bluuebunny/crossref_metadata_2025 huggingface dataset:
Interplay between Nrf2 and αB-crystallin in the lens and heart of zebrafish under proteostatic stress
Authors: Park Jinhee , MacGavin Samantha , Niederbrach Laurie , Mchaourab Hassane S.
Published: April 2023

A coordinated oxidative stress response, partly triggered by the transcription factor Nrf2, protects cells from the continual production of reactive oxygen species. Left unbuffered, reactive oxygen species can lead to protein aggregation which has been implicated in a spectrum of diseases including cataract of the ocular lens and myopathy of the heart. While proteostasis is maintained by diverse families of heat shock proteins, the interplay between the oxidative and proteostatic stress responses in the lens and the heart have not been investigated. Capitalizing on multiple zebrafish lines that have compromised function of Nrf2 and/or the two zebrafish small heat-shock proteins αBa- and αBb-crystallin, we uncovered a transcriptional relationship that leads to a substantial increase in αBb-crystallin transcripts in the heart in response to compromised function of Nrf2. In the lens, the concomitant loss of function of Nrf2 and αBa-crystallin leads to upregulation of the cholesterol biosynthesis pathway thus mitigating the phenotypic consequences of the αBa-crystallin knockout. In contrast, abrogation of Nrf2 function accentuates the penetrance of a heart edema phenotype characteristic of embryos of αB-crystallin knockout lines. Multiple molecular pathways, such as genes involved in extracellular interactions and implicated in cardiomyopathy, are revealed from transcriptome profiling thus identifying novel targets for further investigation. Together our transcriptome/phenotypic analysis establishes an intersection between the oxidative stress and chaperone responses in the lens and the heart.
Comparing chromatin contact maps at scale: methods and insights
Authors: Gunsalus Laura M. , McArthur Evonne , Gjoni Ketrin , Kuang Shuzhen , Pittman Maureen , Capra John A. , Pollard Katherine S.
Published: April 2023

Comparing chromatin contact maps is an essential step in quantifying how three-dimensional (3D) genome organization shapes development, evolution, and disease. However, no gold standard exists for comparing contact maps, and even simple methods often disagree. In this study, we propose novel comparison methods and evaluate them alongside existing approaches using genome-wide Hi-C data and 22,500in silicopredicted contact maps. We also quantify the robustness of methods to common sources of biological and technical variation, such as boundary size and noise. We find that simple difference-based methods such as mean squared error are suitable for initial screening, but biologically informed methods are necessary to identify why maps diverge and propose specific functional hypotheses. We provide a reference guide, codebase, and benchmark for rapidly comparing chromatin contact maps at scale to enable biological insights into the 3D organization of the genome.
Using macromolecular electron densities to improve the enrichment of active compounds in virtual screening
Authors: Ma Wenzhi , Zhang Wei , Le Yuan , Shi Xiaoxuan , Xu Qingbo , Xiao Yang , Dou Yueying , Wang Xiaoman , Zhou Wenbiao , Peng Wei , Zhang Hongbo , Huang Bo
Published: April 2023

The quest for more effective virtual screening algorithms is hindered by the scarcity of training data, calling for innovative approaches. This study presents the first use of experimental electron density (ED) data for improving active compound enrichment in virtual screening, supported by ED’s ability to reflect the time-averaged behavior of ligands and solvents in the binding pocket. Experimental ED-based grid matching score (ExptGMS) was developed to score compounds by measuring the degree of matching between their binding conformations and a series of multi-resolution experimental ED grids. The efficiency of ExptGMS was validated using bothin-silicotests with the Directory of Useful Decoys–Enhanced dataset and wet-lab tests on Covid-19 3CLpro-inhibitors. ExptGMS improved the active compound enrichment in top-ranked molecules by approximately 20%. Furthermore, ExptGMS helped identify four new and active inhibitors of 3CLpro, with the top showing an IC50 value of 1.9 µM. To facilitate the use of ExptGMS, we developed an online database containing experimental ED grids for over 17,000 proteins.
Sequential effect and temporal orienting in pre-stimulus oculomotor inhibition
Authors: Tal-Perry Noam , Yuval-Greenberg Shlomit
Published: April 2023

