bluuebunny/crossref_metadata_2025 huggingface dataset:
Enhanced Airway Epithelial Response to SARS-CoV-2 Infection in Children is Critically Tuned by the Cross-Talk Between Immune and Epithelial Cells
Authors: Magalhães Vladimir G. , Lukassen Sören , Drechsler Maike , Loske Jennifer , Burkart Sandy S. , Wüst Sandra , Jacobsen Eva-Maria , Röhmel Jobst , Mall Marcus A. , Debatin Klaus-Michael , Eils Roland , Autenrieth Stella , Janda Aleš , Lehmann Irina , Binder Marco
Published: May 2023

To cope with novel virus infections to which no prior adaptive immunity exists, the body strongly relies on the innate immune system. In such cases, including infections with SARS-CoV-2, children tend to fair better than adults. In the context of COVID-19, it became evident that a rapid interferon response at the site of primary infection is key for successful control of the virus and prevention of severe disease. The airway epithelium of children was shown to exhibit a primed state already at homeostasis and to respond particularly well to SARS-CoV-2 infection. However, the underlying mechanism for this priming remained elusive. Here we show that interactions between airway mucosal immune cells and epithelial cells are stronger in children, and via cytokine-mediated signaling lead to IRF-1-dependent upregulation of the viral sensors RIG-I and MDA5. Based on a cellularin vitromodel we show that stimulated human peripheral blood mononuclear cells (PBMC) can induce a robust interferon-beta response towards SARS-CoV-2 in a lung epithelial cell line otherwise unresponsive to this virus. This is mediated by type I interferon, interferon-gamma and TNF, and requires induction of both, RIG-I and MDA5. In single cell-analysis of nasal swab samples the same cytokines are found to be elevated in mucosal immune cells of children, correlating with elevated epithelial expression of viral sensors.In vitroanalysis of PBMC derived from healthy adolescents and adults confirm that immune cells of younger individuals show increased cytokine production and potential to prime epithelial cells. In co-culture with SARS-CoV-2-infected A549 cells, PBMC from adolescents significantly enhance the antiviral response. Taken together, our study suggests that higher numbers and a more vigorous activity of innate immune cells in the airway mucosa of children tune the set-point of the epithelial antiviral system. This likely is a major contributor to the robust immune response to SARS-CoV-2 in children. Our findings shed light on the molecular underpinnings of the stunning resilience of children towards severe COVID-19, and may propose a novel concept for immunoprophylactic treatments.
Carrion converging: Skull shape is predicted by feeding ecology in vultures
Authors: Steinfield Katherine R , Felice Ryan N , Kirchner Mackenzie E , Knapp Andrew
Published: May 2023

The link between skull shape and dietary ecology in birds at macroevolutionary scales has recently been called into question by analyses of 3D shape that reveal that cranial anatomy is mainly influenced by other factors such as allometry. It is still unknown whether this form-function disconnect also exists at smaller evolutionary scales, for example within specialized ecological guilds. Vultures are a diverse guild of 23 extant species in two families (Accipitridae and Cathartidae) that exhibit phenotypic convergence as a result of highly-specialized feeding ecology. Vultures are the only known obligate scavengers among vertebrates and are usually grouped together under this single dietary category, but within this specialized diet there are three distinct, species-specific feeding strategies termed ripper, gulper, and scrapper. We use three-dimensional geometric morphometrics to quantify the relative contributions of feeding ecology, allometry, and phylogeny on vulture skull shape, along with several non-vulture raptors of similar size, range and ecology. Families show clear separation in shape, but phylogenetic signal is comparatively weak (Kmult= 0.33). Taking into account the influence of phylogeny, skull shape is not significantly correlated with either skull size or feeding type, but there are examples of strong, significant convergence and parallel shape evolution across feeding groups. Furthermore, skull shape performs strongly in predicting feeding ecology in a phylogenetic discriminant function analysis. These findings highlight the importance of detailed assessment of feeding behavior in studies of ecomorphology, rather than broader dietary categories alone, and reveal that ecology can be readily inferred from form given appropriate information.
Structure and function of the SIT1 proline transporter in complex with the COVID-19 receptor ACE2
Authors: Li Huanyu Z. , Pike Ashley C.W. , Chi Gamma , Hansen Jesper S. , Lee Sarah G. , Rödström Karin E.J. , Bushell Simon R. , Speedman David , Evans Adam , Wang Dong , He Didi , Shrestha Leela , Nasrallah Chady , Burgess-Brown Nicola A. , Dafforn Timothy R. , Carpenter Elisabeth P. , Sauer David B.
Published: May 2023

Proline is widely known as the only proteogenic amino acid with a secondary amine. In addition to its crucial role in protein structure, the secondary amino acid modulates neurotransmission and regulates the kinetics of signaling proteins. To understand the structural basis of proline import, we solved the structure of the proline transporter SIT1 in complex with the COVID-19 viral receptor ACE2 by cryo-electron microscopy. The structure of pipecolate-bound SIT1 reveals the specific sequence requirements for proline transport in the SLC6 family and how this protein excludes amino acids with extended side chains. By comparing apo and substrate-bound SIT1 states, we also identify the structural changes which link substrate release and opening of the cytoplasmic gate, and provide an explanation for how a missense mutation in the transporter causes iminoglycinuria.
Cytomegalovirus-induced inactivation of TSC2 disrupts the coupling of fatty acid biosynthesis to glucose availability resulting in a vulnerability to glucose limitation
Authors: Raymonda Matthew H. , Rodríguez-Sánchez Irene , Schafer Xenia L. , Smorodintsev-Schiller Leonid , Harris Isaac S. , Munger Joshua
Published: May 2023

