CCNT1), a component of the P-TEFb complex important for transcription elongation, was the top hit in the screen and had the largest effect on HIV latency reversal with a wide variety of latency reversal agents. Moreover,CCNT1knockout prevents latency reactivation in a primary CD4+ T cell model of HIV latency without affecting activation of these cells. RNA sequencing data showed that CCNT1 regulates HIV-1 proviral genes to a larger extent than any other host gene and had no significant effects on RNA transcripts in primary T cells after activation. We conclude that CCNT1 function is redundant in T cells but is absolutely required for HIV latency reversal.
Deep mutational scanning and machine learning uncover antimicrobial peptide features driving membrane selectivity
Authors: Randall Justin R. , Vieira Luiz C. , Wilke Claus O. , Davies Bryan W. 
Published: July 2023

AbstractAntimicrobial peptides commonly act by disrupting bacterial membranes, but also frequently damage mammalian membranes. Deciphering the rules governing membrane selectivity is critical to understanding their function and enabling their therapeutic use. Past attempts to decipher these rules have failed because they cannot interrogate adequate peptide sequence variation. To overcome this problem, we develop deep mutational surface localized antimicrobial display (dmSLAY), which reveals comprehensive positional residue importance and flexibility across an antimicrobial peptide sequence. We apply dmSLAY to Protegrin-1, a potent yet toxic antimicrobial peptide, and identify thousands of sequence variants that positively or negatively influence its antibacterial activity. Further analysis reveals that avoiding large aromatic residues and eliminating disulfide bound cysteine pairs while maintaining membrane bound secondary structure greatly improves Protegrin-1 bacterial specificity. Moreover, dmSLAY datasets enable machine learning to expand our analysis to include over 5.7 million sequence variants and reveal full Protegrin-1 mutational profiles driving either bacterial or mammalian membrane specificity. Our results describe an innovative, high-throughput approach for elucidating antimicrobial peptide sequence-structure-function relationships which can inform synthetic peptide-based drug design.
Characterization of covalent inhibitors that disrupt the interaction between the tandem SH2 domains of SYK and FCER1G phospho-ITAM
Authors: Bashore Frances M. , Katis Vittorio L. , Du Yuhong , Sikdar Arunima , Wang Dongxue , Bradshaw William J. , Rygiel Karolina A. , Leisner Tina M. , Chalk Rod , Mishra Swati , Williams Andrew C. , Gileadi Opher , Brennan Paul E. , Wiley Jesse C. , Gockley Jake , Cary Gregory A. , Carter Gregory W. , Young Jessica E. , Pearce Kenneth H. , Fu Haian ,   the Emory-Sage-SGC TREAT-AD Center, Axtman Alison D. 
Published: July 2023

AbstractRNA sequencing and genetic data support spleen tyrosine kinase (SYK) and high affinity immunoglobulin epsilon receptor subunit gamma (FCER1G) as putative targets to be modulated for Alzheimer’s disease (AD) therapy. FCER1G is a component of Fc receptor complexes that contain an immunoreceptor tyrosine-based activation motif (ITAM). SYK interacts with the Fc receptor by binding to doubly phosphorylated ITAM (p-ITAM) via its two tandem SH2 domains (SYK-tSH2). Interaction of the FCER1G p-ITAM with SYK-tSH2 enables SYK activation via phosphorylation. Since SYK activation is reported to exacerbate AD pathology, we hypothesized that disruption of this interaction would be beneficial for AD patients. Herein, we developed biochemical and biophysical assays to enable the discovery of small molecules that perturb the interaction between the FCER1G p-ITAM and SYK-tSH2. We identified two distinct chemotypes using a high-throughput screen (HTS) and orthogonally assessed their binding. Both chemotypes covalently modify SYK-tSH2 and inhibit its interaction with FCER1G p-ITAM.
An inhibitor/anti-inhibitor system controls the activity of lytic transglycosylase MltF inPseudomonas aeruginosa
Authors: Wang Michelle , Ma Sheya Xiao , Darwin Andrew J. 
Published: July 2023