When faced with unfamiliar circumstances, we often turn to our past experiences with similar situations to shape our expectations. This results in the well-established sequential effect, in which previous trials influence the expectations of the current trial. Studies have revealed that, in addition to the classical behavioral metrics, the inhibition of eye movement could be used as a biomarker to study temporal expectations. This pre-stimulus oculomotor inhibition is found a few hundred milliseconds prior to predictable events, with a stronger inhibition for predictable than unpredictable events. The phenomenon has been found to occur in various temporal structures, such as rhythms, cue-association and conditional probability, yet it is still unknown whether it reflects local sequential information of the previous trial. To explore this, we examined the relationship between the sequential effect and the pre-stimulus oculomotor inhibition. Our results (N=40) revealed that inhibition was weaker when the previous trial was longer than the current trial, in line with findings of behavioral metrics. These findings indicate that the pre-stimulus oculomotor inhibition covaries with expectation based on local sequential information, demonstrating the tight connection between this phenomenon and expectation and providing a novel measurement for studying sequential effects in temporal expectation.
Chronosequence of invasion reveals minimal losses of population genomic diversity, niche expansion, and trait divergence in the polyploid, leafy spurge
Authors: Lake Thomas A. , Briscoe Runquist Ryan D. , Flagel Lex E. , Moeller David A.
Published: April 2023

Rapid evolution may play an important role in the range expansion of invasive species and modify forecasts of invasion, which are the backbone of land management strategies. However, losses of genetic variation associated with colonization bottlenecks may constrain trait and niche divergence at leading range edges, thereby impacting management decisions that anticipate future range expansion. The spatial and temporal scales over which adaptation contributes to invasion dynamics remains unresolved. We leveraged detailed records of the ∼130 year invasion history of the invasive polyploid plant, leafy spurge (Euphorbia virgata), across ∼500km in Minnesota, U.S.A. We examined the consequences of range expansion for population genomic diversity, niche breadth, and the evolution of germination behavior. Using genotyping-by-sequencing, we found some population structure in the range core, where introduction occurred, but panmixia among all other populations. Range expansion was accompanied by only modest losses in sequence diversity, with small, isolated populations at the leading edge harboring similar levels of diversity to those in the range core. The climatic niche expanded during most of range expansion, and the niche of the range core was largely non-overlapping with the invasion front. Ecological niche models indicated that mean temperature of the warmest quarter was the strongest determinant of habitat suitability and that populations at the leading edge had the lowest habitat suitability. Guided by these findings, we tested for rapid evolution in germination behavior over the time course of range expansion using a common garden experiment and temperature manipulations. Germination behavior diverged from early to late phases of the invasion, with populations from later phases having higher dormancy at lower temperatures. Our results suggest that trait evolution may have contributed to niche expansion during invasion and that distribution models, which inform future management planning, may underestimate invasion potential without accounting for evolution.
A coarse-grained resource allocation model of carbon and nitrogen metabolism in unicellular microbes
Authors: Kleijn Istvan T. , Marguerat Samuel , Shahrezaei Vahid
Published: April 2023

Coarse-grained resource allocation models (C-GRAMs) are simple mathematical models of whole cell physiology, where large components of the macromolecular composition are abstracted into single entities. The dynamics and steady-state behaviour of such models provides insights on optimal allocation of cellular resources and have explained experimentally observed cellular growth laws. Here, we formulate a minimal C-GRAM with nitrogen and carbon pathways converging on biomass production, with parameterizations accounting for respiro-fermentative and purely respiratory growth. The model describes the effects of the uptake of sugars, ammonium, and/or compound nutrients such as amino acids on the translational resource allocation towards proteome sectors that maximised the growth rate. It robustly recovers cellular growth laws including the Monod law and the ribosomal growth law. Furthermore, we show how the growth-maximizing balance between carbon uptake, recycling, and excretion depends on the nutrient environment. Lastly, we find a robust linear correlation between the ribosome fraction and the abundance of amino acid equivalents in the optimal cell, which supports the view that simple regulation of translational gene expression can enable cells to achieve an approximately optimal growth state.
Performance comparison of high throughput single-cell RNA-Seq platforms in complex tissues
Authors: Colino-Sanguino Yolanda , de la Fuente Laura Rodriguez , Gloss Brian , Law Andrew M. K. , Handler Kristina , Pajic Marina , Salomon Robert , Gallego-Ortega David , Valdes-Mora Fatima
Published: April 2023