Human cytomegalovirus (HCMV) modulates cellular metabolism to support productive infection, and the HCMV UL38 protein drives many aspects of this HCMV-induced metabolic program. However, it remains to be determined whether virally-induced metabolic alterations might induce novel therapeutic vulnerabilities in virally infected cells. Here, we explore how HCMV infection and the UL38 protein modulate cellular metabolism and how these changes alter the response to nutrient limitation. We find that expression of UL38, either in the context of HCMV infection or in isolation, sensitizes cells to glucose limitation resulting in cell death. This sensitivity is mediated through UL38’s inactivation of the TSC complex subunit 2 (TSC2) protein, a central metabolic regulator that possesses tumor-suppressive properties. Further, expression of UL38 or the inactivation of TSC2 results in anabolic rigidity in that the resulting increased levels of fatty acid biosynthesis are insensitive to glucose limitation. This failure to regulate fatty acid biosynthesis in response to glucose availability sensitizes cells to glucose limitation, resulting in cell death unless fatty acid biosynthesis is inhibited. These experiments identify a regulatory circuit between glycolysis and fatty acid biosynthesis that is critical for cell survival upon glucose limitation and highlight a metabolic vulnerability associated with viral infection and the inactivation of normal metabolic regulatory controls.

Importance

Viruses modulate host cell metabolism to support the mass production of viral progeny. For Human Cytomegalovirus, we find that the viral UL38 protein is critical for driving these pro-viral metabolic changes. However, our results indicate that these changes come at a cost, as UL38 induces an anabolic rigidity that leads to a metabolic vulnerability. We find that UL38 decouples the link between glucose availability and fatty acid biosynthetic activity. Normal cells respond to glucose limitation by down-regulating fatty acid biosynthesis. Expression of UL38 results in the inability to modulate fatty acid biosynthesis in response to glucose limitation, which results in cell death. We find this vulnerability in the context of viral infection, but this linkage between fatty acid biosynthesis, glucose availability, and cell death could have broader implications in other contexts or pathologies that rely on glycolytic remodeling, for example, oncogenesis.
A Novel Pan-RAS Inhibitor with a Unique Mechanism of Action Blocks Tumor Growth in Mouse Models of GI Cancer
Authors: Foote Jeremy B. , Mattox Tyler E. , Keeton Adam B. , Chen Xi , Smith Forrest , Berry Kristy L. , Holmes Thomas , Wang Junwei , Huang Chung-Hui , Ward Antonio B. , Mitra Amit K. , Ramirez-Alcantara Veronica , Hardy Cherlene , Fleten Karrianne G. , Flatmark Kjersti , Yoon Karina J. , Sarvesh Sujith , Nagaraju Ganji Purnachandra , Bandi Dhana Sekhar Reddy , Maxuitenko Yulia Y. , Valiyaveettil Jacob , Carstens Julienne L. , Buchsbaum Donald J. , Yang Jennifer , Zhou Gang , Nurmemmedov Elmar , Babic Ivan , Gaponenko Vadim , Abdelkarim Hazem , Boyd Michael R. , Gorman Gregory S. , Manne Upender , Bae Sejong , El-Rayes Bassel F. , Piazza Gary A.
Published: May 2023

Here, we describe a novel pan-RAS inhibitor, ADT-007, that potently inhibited the growth of RAS mutant cancer cells irrespective of the RAS mutation or isozyme. RASWTcancer cells with GTP-activated RAS from upstream mutations were equally sensitive. Conversely, RASWTcancer cells harboring downstream BRAF mutations and normal cells were essentially insensitive to ADT-007. Sensitivity of cancer cells to ADT-007 required activated RAS and dependence on RAS for proliferation, while insensitivity was attributed to metabolic deactivation by UDP-glucuronosyltransferases expressed in RASWTand normal cells but repressed in RAS mutant cancer cells. ADT-007 binds nucleotide-free RAS to block GTP activation of effector interactions and MAPK/AKT signaling, resulting in mitotic arrest and apoptosis. ADT-007 displayed unique advantages over mutant-specific KRAS and pan-KRAS inhibitors, as well as other pan-RAS inhibitors that could impactin vivoantitumor efficacy by escaping compensatory mechanisms leading to resistance. Local administration of ADT-007 showed robust antitumor activity in syngeneic immune-competent and xenogeneic immune-deficient mouse models of colorectal and pancreatic cancer. The antitumor activity of ADT-007 was associated with the suppression of MAPK signaling and activation of innate and adaptive immunity in the tumor immune microenvironment. Oral administration of ADT-007 prodrug also inhibited tumor growth, supporting further development of this novel class of pan-RAS inhibitors for RAS-driven cancers.