ABSTRACTMost bacterial cell envelopes contain a cell wall layer made of peptidoglycan. The synthesis of new peptidoglycan is critical for cell growth, division and morphogenesis, and is also coordinated with peptidoglycan hydrolysis to accommodate the new material. However, the enzymes that cleave peptidoglycan must be carefully controlled to avoid autolysis. In recent years, some control mechanisms have begun to emerge, although there are many more questions than answers for how most cell wall hydrolases are regulated. Here, we report a novel cell wall hydrolase control mechanism inPseudomonas aeruginosa, which we discovered during our characterization of a mutant sensitive to the overproduction of a secretin protein. The mutation affected an uncharacterized Sel1-like repeat protein encoded by the PA3978 locus. In addition to the secretin-sensitivity phenotype, PA3978 disruption also increased resistance to a β-lactam antibiotic used in the clinic.In vivoandin vitroanalysis revealed that PA3978 binds to the catalytic domain of the lytic transglycosylase MltF and inhibits its activity. ΔPA3978 mutant phenotypes were suppressed by deletingmltF, consistent with them having been caused by elevated MltF activity. We also discovered another interaction partner of PA3978 encoded by the PA5502 locus. The phenotypes of a ΔPA5502 mutant suggested that PA5502 interferes with the inhibitory function of PA3978 towards MltF, and we confirmed that activity for PA5502in vitro. Therefore, PA3978 and PA5502 form an inhibitor/anti-inhibitor system that controls MltF activity. We propose to name these proteins Ilt (inhibitor of lytic transglycosylase) and Lii (lytic transglycosylase inhibitor, inhibitor).IMPORTANCEA peptidoglycan cell wall is an essential component of almost all bacterial cell envelopes, which determines cell shape and prevents osmotic rupture. Antibiotics that interfere with peptidoglycan synthesis have been one of the most important treatments for bacterial infections. Peptidoglycan must also be hydrolyzed to incorporate new material for cell growth and division, and to help accommodate important envelope-spanning systems. However, the enzymes that hydrolyze peptidoglycan must be carefully controlled to prevent autolysis. Exactly how this control is achieved is poorly understood in most cases, but is a highly active area of current research. Identifying hydrolase control mechanisms has the potential to provide new targets for therapeutic intervention. The work here reports the important discovery of a novel inhibitor/anti-nhibitor system that controls the activity of a cell wall hydrolase in the human pathogenPseudomonas aeruginosa, and which also affects resistance to an antibiotic used in the clinic.
Intrinsic neural timescales attenuate information transfer along the uni-transmodal hierarchy
Authors: Çatal Yasir , Wolman Angelika , Abbasi Samira , Northoff Georg 
Published: July 2023

AbstractThe brain’s intrinsic timescales are organized in a hierarchy with shorter timescales in sensory regions and longer ones in associative regions. This timescale hierarchy overlaps with the timing demands of sensory information. Our question was how does this timescale hierarchy affect information transfer. We used a model of the timescale hierarchy based on connected excitatory and inhibitory populations across the cortex. We found that a hierarchy of information transfer follows the hierarchy of timescales with higher information transfer in sensory areas while it is lower in associative regions. Probing the effect of changes in timescale hierarchy on information transfer, we changed various model parameters which all, through, the loss of hierarchy, induced increased information transfer. Finally, the steepness of the timescale hierarchy relates negatively to total information transfer. Human MEG data confirmed our results. In sum, we demonstrate a key role of the brain’s timescale hierarchy in mediating information transfer.
Network Statistics of the Whole-Brain Connectome ofDrosophila
Authors: Lin Albert , Yang Runzhe , Dorkenwald Sven , Matsliah Arie , Sterling Amy R. , Schlegel Philipp , Yu Szi-chieh , McKellar Claire E. , Costa Marta , Eichler Katharina , Bates Alexander Shakeel , Eckstein Nils , Funke Jan , Jefferis Gregory S.X.E. , Murthy Mala 
Published: July 2023