Single-cell transcriptomics has emerged as the preferred tool to define cell identity through the analysis of gene expression signatures. However, there are limited studies that have comprehensively compared the performance of different scRNAseq systems in complex tissues. Here, we present a systematic comparison of two well-established high throughput 3’-scRNAseq platforms: 10x Chromium and BD Rhapsody, using tumours that present high cell diversity. Our experimental design includes both fresh and artificially damaged samples from the same tumours, which also provides a comparable dataset to examine their performance under challenging conditions. The performance metrics used in this study consist of gene sensitivity, mitochondrial content, reproducibility, clustering capabilities, cell type representation and ambient RNA contamination. These analyses showed that BD Rhapsody and 10x Chromium have similar gene sensitivity, while BD Rhapsody has the highest mitochondrial content. Interestingly, we found cell type detection biases between platforms, including a lower proportion of endothelial and myofibroblast cells in BD Rhapsody and lower gene sensitivity in granulocytes for 10x Chromium. Moreover, the source of the ambient noise was different between plate-based and droplet-based platforms. In conclusion, our reported platform differential performance should be considered for the selection of the scRNAseq method during the study experimental designs.
Distinct roles ofBdnf IandBdnf IVtranscript variant expression in hippocampal neurons
Authors: Bach Svitlana V. , Bauman Allison J. , Hosein Darya , Tuscher Jennifer J. , Ianov Lara , Greathouse Kelsey M. , Henderson Benjamin W. , Herskowitz Jeremy H. , Martinowich Keri , Day Jeremy J.
Published: April 2023

Brain-derived neurotrophic factor (Bdnf) plays a critical role in brain development, dendritic growth, synaptic plasticity, as well as learning and memory. The rodentBdnfgene contains nine 5′ non-coding exons (I-IXa), which are spliced to a common 3′ coding exon (IX). Transcription of individualBdnfvariants, which all encode the same BDNF protein, is initiated at unique promoters upstream of each non-coding exon, enabling precise spatiotemporal and activity-dependent regulation ofBdnfexpression. Although prior evidence suggests thatBdnftranscripts containing exonI(Bdnf I) or exonIV(Bdnf IV) are uniquely regulated by neuronal activity, the functional significance of differentBdnftranscript variants remains unclear. To investigate functional roles of activity-dependentBdnf IandIVtranscripts, we used a CRISPR activation (CRISPRa) system in which catalytically-dead Cas9 (dCas9) fused to a transcriptional activator (VPR) is targeted to individualBdnfpromoters with single guide RNAs (sgRNAs), resulting in transcript-specificBdnfupregulation.Bdnf Iupregulation is associated with gene expression changes linked to dendritic growth, whileBdnf IVupregulation is associated with genes that regulate protein catabolism. Upregulation ofBdnf I, but notBdnf IV, increased mushroom spine density, volume, length, and head diameter, and also produced more complex dendritic arbors in cultured rat hippocampal neurons. In contrast, upregulation ofBdnf IV, but notBdnf I, in the rat hippocampus attenuated contextual fear expression. Our data suggest that whileBdnf IandIVare both activity-dependent, BDNF produced from these promoters may serve unique cellular, synaptic, and behavioral functions.
“It's your fault!” – said a public client to modernity advocates: an exploration of UK public sector’s viewpoints on the modern methods of construction
Authors: Saad Ali M. , Zulu Sambo Lyson , Dulaimi Mohammed
Published: April 2023

Purpose

The staggering demand for construction projects to meet a spectrum of public needs is projected to outstrip the industry’s supply capability. The modern methods of construction (MMC) offers wider control due to shifting key construction processes offsite. Public clients play a significant role due to their purchasing power; however, their uptake of MMC is low, despite the benefits. The purpose of this study is to reveal the reasoning behind such low adoption. The research gap, herewith, is our lack of understanding of the influence of public clients perceptions on their adoption’s indecision.

Design/methodology/approach

This study used a qualitative approach to investigate the motives behind the public sector’s low MMC adoption. Semi-structured interviews with 14 of the United Kingdom’s public sector decision-makers, industry leaders and experts have been conducted. Perspectives were argued against the diffusion of innovation (DOI) theory.

Findings

Overall, the innovation’s attributes informed the authors of the positive perceptions from the public sector, demonstrating that the low adoption of MMC is not linked to any embedded issues with the innovation itself rather being predominantly related to the dynamics between supply and demand. The former (supply), reflected a failure in communicating confidence, and the latter (demand), attained characteristics that are limiting wider uptake.

Originality/value

To the best of the authors’ knowledge, this is the first study to apply the DOI theory to reveal the relationship between UK public clients’ perceptions and their decision-making. Moreover, this paper addresses the scant attention to the use of theories to explain the flow of innovations in the construction context.
Simmelian ties for SMEs' green-innovation improvement in manufacturing industries: mediating and moderating effects
Authors: Cheng Xinsheng , Xu Yingjie , Li Fengshu
Published: April 2023

Purpose

This study had a threefold aim: to examine the impact of a Simmelian-tie tripartite alliance on corporate green innovation; to determine the chain-mediating roles of knowledge acquisition and knowledge integration; and to identify the moderating effect of network routines on the relationship between a Simmelian tie and green innovation.