SIGNIFICANCE

ADT-007 has unique pharmacological properties with distinct advantages over other RAS inhibitors by circumventing resistance and activating antitumor immunity. ADT-007 prodrugs and analogs with oral bioavailability warrant further development for RAS-driven cancers.
Studying stochastic systems biology of the cell with single-cell genomics data
Authors: Gorin Gennady , Vastola John J. , Pachter Lior
Published: May 2023

Recent experimental developments in genome-wide RNA quantification hold considerable promise for systems biology. However, rigorously probing the biology of living cells requires a unified mathematical framework that accounts for single-molecule biological stochasticity in the context of technical variation associated with genomics assays. We review models for a variety of RNA transcription processes, as well as the encapsulation and library construction steps of microfluidics-based single-cell RNA sequencing, and present a framework to integrate these phenomena by the manipulation of generating functions. Finally, we use simulated scenarios and biological data to illustrate the implications and applications of the approach.
Abcg2a is the functional homolog of human ABCG2 expressed at the zebrafish blood-brain barrier
Authors: Thomas Joanna R. , Frye William J. E. , Robey Robert W. , Warner Andrew C. , Butcher Donna , Matta Jennifer L. , Morgan Tamara C. , Edmondson Elijah F. , Salazar Paula B. , Ambudkar Suresh V. , Gottesman Michael M.
Published: May 2023

Background

A principal protective component of the mammalian blood-brain barrier (BBB) is the high expression of the multidrug efflux transporters P-glycoprotein (P-gp, encoded byABCB1) and ABCG2 (encoded byABCG2) on the lumenal surface of endothelial cells. The zebrafish P-gp homolog Abcb4 is expressed at the BBB and phenocopies human P-gp. Comparatively little is known about the four zebrafish homologs of the humanABCG2gene:abcg2a,abcg2b,abcg2c, andabcg2d. Here we report the functional characterization and brain tissue distribution of zebrafish ABCG2 homologs.

Methods

To determine substrates of the transporters, we stably expressed each in HEK-293 cells and performed cytotoxicity and fluorescent efflux assays with known ABCG2 substrates. To assess the expression of transporter homologs, we used a combination of RNAscopein situhybridization probes and immunohistochemistry to stain paraffin-embedded sections of adult and larval zebrafish.

Results

We found Abcg2a had the greatest substrate overlap with ABCG2, and Abcg2d appeared to be the least functionally similar. We identifiedabcg2aas the only homolog expressed at the adult and larval zebrafish BBB, based on its localization to claudin-5 positive brain vasculature.

Conclusions

These results demonstrate the conserved function of zebrafish Abcg2a and suggest that zebrafish may be an appropriate model organism for the studying the role of ABCG2 at the BBB.
Human Herpesvirus 8 ORF57 protein is able to reduce TDP-43 pathology: Network analysis Identifies Interacting Pathways
Authors: Webber Chelsea J , Murphy Caroline N. , Rondón-Ortiz Alejandro N. , van der Spek Sophie J.F. , Kelly Elena X. , Lampl Noah M. , Chiesa Giulio , Khalil Ahmad S. , Emili Andrew , Wolozin Benjamin
Published: May 2023

Aggregation of TAR DNA-binding protein 43kDa (TDP-43) is thought to drive the pathophysiology of ALS and some Frontotemporal dementias. TDP-43 is normally a nuclear protein that in neurons translocates to the cytoplasm and forms insoluble aggregates upon activation of the integrated stress response (ISR). Viruses evolved to control the ISR. In the case of Herpesvirus 8, the protein ORF57 acts to bind protein kinase R, inhibit phosphorylation of eIF2α and reduce activation of the ISR. We hypothesized that ORF57 might also possess the ability to inhibit aggregation of TDP-43. ORF57 was expressed in the neuronal SH-SY5Y line and its effects on TDP-43 aggregation characterized. We report that ORF57 inhibits TDP-43 aggregation by 55% and elicits a 2.45-fold increase in the rate of dispersion of existing TDP-43 granules. These changes were associated with a 50% decrease in cell death. Proteomic studies were carried out to identify the protein interaction network of ORF57. We observed that ORF57 directly binds to TDP-43 as well as interacts with many components of the ISR, including elements of the proteostasis machinery known to reduce TDP-43 aggregation. We propose that viral proteins designed to inhibit a chronic ISR can be engineered to remove aggregated proteins and dampen a chronic ISR.
Sequencing, fast and slow: profiling microbiomes in human samples with nanopore sequencing
Authors: Park Yunseol , Lee Jeesu , Shim Hyunjin
Published: May 2023

Rapid and accurate pathogen identification is crucial in effectively combating infectious diseases. However, the current diagnostic tools for bacterial infections predominantly rely on century-old culture-based methods. Furthermore, recent research highlights the significance of host-microbe interactions within the host microbiota in influencing the outcome of infection episodes. As our understanding of science and medicine continues to advance, there is a pressing need for innovative diagnostic methods that can identify pathogens and also rapidly and accurately profile the microbiome landscape in human samples. In clinical settings, such diagnostic tools will become a powerful predictive instrument in directing the diagnosis and prognosis of infectious diseases by providing comprehensive insights into the patient’s microbiota. Here, we explore the potential of long-read sequencing in profiling the microbiome landscape from various human samples in terms of speed and accuracy. Using nanopore sequencers, we generate native DNA sequences from saliva and stool samples rapidly, from which each long-read is basecalled in real-time to provide downstream analyses such as taxonomic classification and antimicrobial resistance through the built-in software (< 12 hours). Subsequently, we utilize the nanopore sequence data for in-depth analysis of each microbial species in terms of host-microbe interaction types and deep learning-based classification of unidentified reads. We find that the nanopore sequence data encompass complex information regarding the microbiome composition of the host and its microbial communities, and also shed light on the unexplored human mobilome including bacteriophages. In this study, we use two different systems of long-read sequencing to give insights into human microbiome samples in the ‘slow’ and ‘fast’ modes, which raises additional inquiries regarding the precision of this novel technology and the feasibility of extracting native DNA sequences from other human microbiomes.
Activating M1 muscarinic cholinergic receptors induces destabilization of resistant contextual fear memories in rats
Authors: Abouelnaga Karim H. , Huff Andrew E. , Messer William S. , Winters Boyer D.
Published: May 2023