AbstractBrains comprise complex networks of neurons and connections. Network analysis applied to the wiring diagrams of brains can offer insights into how brains support computations and regulate information flow. The completion of the first whole-brain connectome of an adultDrosophila, the largest connectome to date, containing 130,000 neurons and millions of connections, offers an unprecedented opportunity to analyze its network properties and topological features. To gain insights into local connectivity, we computed the prevalence of two- and three-node network motifs, examined their strengths and neurotransmitter compositions, and compared these topological metrics with wiring diagrams of other animals. We discovered that the network of the fly brain displays rich club organization, with a large population (30% percent of the connectome) of highly connected neurons. We identified subsets of rich club neurons that may serve as integrators or broadcasters of signals. Finally, we examined subnetworks based on 78 anatomically defined brain regions or neuropils. These data products are shared within the FlyWire Codex and will serve as a foundation for models and experiments exploring the relationship between neural activity and anatomical structure.
How spokespeople help or hurt business through crisis messaging: experiments testing the roles of narratives, non-narratives and counterargument
Authors: Clementson David , Page Tyler 
Published: July 2023

PurposeWhen an audience mentally counterargues a spokesperson, the message is backfiring. In such cases, audience members are practically persuading themselves to take the opposite position advocated by the spokesperson. Yet spokespeople who are professional persuaders serving corporations often seem to instill counterargument. This paper examines the role of counterargument as the conduit through which a spokesperson's different message types affect a company during a crisis. The authors explore the paradox of spokespeople's (in)effectiveness by testing divides in research drawn from normative crisis communication theory, narrative persuasion theory and the theory of reporting bias.Design/methodology/approachTwo controlled, randomized experiments are reported. Participants (total N = 828) watch video clips of media interviews of a company spokesperson fielding questions about a scandal.FindingsIn the first study, non-narrative information most effectively bolsters purchase intentions and reduces negative word-of-mouth. The effect is mediated by decreased counterargument. The second study replicates the results concerning on-topic narratives compared with spinning, while on-topic narratives and non-narratives perform equally well.Originality/valueThis study addresses conflicts between two distinct traditions of theory as well as between normative crisis communication and its frequent practice. Reducing counterargument matters in the context of non-narrative persuasion, and non-narratives can perform at least as well as narratives in crisis communication.
Making sense of health in PE: conceptions of health among Swedish physical education teachers
Authors: Korp Peter , Quennerstedt Mikael , Barker Dean , Johansson Anna 
Published: July 2023

PurposeOver the last couple of decades, health has become a central part of the subject content in physical education (PE) curricula in many countries. As a result, issues of health have been foregrounded much more clearly in the teaching of PE. The aim of this study was to explore how Swedish PE teachers make sense of health in relation to their teaching practices. This was done through investigating conceptions and theories about health in the teachers' descriptions of their teaching practices.Design/methodology/approachThe data analyzed in this paper were collected through focus group and individual interviews with PE teachers in the grades 7–9 within compulsory schools in Sweden. The data were analyzed using thematic analysis.FindingsFour dominant themes were identified in the data: 1) Health as a healthy attitude, 2) Health as a functional ability, 3) Health as fitness, 4) Health as mental wellbeing. There is a clear impact from healthism and obesity discourses on the teachers' accounts of health, but there is also an impact from holistic views and approaches to health. The authors contend that teachers should be explicit in what they mean by health in relation to what they teach, how they teach and why they teach health in a certain way.Originality/valueThe knowledge produced by this study is crucial since teachers' assumptions regarding health affect the subject content (what), the pedagogies (how), as well as the reasons (why) they teach health and therefore what students learn regarding health.
Impact of workplace incivility and emotional exhaustion on job outcomes – a study of the higher education sector
Authors: Parray Zahoor Ahmad , Islam Shahbaz ul , Shah Tanveer Ahmad 
Published: July 2023