Design/methodology/approach

Data were collected through 487 valid survey questionnaires from Chinese small and medium-sized manufacturing enterprises (SMEs). The authors examined the data through a structural model using partial least-squares structural-equation modeling (PLS-SEM) to test the research hypotheses.

Findings

The results reveal several key factors with positive impacts on enterprise green innovation. Specifically, a Simmelian tie significantly and positively affects enterprise green innovation. The results further reveal that knowledge acquisition and integration play mediating roles, while a network routine positively moderates the relationships among a Simmelian tie, knowledge acquisition and integration, and corporate green innovation.

Originality/value

This study is among the earliest empirical studies to investigate the influence of Simmelian ties on corporate green innovation for manufacturing companies. This study provides a theoretical basis for managers of firms, especially those of SMEs with limited resources, to fully use Simmelian ties to achieve environmentally sustainable innovation. In addition, this study validates and extends knowledge-management theory by verifying the linking roles of knowledge acquisition and integration and facilitating role of network routines.
Technology adaptation: micro new ventures in a COVID-19 lockdown
Authors: Felzensztein Christian , Tretiakov Alexei
Published: April 2023

Purpose

There is a paucity of evidence on how small new ventures cope with shifts from physical space to cyberspace imposed by external crises, such as pandemics. Further, even though the concept of space is highly relevant to understanding entrepreneurship, the concept has been underutilised in entrepreneurship research. In particular, the potential of understanding entrepreneurship in terms of the interplay between physical space and cyberspace is yet to be explored. The authors address these research gaps by pursuing the following research question: How did micro new ventures experience the shift from physical space to cyberspace (technology adaptation) imposed by the coronavirus disease 2019 (COVID-19) crisis?

Design/methodology/approach

Data were collected via semi-structured interviews with founders of start-ups associated with two incubators, in Spain and Monaco. Thematic analysis of interview transcripts was conducted, approaching the data with the focus on firm positioning in “real” space and in cyberspace and on possible transformations of business models.

Findings

The pandemic opened new opportunities for small new ventures, as many start-ups were successful in shifting into cyberspace by undergoing a radical digital transformation and ended up with more scalable business models and in many cases transformed themselves into micro-multinationals.

Research limitations/implications

Overall, firms tended to shift from physical space to cyberspace, following the firms' customers to cyberspace, finding new and more international, customers in cyberspace or guiding the firms' existing customer base into cyberspace. Firms that maintained the pre-pandemic position were either already fully digital or had sufficient resources to hold position in the anticipation of the post-pandemic future.

Originality/value

The authors introduce the concept of cyberspace in the context of entrepreneurship studies and explore the trajectories of firms in a crisis.
Tourism and public insecurity: what are its roots?
Authors: Coutinho Ana Catarina , Nóbrega Wilker Ricardo
Published: April 2023

Purpose

Studies examining public insecurity and tourism tend to develop their research from the tourist's perspective, thereby focusing on its consequences, which insufficiently and poorly contribute to the development process. With that in mind, the purpose of this study is to discuss the root causes of public insecurity and the urban development process surrounding tourism dynamics in Brazil's northeast region.

Design/methodology/approach

The complexity method was used to collect both documentary and normative data to understand the reality beyond the data on accommodations and vertical real estate developments over time. These data were organized in ArcGIS (version 10.5) and are discussed within the context of urban development, public insecurity and tourism theories.

Findings

The results of this study demonstrate that the relationship between tourism and public insecurity is rooted in discussions surrounding the urban development process, remodeled by the physical and symbolic dimensions surrounding the production of space. Nevertheless, the symbolism of tourism is not a constant when it comes to socio-spatial changes but rather acts as a physical and secondary dynamic throughout the entire reconfiguration process.

Originality/value

The findings of this study indicate that this study can be used for the elaboration of security policies in tourist destinations in Latin America that present high levels of violence, considering the discourses at implementing urban legislation.
Factors leading to sustainable consumption behavior: an empirical investigation among millennial consumers
Authors: Ghaffar Abdul , Islam Tahir
Published: April 2023

Purpose

Promoting sustainable consumption is key to global sustainable development. The current study aims to explore the impact of environmental risk perception, environmental knowledge, social pressure and health consciousness on sustainable behavior intention among millennial consumers.

Design/methodology/approach

This study used a survey method and a self-administered questionnaire to obtain data from the millennial generation. Smart partial least square (PLS) 4.0 was used to analyze data. This research used judgmental sampling and collected 596 valid responses.