Destabilization of previously consolidated memories places them in a labile state in which they are open to modification. However, strongly encoded fear memories tend to be destabilization-resistant and the conditions required to destabilize such memories remain poorly understood. Our lab has previously shown that exposure to salient novel contextual cues during memory reactivation can destabilize strongly encoded object location memories and that activity at muscarinic cholinergic receptors is critical for this effect. In the current study, we similarly targeted destabilization-resistant fear memories, hypothesizing that exposure to salient novelty at the time of reactivation would induce destabilization of strongly encoded fear memories in a muscarinic receptor-dependent manner. First, we show that contextual fear memories induced by 3 context-shock pairings readily destabilize upon memory reactivation, and that this destabilization is blocked by systemic (ip) administration of the muscarinic receptor antagonist scopolamine (0.3mg/kg) in male rats. Next, we demonstrate that more strongly encoded fear memories (induced with 5 context-shock pairings) resist destabilization. Consistent with our previous work, however, we report that salient novelty (a change in floor texture) presented during the reactivation session promotes destabilization of resistant contextual fear memories in a muscarinic receptor-dependent manner. Finally, the effect of salient novelty on memory destabilization was mimicked by stimulating muscarinic receptors with the selective M1 agonist CDD-0102A (ip, 0.3mg/kg). These findings reveal further generalizability of our previous results implicating novel cues and M1 muscarinic signaling in promoting destabilization of resistant memories and suggest possible therapeutic options for disorders characterized by persistent, maladaptive fear memories such as PTSD and phobias.
Dynamic nuclear polarization illuminates key protein-lipid interactions in the native bacterial cell envelope
Authors: Kent James E. , Ackermann Bryce E. , Debelouchina Galia T. , Marassi Francesca M.
Published: May 2023

Elucidating the structure and interactions of proteins in native environments has become a fundamental goal of structural biology. Nuclear magnetic resonance (NMR) spectroscopy is well suited for this task but often suffers from low sensitivity, especially in complex biological settings. Here, we use a sensitivity-enhancement technique called dynamic nuclear polarization (DNP) to overcome this challenge. We apply DNP to capture the membrane interactions of the outer membrane protein Ail, a key component of the host invasion pathway ofYersinia pestis. We show that the DNP-enhanced NMR spectra of Ail in native bacterial cell envelopes are well resolved and enriched in correlations that are invisible in conventional solid-state NMR experiments. Furthermore, we demonstrate the ability of DNP to capture elusive interactions between the protein and the surrounding lipopolysaccharide layer. Our results support a model where the extracellular loop arginine residues remodel the membrane environment, a process that is crucial for host invasion and pathogenesis.
Music Affects State Anxiety and Brain Connectivity
Authors: Pedersen Mangor , Shepherd Daniel , Vashista Geet , Kercher Amy , Hautus Michael. J.
Published: May 2023

Stress, anxiety, and depressive symptoms can be reduced by listening to music, but the underlying mechanisms remain unclear. To address this gap, we measured brain connectivity while participants listened to songs of different genres: ambient, pop, and metal. Additionally, affective ratings were obtained while participants (n= 30) listened to the six different songs, and subjective ratings of state anxiety were solicited at the terminus of each song. Electroencephalography (EEG) connectivity combining weighted Phase Lag Index and graph theory was utilised to document brain activity during listening. Repeated-measures ANOVA indicated that listening to more pleasant and less arousing songs was associated with lower self-reported state anxiety levels than songs rated unpleasant and highly arousing. Of interest, EEG alpha connectivity differed across two ambient songs, particularly in the frontal lobes, despite being from the same genre and rated as highly pleasant and low in arousal. We also observed a sex effect on EEG results, where female participants (n= 18) displayed stronger connectivity than male participants (n= 12). Combined, these results suggest that ambient songs reduce state anxiety but have divergent brain responses, possibly reflecting the complex nature of music listening, including sensory processing, emotion and cognition.
Evaluation of a deuterated triarylmethyl spin probe for in vivo R2*-based EPR oximetric imaging with enhanced dynamic range
Authors: Kishimoto Shun , Devasahayam Nallathamby , Chandramouli Gadisetti VR , Murugesan Ramachandran , Otowa Yasunori , Yamashita Kota , Yamamoto Kazutoshi , Brender Jeffrey R , Krishna Murali C
Published: May 2023

Purpose

In this study, we compared two triarylmethyl (TAM) spin probes, Ox071 and Ox063 for their efficacy in measuring tissue oxygen concentration by R2*-based oximetry in hypoxic and normoxic conditions.