PurposeThe main goal of this research study is to look at the mediating effect of emotional exhaustion in the association between workplace incivility and job outcomes (job stress, job satisfaction and employee turnover intentions) in the higher education sector.Design/methodology/approachThe authors gathered field data from individuals working in the Higher Education Sector of Jammu and Kashmir to test the proposed study paradigm. A total of 550 respondents reported their perceptions of workplace incivility, emotional exhaustion and job-related outcomes (job stress, job satisfaction and employee turnover intention) at Time 1 in the Kashmir division and Time 2 in the Jammu division of Jammu and Kashmir via a two-wave data collection design.FindingsThe findings supported the hypothesized relationships, demonstrating that emotional exhaustion acts as a mediator between workplace incivility and employee job outcomes (job stress, employee job satisfaction and employee intention to leave).Research limitations/implicationsThe research was undertaken in Jammu and Kashmir's higher education sectors. As a result, the findings may not apply to other sectors because workplace incivility may be regarded differently in different sectors.Practical implicationsThe findings of this research study will assist organizations and practitioners in comprehending the significance of workplace incivility and emotional exhaustion, as well as how they positively impact job-related outcomes (employee job stress, turnover intention) and negatively on job satisfaction.Originality/valueThis research study added to the existing Self-Determination Theory model developed by Deci and associates (2017) by incorporating Emotional Exhaustion, and workplace incivility as autonomous intrinsic and workplace context factors respectively into the SDT model to study work behaviors in terms of job outcomes. This study adds to existing knowledge on SDTs by suggesting and testing emotional exhaustion as a mechanism for determining the impact of workplace incivility on employee job outcomes.Contribution to impact
Operations of cost-effective charities: a qualitative study
Authors: Shevchenko Anton , Hajmohammad Sara , Pagell Mark 
Published: July 2023

PurposePeople donate to charities with the aim of improving society. Yet, many charities fail to use donations efficiently or have ineffective interventions. The authors explore the strategic operational priorities and processes that enable charities to efficiently implement their interventions and have a positive impact on society.Design/methodology/approachThe authors first review the literature on charities to gain a deeper understanding of the current state of knowledge on charity operations. The authors then employ the lens of paradox theory and perform a qualitative investigation of six case studies to explore various aspects of the operations of charities that are known for being cost-effective.FindingsThe authors reveal how the strategic operational decisions of charities, as well as the processes they implement, help them resolve the tensions arising from the cost-effectiveness paradox. The authors show that cost-effective charities make strategic operational decisions that help maintain two diverging priorities: prioritizing the status quo and prioritizing change in how they deliver value. Another set of strategic decisions helps balance these two diverging priorities. The authors then show how these charities create and then maintain cost-effective operations.Originality/valueThe authors address recent calls for research on non-profit organizations in the field of operations management. To authors’ knowledge, it is the first in-depth study of exemplary charity operations. The results can be used by charity executives as a benchmarking tool when they develop and implement their charitable interventions and by government agencies and potential donors when they select charities for their donations. Finally, the results should have implications for other organizations trying to have a positive societal impact.
The failure of online endorsement systems in investment communities: evidence from Yahoo! Finance
Authors: Xie Peng , Du Hongwei , Wu Jiming , Chen Ting 
Published: July 2023

PurposeIn prior literature, online endorsement system allowing the users to “like” or “dislike” shared information is found very useful in information filtering and trust elicitation in most social networks. This paper shows that such systems could fail in the context of investment communities due to several psychological biases.Design/methodology/approachThis study develops a series of regression analyses to model the “like”/“dislike” voting process and whether or not such endorsement distinguishes between valuable information and noise. Trading simulations are also used to validate the practical implications of the findings.FindingsThe main findings of this research are twofold: (1) in the context of investment communities, online endorsement system fails to signify value-relevant information and (2) bullish information and “wisdom over the past event” information receive more “likes” and fewer “dislikes” on average, but they underperform in stock market price discovery.Originality/valueThis study demonstrates that biased endorsement may lead to the failure of the online endorsement system as information gatekeeper in investment communities. Two underlying mechanisms are proposed and tested. This study opens up new research opportunities to investigate the causes of biased endorsement in online environment and motivates the development of alternative information filtering systems.