Findings

The present study indicates that sustainable consumption is becoming more prevalent among millennials. The authors observed that a high level of environmental risk perception, environmental knowledge, social pressure and health consciousness are the antecedents of sustainable behavioral intention, ultimately leading to sustainable consumption behavior.

Research limitations/implications

The current study highlights the millennial generation's sustainable consumption behavior. Researchers, policymakers, scientists, managers, industry professionals and brand managers can use the research findings to establish a sustainable framework.

Originality/value

This research finds that promoting ecological consumption and environmental consciousness can help developing countries achieve environmental sustainability and ecological balance. The research findings add to the literature by offering new insights into customers' pricing perception for sustainable products and sustainable product availability toward sustainable consumption behavior in developing countries.
The power of presentation: How attire, cosmetics, and posture impact the source credibility of women expert witnesses
Authors: Jones Ashley C. T. , Repke Alexandra , Batastini Ashley B. , Sacco Donald , Dahlen Eric R. , Mohn Richard S.
Published: April 2023

Gender stereotypes may negatively affect perceptions of women professionals' credibility, including forensic experts. This study investigated the impact of behavior‐based and appearance‐based factors on women expert witness's credibility. Jury‐eligible adults were shown one of 16 conditions depicting a woman expert which varied based on combinations of three primary independent variables: (1) attire, (2) cosmetic use, and (3) posture. Expert attractiveness and participants' sexist attitudes served as covariates. Results revealed that women experts were seen as marginally more credible when wearing a skirt suit with a closed posture stance than when wearing a pant suit with a closed posture. Secondary analyses indicated expert attractiveness and participant sexist attitudes accounted for the most variability in credibility scores. Credibility of women expert witnesses may be impacted by irrelevant peripheral cues. Findings can inform discussions aimed at mitigating extraneous factors that inadvertently undermine the reception of women expert witness testimony.
Factors behind the threshold‐like changes in lake ecosystems along a water colour gradient: The effects of dissolved organic carbon and iron on euphotic depth, mixing depth and phytoplankton biomass
Authors: Horppila Jukka , Keskinen Saana , Nurmesniemi Miia , Nurminen Leena , Pippingsköld Ella , Rajala Salla , Sainio Kari , Estlander Satu
Published: April 2023

The effects of water colour, dissolved organic carbon (DOC), iron (Fe) and fetch on the mixing depth (Zmix), euphotic depth (Zeu) and phytoplankton biomass of lakes were studied to clarify the factors behind changes in lake productivity along a DOC gradient.

The study was conducted by field sampling 102 lakes in Finland. The lakes were situated mainly in forested areas.

At DOC concentrations below 15 mg/L, light attenuation was explained both by Fe and DOC, but at higher DOC concentrations the effect of Fe faded. For the absorption of different wavelengths of photosynthetic light, both DOC and Fe had a significant effect up to 475 nm, but for longer wavelengths only the effect of DOC was significant.

Both Zmix and Zeu decreased logarithmically with increasing DOC and water colour. Water colour was determined by DOC and Fe. Zmix increased along with increasing fetch. Zmix exceeded Zeu when DOC concentration was >14.4 mg/L and water colour >106 mg Pt/L (platinum as chloroplatinate ion 3).

Above the 14.4 mg/L DOC threshold, the illuminated part of the mixed layer decreased logarithmically with increasing water colour, leaving an increasing part of the mixed epilimnion below the photosynthetic layer. Chlorophyll‐a concentration showed a unimodal relationship with DOC, with the highest biomass occurring at DOC concentrations of 15.7–15.9 mg/L.

The results suggested that above DOC concentration 14 mg/L and water colour 106 mg Pt/L, both quality and quantity of light in the epilimnion restrict production by phytoplankton. This can explain the observed threshold‐like changes in lake productivity along a DOC gradient.
Toward developing care outcome quality indicators for home care for older people: A prospective cohort study in Japan
Authors: Eltaybani Sameh , Kitamura Satomi , Fukui Chie , Igarashi Ayumi , Sakka Mariko , Noguchi‐Watanabe Maiko , Takaoka Manami , Inagaki Asa , Yasaka Taisuke , Kobayashi Hiromi , Yamamoto‐Mitani Noriko
Published: April 2023

Introduction

Care quality in Japan's long‐term care (LTC) agencies, including home care, is the responsibility primarily of individual agencies, and the evaluation of service processes and outcomes is minimal.

Objectives

To describe the development of quality indicators for LTC (QIs‐LTC) in Japan.