Methods

The R2* dependence with spin probe and oxygen was calibrated using standard phantom solutions at 1, 2, 5, 10 mM spin probe and 0, 2, 5, 10, 21% oxygen concentrations. For a hypoxic model, in vivo imaging of a MIA PaCa-2 tumor implanted in the hind leg of a mouse was performed on successive days by using either Ox071 or Ox063. For normoxic model, renal imaging of healthy athymic mice was performed under similar conditions. The 3D spin density images acquired under three different gradients and reconstructed by single point imaging modality were used for computing the R2 * values.

Results

The signal intensities of Ox071 were about three times greater in the phantom solutions than Ox063 in the entire pO2range investigated. Although histograms computed from the pO2images of the tumor were skewed towards low pO2levels for both spin probes due to R2* signal loss, more frequency counts in the normoxic region at pO2> 32 mmHg could be detected with Ox071. In the normoxic model in kidney, the high pO2cortex and the low pO2medulla regions were well delineated. The histograms of high-resolution kidney oximetry images using Ox071 were nearly symmetrical and frequency counts were seen up to 55 mmHg which were missed in Ox063 imaging.

Conclusion

This study illustrates Ox071 as a better oximetric probe than Ox063 in terms of sensitivity and the pO2dynamic range.
Functional and genetic adaptations contributing toEnterococcus faecalispersistence in the female urinary tract
Authors: Sharon Belle M. , Arute Amanda P. , Nguyen Amber , Tiwari Suman , Bonthu Sri Snehita Reddy , Hulyalkar Neha V. , Neugent Michael L. , Araya Dennise Palacios , Dillon Nicholas A. , Zimmern Philippe E. , Palmer Kelli L. , De Nisco Nicole J.
Published: May 2023

Enterococcus faecalisis the leading Gram-positive bacterial species implicated in urinary tract infection (UTI). An opportunistic pathogen,E. faecalisis a commensal of the human gastrointestinal tract (GIT) and its presence in the GIT is a predisposing factor for UTI. The mechanisms by whichE. faecaliscolonizes and survives in the urinary tract (UT) are poorly understood, especially in uncomplicated or recurrent UTI. The UT is distinct from the GIT and is characterized by a sparse nutrient landscape and unique environmental stressors. In this study, we isolated and sequenced a collection of 37 clinicalE. faecalisstrains from the urine of primarily postmenopausal women. We generated 33 closed genome assemblies and four highly contiguous draft assemblies and conducted a comparative genomics to identify genetic features enriched in urinaryE. faecaliswith respect toE. faecalisisolated from the human GIT and blood. Phylogenetic analysis revealed high diversity among urinary strains and a closer relatedness between urine and gut isolates than blood isolates. Plasmid replicon (rep) typing further underscored possible UT-GIT interconnection identifying nine shared rep types between urine and gutE. faecalis. Both genotypic and phenotypic analysis of antimicrobial resistance among urinaryE. faecalisrevealed infrequent resistance to front-line UTI antibiotics nitrofurantoin and fluoroquinolones and no vancomycin resistance. Finally, we identified 19 candidate genes enriched among urinary strains that may play a role in adaptation to the UT. These genes are involved in the core processes of sugar transport, cobalamin import, glucose metabolism, and post-transcriptional regulation of gene expression.

IMPORTANCE

Urinary tract infection (UTI) is a global health issue that imposes substantial burden on healthcare systems. Women are disproportionately affected by UTI with >60% of women experiencing at least one UTI in their lifetime. UTIs can recur, particularly in postmenopausal women, leading to diminished quality of life and potentially life-threatening complications. Understanding how pathogens colonize and survive in the urinary tract is necessary to identify new therapeutic targets that are urgently needed due to rising rates of antimicrobial resistance. HowEnterococcus faecalis, a bacterium commonly associated with UTI, adapts to the urinary tract remains understudied. Here, we generated a collection of high-quality closed genome assemblies of clinical urinaryE. faecalisisolated from the urine of postmenopausal women that we used alongside detailed clinical metadata to perform a robust comparative genomic investigation of genetic factors that may mediate urinaryE. faecalisadaptation to the female urinary tract.
WITHDRAWN: Effects of antidiabetic drugs on mortality risks in individuals with type 2 diabetes: A prospective cohort study of UK Biobank participants
Authors: Araldi Elisa , Jutzeler Catherine R. , Ristow Michael
Published: May 2023

Withdrawal Statement

The authors have withdrawn this manuscript owing to having been informed by the UK Biobank Research Development Team that the use of a subset of prescription data in our analyses does not comply with the Control of Patient Information (COPI, 2020) notice.

Specifically, ‘these prescription data could only be used for the purpose of COVID-19 research’. While we have analyzed the impact of these prescription drugs on COVID-19 mortality, as contained in the present manuscript, any additional analyses, as also contained within, appear to be incongruent with the COPI notice.

We hence abide by the request of UK Biobank Research Development Team to withdraw the entire publication. We apologize for any inconvenience this may cause. It should be noted that the scientific content, methods and validity of the results in the entire publication remain unaffected by both the request and the subsequent retraction.

Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.
A scoping review of behavioural science approaches and frameworks for health protection and emergency response
Authors: Zelenka Martin Alice , Weston Dale , Kesten Jo , French Clare
Published: May 2023

Aim

Rapid intervention development, implementation and evaluation is required for emergency public health contexts, such as the recent COVID-19 pandemic. A novel Agile Co-production and Evaluation (ACE) framework has been developed to assist this endeavour in future public health emergencies. This scoping review aimed to map available behavioural science resources that can be used to develop and evaluate public health guidance, messaging, and interventions in emergency contexts onto components of ACE: rapid development and implementation, co-production with patients or the public including seldom heard voices from diverse communities, and inclusion of evaluation.

Methods

A scoping review methodology was used. Searches were run on MEDLINE, EMBASE, PsychInfo, and Google, with search terms covering emergency response and behavioural science. Papers published since 2014 and which discussed a framework or guidance for using behavioural science in response to a public health emergency, were included. A narrative synthesis was conducted.

Results

Seventeen records were included in the synthesis. The records covered a range of emergency contexts, the most frequent of which were COVID-19 (n=7) and non-specific emergencies (n=4). One record evaluated existing tools, six proposed new tools, and ten described existing tools. Commonly used tools included the Behavioural Change Wheel, Capability, Opportunity, and Motivation Behaviour model (COM-B model) and social identity theory. Three records discuss co-production with the target audience and consideration of diverse populations. Four records incorporate rapid testing, evaluation, or validation methods. Six records state that their tool is designed to be implemented rapidly. No records cover all components of ACE.

Conclusion

We recommend that future research explores how to create guidance involving rapid implementation, co-production with patients or the public including seldom-heard voices from diverse communities, and evaluation.
Identification of plants functional counterparts of the metazoan Mediator of DNA Damage Checkpoint 1
Authors: Lorković Zdravko J. , Klingenbrunner Michael , Cho Chung Hyun , Berger Frédéric
Published: May 2023

Induction of DNA damage triggers rapid phosphorylation of the histone H2A.X (γH2A.X). In animals, mediator of DNA damage checkpoint 1 (MDC1) binds γH2A.X through a tandem BRCA1 carboxyl-terminal (tBRCT) domain and mediates recruitment of downstream effectors of DNA damage response (DDR). However, readers of this modification in plants have remained elusive. We report that fromArabidopsisBRCT domain proteome, BCP1-4 proteins with tBRCT domains are involved in DDR. Through its tBRCT domain BCP4 binds γH2A.Xin vitroand localizes to DNA damage-induced foci in an H2A.X dependent manner. BCP4 also contains a domain that interacts directly with NBS1 and thus acts as a functional counterpart of MDC1. We also show that BCP1, that contains two tBRCT domains, co-localizes with γH2A.X but it does not bind γH2A.X suggesting functional similarity with human PAXIP1. A phylogenetic analysis supports that PAXIP1 and MDC1 in metazoa and their plant counterparts evolved independently from common ancestors with tBRCT domains. Collectively, our study reveals missing components and provides mechanistic and evolutionary insights into plant DDR.
Tissue-intrinsic Wnt signals antagonize Nodal-driven AVE differentiation
Authors: Schumacher Sina , Fernkorn Max , Marten Michelle , Kim Yung Su , Bedzhov Ivan , Schröter Christian
Published: May 2023

The anterior-posterior axis of the mammalian embryo is laid down by the anterior visceral endoderm (AVE), an extraembryonic signaling center that is specified within the visceral endoderm. Current models posit that AVE differentiation is promoted globally by epiblast-derived Nodal signals, and spatially restricted by a BMP gradient established by the extraembryonic ectoderm. Here, we report spatially restricted AVE differentiation in bilayered embryo-like aggregates made from mouse embryonic stem cells that lack an extraembryonic ectoderm. Notably, clusters of AVE cells also form in pure visceral endoderm cultures upon activation of Nodal signaling, indicating that tissue-intrinsic factors restrict AVE differentiation. We identify Wnt signaling as a tissue-intrinsic factor that antagonizes AVE-inducing Nodal signals. Together, our results suggest that interactions between epiblast and visceral endoderm alone enable local AVE differentiation in the absence of graded BMP signals. This may be a flexible solution for axis patterning in a wide range of embryo geometries.
Crosstalk between the plasma membrane and cell-cell adhesion maintains epithelial identity for correct polarised cell divisions
Authors: Hosawi Manal M. , Cheng Jiaoqi , Fankhaenel Maria , Przewloka Marcin R. , Elias Salah
Published: May 2023

Polarised epithelial cell divisions represent a fundamental mechanism for tissue maintenance and morphogenesis; their dysregulation often leads to developmental disorders and cancer. Morphological and mechanical changes in the plasma membrane influence the organisation and crosstalk of microtubules and actin at the cell cortex, thereby regulating the mitotic spindle machinery and chromosome segregation. Yet, the precise mechanisms linking plasma membrane remodelling to cell polarity and cortical cytoskeleton dynamics to ensure accurate execution of mitosis in mammalian epithelial cells remain poorly understood. Here we experimentally manipulated the density of mammary epithelial cells in culture, which led to several mitotic defects. We found that perturbation of cell-cell adhesion integrity impairs the dynamics of the plasma membrane during mitosis, affecting the shape and size of mitotic cells and resulting in defects in mitosis progression and generating daughter cells with aberrant cytoarchitecture. In these conditions, F-actin-astral microtubule crosstalk is impaired leading to mitotic spindle misassembly and misorientation, which in turn contributes to chromosome mis-segregation. Mechanistically, we identify the S100 Ca2+-binding protein A11 (S100A11) as a key membrane-associated regulator that forms a complex with E-cadherin and LGN to coordinate plasma membrane remodelling with E-cadherin-mediated cell adhesion and LGN-dependent mitotic spindle machinery. We conclude that plasma membrane-mediated maintenance of mammalian epithelial cell identity is crucial for correct execution of polarised cell divisions, genome maintenance and safeguarding tissue integrity.
Fascin-induced bundling protects actin filaments from disassembly by cofilin
Authors: Chikireddy Jahnavi , Lengagne Léana , Borgne Rémi Le , Wioland Hugo , Romet-Lemonne Guillaume , Jégou Antoine
Published: May 2023