Methods

QIs‐LTC were developed through literature review and expert panel discussions and then were piloted and used in a 2‐year longitudinal survey. The survey (launched in September 2019) targeted older people receiving home care (n = 1450), their family members (n = 880), their professional home care providers (n = 577), and managers of home care agencies (n = 122).

Results

Across eight domains (maintaining dignity, minimizing symptoms and disease deterioration, maintaining nutritional status, maintaining bladder/bowel control, encouraging physical activities, experiencing sound sleep, maintaining serenity and contentedness, and maintaining family's well‐being), 24 care quality objectives were set with 24 outcome QIs‐LTC and 144 process QIs‐LTC. In the survey, 84.8% of clients were using home care nursing, 26.3% were living alone, and 39.5% had dementia. In the month preceding the data collection, 13.9% of clients had a new disease or worsening of an existing disease, 8.8% were hospitalized at least once, and 47.9% did not participate in activities of interest. About 20% of clients' families were unable to spend time peacefully, and 52.8% were exhausted from the client's care.

Conclusions

The QIs‐LTC developed in the current study are generic and client‐ and family‐centered. They encompass objective and subjective information and would facilitate standardized monitoring if adopted and comparison between LTC settings, including home care. In addition, future research directives are outlined. Geriatr Gerontol Int 2023; 23: 383–394.
Amplifying invisibility: COVID‐19 and Zimbabwean migrant farm workers in South Africa
Authors: Addison Lincoln
Published: April 2023

How does the COVID‐19 pandemic impact migrant worker visibility? This paper examines how the pandemic underscores the invisibility of Zimbabwean migrant farm workers employed at ZZ2, one of the largest commercial farms in South Africa. I argue that Zimbabweans are made invisible in three ways. First, employer and state restrictions on mobility, alongside rising xenophobia in South Africa, leave migrant workers hyper‐visible to ZZ2 management, yet invisible to most people outside the farm. Second, ZZ2 avoids discussion of its migrant workforce in public forums, even as it faces increased scrutiny for its treatment of its workers during the pandemic. Third, the most prominent critic of ZZ2—the Economic Freedom Fighters (EFF)—grants migrant workers only a partial visibility as undifferentiated foreigners with no voice, a construction that ultimately maintains their invisibility at the company. Taken together, these interlocking forms of invisibilization diminish the structural and associational power of workers.
Ursodeoxycholic acid is associated with a reduction in SARS‐CoV‐2 infection and reduced severity of COVID‐19 in patients with cirrhosis
Authors: John Binu V. , Bastaich Dustin , Webb Gwilym , Brevini Teresa , Moon Andrew , Ferreira Raphaella D. , Chin Allison M. , Kaplan David E. , Taddei Tamar H. , Serper Marina , Mahmud Nadim , Deng Yangyang , Chao Hann‐Hsiang , Sampaziotis Fotios , Dahman Bassam
Published: April 2023

Background and aims

Studies have demonstrated that reducing farnesoid X receptor activity with ursodeoxycholic acid (UDCA) downregulates angiotensin‐converting enzyme in human lung, intestinal and cholangiocytes organoids in vitro, in human lungs and livers perfused ex situ, reducing internalization of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) into the host cell. This offers a potential novel target against coronavirus disease 2019 (COVID‐19). The objective of our study was to compare the association between UDCA exposure and SARS‐CoV‐2 infection, as well as varying severities of COVID‐19, in a large national cohort of participants with cirrhosis.

Methods

In this retrospective cohort study among participants with cirrhosis in the Veterans Outcomes and Costs Associated with Liver cohort, we compared participants with exposure to UDCA, with a propensity score (PS) matched group of participants without UDCA exposure, matched for clinical characteristics, and vaccination status. The outcomes included SARS‐CoV‐2 infection, symptomatic, at least moderate, severe, or critical COVID‐19, and COVID‐19‐related death.

Results

We compared 1607 participants with cirrhosis who were on UDCA, with 1607 PS‐matched controls. On multivariable logistic regression, UDCA exposure was associated with reduced odds of developing SARS‐CoV‐2 infection (adjusted odds ratio [aOR] 0.54, 95% confidence interval [CI] 0.41–0.71, p < 0.0001). Among patients who developed COVID‐19, UDCA use was associated with reduced disease severity, including symptomatic COVID‐19 (aOR 0.54, 95% CI 0.39–0.73, p < 0.0001), at least moderate COVID‐19 (aOR 0.51, 95% CI 0.32–0.81, p = 0.005), and severe or critical COVID‐19 (aOR 0.48, 95% CI 0.25–0.94, p = 0.03).