Actin filament turnover plays a central role in shaping actin networks, yet the feedback mechanism between network architecture and filament assembly dynamics remains unclear. The activity of ADF/cofilin, the main protein family responsible for filament disassembly, has been mainly studied at the single filament level. Here, we report that fascin, by crosslinking filaments into bundles, strongly slows down filament disassembly by cofilin. We show that this is mainly due to a slower nucleation of the first cofilin clusters, which occurs up to 100-fold slower on large bundles compared to single filaments. In contrast, severing at cofilin cluster boundaries is unaffected by fascin bundling. After the nucleation of an initial cofilin cluster on a filament of a bundle, we observe the local removal of fascin. Surprisingly, the nucleation of cofilin clusters on adjacent filaments is highly enhanced, locally. We propose that this inter-filament cooperativity in cofilin binding arises from the local propagation of the cofilin-induced change in helicity from one filament to the other filaments of the bundle. Taken together, these observations reveal the molecular events explaining why, despite inter-filament cooperativity, fascin crosslinking protects actin filaments from cofilin-induced disassembly. These findings highlight the important role played by crosslinkers in organizing actin networks and modulating the activity of other regulatory proteins.
Native extracellular matrix promotes human neuromuscular organoid morphogenesis and function
Authors: Auletta Beatrice , Rossi Lucia , Cecchinato Francesca , Barbato Gilda , Lauroja Agnese , Chiolerio Pietro , Cecconi Giada , Maghin Edoardo , Easler Maria , Raffa Paolo , Angiolillo Silvia , Qin Wei , Calabrò Sonia , Villa Chiara , Gagliano Onelia , Laterza Cecilia , Cacchiarelli Davide , Cescon Matilde , Giomo Monica , Torrente Yvan , Luni Camilla , Piccoli Martina , Elvassore Nicola , Urciuolo Anna
Published: May 2023

Human neuromuscular organoids (NMOs) derived from induced pluripotent stem cells (hiPSCs) hold a great potential to study (dys)functional human skeletal muscle (SkM) in vitro. The three-dimensional (3D) self-assembly of NMOs leads to the generation of spheroids, whose 3D organization cannot be controlled. Indeed, proper development, maturation and function of the innervated SkM require a well-defined multiscale 3D organization of the cells in a tissue-specific extracellular matrix (ECM) context. We hypothesized that extracellular structural imprinting along with hiPSC small-molecule-based differentiation could provide self-assembly guidance driving NMO morphogenesis and promoting the maturation and function of the human neuronal-coupled SkM in vitro models. We found that SkM ECM, provided as decellularized skeletal muscle, is able to reproducibly guide the morphogenesis of differentiating hiPSC toward multiscale structured tissue-like NMOs (t-NMOs). T-NMOs show contractile activity and possess functional neuromuscular junctions (NMJs), with mature neuromuscular system upon 30 days of hiPSC differentiation. We found that t-NMO could mimic altered muscle contraction upon administration of neurotoxins that act at NMJ level. Finally, we used hiPSCs derived from patients affected by Duchenne Muscular Dystrophy (DMD) to produce DMD t-NMOs that, upon neuronal stimulation, were able to mimic the altered SkM contractility and calcium dynamics typical of the disease. Altogether, our data confirm the ability of t-NMO platform to model in vitro human neuromuscular system (patho)physiology.
The effects of innovation types and customer participation on organizational performance in complex services
Authors: Samuelsson Peter
Published: May 2023

Purpose

This study aims to explain the effects of different types of innovations on organizational performance in terms of firms’ external effectiveness and internal efficiency. The study examines the interrelationship of technical and nontechnical innovations in complex services and the mediating effect of customer participation on the relationship between innovation type and organizational performance.

Design/methodology/approach

The study draws on a neo-Schumpeterian model for innovation to examine the complex service setting of healthcare provision. Data from Statistics Sweden, containing 38 hospitals and 242 primary care units in Sweden, provided the study's results.

Findings

The findings show the importance of combining different types of innovations in complex services, demonstrating a mediating effect of nontechnical innovation on both the relationship between technical innovations and external effectiveness and internal efficiency. Moreover, the results show that customer participation has a positive mediating effect for technical innovation and nontechnical innovation on external effectiveness. However, there is no such significant effect on internal efficiency.

Research limitations/implications

The findings are based on self-assessment data, which has inherent limitations. The innovation data used were cross-sectional, which may lack reliability (although self-assessed data counter this risk to some extent).

Practical implications

Managers should pursue both technical and nontechnical innovations for gains in external effectiveness and internal efficiency. However, complex services call for technical innovations to be accompanied by nontechnical innovations to support positive effects. The results cause a dilemma for managing customer participation in complex services. As the results show customer participation resulting in external effectiveness, they also fail to establish an effect on internal efficiency.

Originality/value

The primary contribution is to add to the knowledge of different types of innovation in complex services by demonstrating their interdependent effects on both external effectiveness and internal efficiency. Furthermore, the study tests and advances the mediating effect of customer participation in complex services on organizational performance.
Burnout effect on working mothers in leadership positions during the COVID-19 lockdown
Authors: Mucharraz y Cano Yvette , Davila Ruiz Diana , Cuilty Esquivel Karla
Published: May 2023

Purpose

This study aims to understand how the recent COVID-19 pandemic impacted burnout levels among working mothers in leadership positions and how income and work schemes play an important role in their burnout.

Design/methodology/approach

Data were collected from 961 working mothers and fathers in leadership positions in Mexico under different work schemes during the COVID-19 lockdown. Snowball sampling was used in this study. The Maslach Burnout Inventory General Survey was distributed online, using the burnout scale, with income and work schemes as categorical variables.

Findings

Burnout levels among working mothers in leadership positions were higher than those among working fathers. The hybrid work scheme (i.e. working from home combined with working from office) lessens burnout in working mothers, contributing both theoretically and empirically to better understanding burnout levels of mothers in leadership positions.

Practical implications

The findings can encourage human resource areas to reflect on the overexertion and work stress of mothers in leadership positions, and potential support resources can be provided to motivate them and retain their talent.

Originality/value

The introduction of the notion of lockdown in a conceptual model to observe its interaction with burnout and hybrid work schemes (i.e. working from the office and home) has rarely been discussed in existing literature. The impact, especially for working mothers in leadership positions, must be thus carefully considered while dealing with future crises, thereby helping to develop policies and processes accordingly.
Managerial ownership and financial distress: evidence from the Chinese stock market
Authors: Shan Yuan George , Troshani Indrit , Wang Jimin , Zhang Lu
Published: May 2023

Purpose

This study investigates the convergence-of-interest and entrenchment effects on the relationship between managerial ownership and financial distress using evidence from the Chinese stock market. It also analyzes whether the relationship is mediated by research and development (R&D) investment.

Design/methodology/approach

Using a dataset consisting of 19,059 firm-year observations of Chinese listed companies in the Shanghai and Shenzhen Stock Exchanges between 2010 and 2020, this study employs both piecewise and curvilinear models.

Findings

The results indicate that managerial ownership has a negative association with firm financial distress in both the low (below 12%) and high (above 18%) convergence-of-interest regions of managerial ownership, suggesting that managerial ownership in this region may contribute to improve firm financial status. Meanwhile, managerial ownership has a positive association with firm financial distress in the entrenchment region (12–18%), implying that managerial ownership in the entrenchment region may contribute to impair firm financial status. Furthermore, the results show that R&D investment mediates the association between managerial ownership and financial distress.

Originality/value

This study is the first to provide evidence of a nonlinear relationship between managerial ownership and financial distress, and identify the entrenchment region in the Chinese setting.
Do a non-core worker's procedural justice concerns influence their engagement in helping behavior? A multi-method study
Authors: Farhan Mohammed , Krejci Caroline C. , Cantor David E.
Published: May 2023

Purpose

The purpose of this research is to examine how a change in team dynamics impacts an individual's motivation to engage in helping behavior and operational performance.

Design/methodology/approach

An online vignette experiment and a hybrid discrete event and agent-based simulation model are used.

Findings

Study findings demonstrate how a non-core worker's perception of team dynamics influence engagement in helping behavior and system performance.

Originality/value

This study provides a further understanding on how team members react to changes in team processes. This study theorizes on how an individual team member responds to fairness concerns. This study also advances our understanding of the critical importance of helping behavior in a retail logistics setting. This research illustrates how the theory of strategic core and procedural justice literature can be adopted to explain team dynamics in supply chain management.
Inner transitions in higher education in Sweden: incorporating intra-personal skills in education for sustainable development
Authors: Libertson Frans
Published: May 2023

Purpose

Humanity is facing an unprecedented challenge of climate crises. Rapid changes to the physical environment and living conditions will be accompanied by challenges to mental health and well-being. Consequently, education for sustainable development should also include coping strategies for stress and anxiety. Adding intra-personal skills to the curriculum, such as self-reflection and mindfulness training, could aid in this education. This case study aims to explore the barriers to and drivers for fostering inner transitions through intra-personal skills training and mindfulness.

Design/methodology/approach

This case study from Lund University, Sweden, constitutes a critical case for investigating inner transitions in education. Data collection was designed around semi-structured qualitative interviews, to investigate the barriers to and drivers for intra-personal skills and mindfulness in education for sustainable development at all institutional levels of the university.

Findings

The results indicate that education for sustainable development already includes elements of introspection, albeit informally. However, there is a lack in a fundamental understanding of intra-personal skills and how they relate to other key competences for sustainable development. To make intra-personal skills training a formal component of the education, it must receive the full support from all levels of the university.

Originality/value

The study outlines general recommendations for universities to challenge existing policies while also finding ways to work around them. In the meantime, universities should make intra-personal skills training an informal learning activity. Recognizing that the students’ prior knowledge in this area is a potential asset, universities should collaborate with their students to support student-led intra-personal skills training.