Conclusions

In participants with cirrhosis, UDCA exposure was associated with both a decrease in SARS‐CoV‐2 infection, and reduction in symptomatic, at least moderate, and severe/critical COVID‐19.
Effects of Leader Group Prototypicality on Leadership Outcomes through Leader Identity Threat: The Moderating Effects of Leader Perceptions of Organizational Support
Authors: Rodgers Matthew S. , Kim Tae‐Yeol , Chen Tingting , David Emily
Published: April 2023

We theorized and tested how both team‐assessed leader group prototypicality (i.e., followers' collective perceptions of the extent to which a leader is viewed as being representative of the group prototype) and leader‐team congruence on this factor relate to leader identity threat. We also proposed that leader identity threat, subsequently, negatively affects both leadership effectiveness and team performance, and that leader perceptions of organizational support mitigate the relationships. Using a multi‐source and time‐lagged survey design to collect data at the leader (team) level from 402 group members and their 90 group leaders, the results generally support our research hypotheses. For example, both team‐assessed leader group prototypicality and leader‐team congruence on leader group prototypicality negatively relate to leader identity threat. In addition, the effects of leader identity threat on leadership effectiveness and team performance were weaker when leader perceptions of organizational support were higher rather than lower.
Factors associated with thrombotic and hemorrhagic complications in pediatric liver transplant: A multi‐center analysis from the Starzl Network for Excellence in Pediatric Transplantation
Authors: Soltys Kyle , Lemoine Caroline , Zhang Xingyu , Bhat Rukhmi , Bucuvalas John , Rasmussen Sara , Romero Rene , Batsis Irini , Sayed Blayne , Tunno John , Confair Cassandra , Vargas Sarah , Superina Riccardo , Mazariegos George
Published: April 2023

Background

Survival after pediatric liver transplantation (PLT) is negatively impacted by thrombotic and hemorrhagic complications. Limited data exists regarding factors associated with these complications and utilization of anticoagulation.

Methods

Retrospective review of donor, recipient variables and outcomes from four centers participating in the Starzl Network for Excellence in Pediatric Transplantation.

Results

76 PLT included 39 (51%) technical variant transplants, with mean follow‐up 628 ± 193.6 days. Median age/weight at transplant were 59.3 ± 53.8 months and 19.6 ± 17.2 kg. Seven (9.2%) transplants experienced intraoperative hepatic artery thrombosis (iHAT), all successfully corrected. Four HAT recurred postoperatively on POD 1,7,8 and 616. All three portal vein thromboses (PVT) occurred on POD1. Anticoagulation protocols were initiated intraoperatively in 50 and postoperatively in 66 and were active for all thrombotic and hemorrhagic events. Two patients were re‐transplanted for HAT. Two patients died without having thrombotic or hemorrhagic complications. iHAT and post‐operative HAT were associated with lower hepatic arterial flows. iHAT was associated with donor variant anatomy, reduced allografts and intraoperative blood loss. Intraoperative ultrasound could not predict post‐operative HAT nor PVT. Surgeon pre‐operative concern regarding the native portal vein correlated with postoperative PVT. Lower hepatic arterial and portal flows, higher estimated blood losses, higher prothrombin time and use of arterial interposition grafts were associated with postoperative hemorrhagic complications.

Conclusions

Thrombotic and hemorrhagic complications after pediatric liver transplant remain rare but significant events. Their occurrence can be predicted with pre‐operative assessment of donor and recipient vascular anatomy and direct flow measurement but may not be predicted with ultrasound evaluation nor prevented with anticoagulation.
Dissecting the contributions of the peripheral chemoreflex and myocardial hypoxia to fetal heart rate decelerations in near‐term fetal sheep
Authors: Lear Christopher A. , Beacom Michael J. , Dhillon Simerdeep K. , Lear Benjamin A. , Mills Olivia J. , Gunning Mark I. , Westgate Jenny A. , Bennet Laura , Gunn Alistair J.
Published: April 2023

Brief repeated fetal hypoxaemia during labour can trigger intrapartum decelerations of the fetal heart rate (FHR) via the peripheral chemoreflex or the direct effects of myocardial hypoxia, but the relative contribution of these two mechanisms and how this balance changes with evolving fetal compromise remain unknown. In the present study, chronically instrumented near‐term fetal sheep received surgical vagotomy (n = 8) or sham vagotomy (control, n = 11) to disable the peripheral chemoreflex and unmask myocardial hypoxia. One‐minute complete umbilical cord occlusions (UCOs) were performed every 2.5 min for 4 h or until arterial pressure fell below 20 mmHg. Hypotension and severe acidaemia developed progressively after 65.7 ± 7.2 UCOs in control fetuses and 49.5 ± 7.8 UCOs after vagotomy. Vagotomy was associated with faster development of metabolic acidaemia and faster impairment of arterial pressure during UCOs without impairing centralization of blood flow or neurophysiological adaptation to UCOs. During the first half of the UCO series, before severe hypotension developed, vagotomy was associated with a marked increase in FHR during UCOs. After the onset of evolving severe hypotension, FHR fell faster in control fetuses during the first 20 s of UCOs, but FHR during the final 40 s of UCOs became progressively more similar between groups, with no difference in the nadir of decelerations. In conclusion, FHR decelerations were initiated and sustained by the peripheral chemoreflex at a time when fetuses were able to maintain arterial pressure. After the onset of evolving hypotension and acidaemia, the peripheral chemoreflex continued to initiate decelerations, but myocardial hypoxia became progressively more important in sustaining and deepening decelerations.

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Key points

Brief repeated hypoxaemia during labour can trigger fetal heart rate decelerations by either the peripheral chemoreflex or myocardial hypoxia, but how this balance changes with fetal compromise is unknown.

Reflex control of fetal heart rate was disabled by vagotomy to unmask the effects of myocardial hypoxia in chronically instrumented fetal sheep. Fetuses were then subjected to repeated brief hypoxaemia consistent with the rates of uterine contractions during labour.

We show that the peripheral chemoreflex controls brief decelerations in their entirety at a time when fetuses were able to maintain normal or increased arterial pressure.

The peripheral chemoreflex still initiated decelerations even after the onset of evolving hypotension and acidaemia, but myocardial hypoxia made an increasing contribution to sustain and deepen decelerations.
Maintaining hypoxia environment of subchondral bone alleviates osteoarthritis progression
Authors: Zhang Hao , Wang Lipeng , Cui Jin , Wang Sicheng , Han Yafei , Shao Hongda , Wang Cheng , Hu Yan , Li Xiaoqun , Zhou Qirong , Guo Jiawei , Zhuang Xinchen , Sheng Shihao , Zhang Tao , Zhou Dongyang , Chen Jiao , Wang Fuxiao , Gao Qianmin , Jing Yingying , Chen Xiao , Su Jiacan
Published: April 2023

Abnormal subchondral bone remodeling featured by overactivated osteoclastogenesis leads to articular cartilage degeneration and osteoarthritis (OA) progression, but the mechanism is unclear. We used lymphocyte cytosolic protein 1 (
Lcp1
) knockout mice to suppress subchondral osteoclasts in a mice OA model with anterior cruciate ligament transection (ACLT), and
Lcp1
−/−
mice showed decreased bone remodeling in subchondral bone and retarded cartilage degeneration. For mechanisms, the activated osteoclasts in subchondral bone induced type-H vessels and elevated oxygen concentration, which ubiquitylated hypoxia-inducible factor 1 alpha subunit (HIF-1α) in chondrocytes and led to cartilage degeneration.
Lcp1
knockout impeded angiogenesis, which maintained hypoxia environment in joints and delayed the OA progression. Stabilization of HIF-1α delayed cartilage degeneration, and knockdown of
Hif1a
abolished the protective effects of
Lcp1
knockout. Last, we showed that Oroxylin A, an
Lcp1-
encoded protein
l
-plastin (LPL) inhibitor, could alleviate OA progression. In conclusion, maintaining hypoxic environment is an attractive strategy for OA treatment.
Transformation of coral communities subjected to an unprecedented heatwave is modulated by local disturbance
Authors: Baum Julia K. , Claar Danielle C. , Tietjen Kristina L. , Magel Jennifer M. T. , Maucieri Dominique G. , Cobb Kim M. , McDevitt-Irwin Jamie M.
Published: April 2023

Corals are imminently threatened by climate change–amplified marine heatwaves. However, how to conserve coral reefs remains unclear, since those without local anthropogenic disturbances often seem equally or more susceptible to thermal stress as impacted ones. We disentangle this apparent paradox, revealing that the relationship between reef disturbance and heatwave impacts depends upon the scale of biological organization. We show that a tropical heatwave of globally unprecedented duration (~1 year) culminated in an 89% loss of hard coral cover. At the community level, losses depended on pre-heatwave community structure, with undisturbed sites, which were dominated by competitive corals, undergoing the greatest losses. In contrast, at the species level, survivorship of individual corals typically declined as local disturbance intensified. Our study reveals both that prolonged heatwaves projected under climate change will still have winners and losers and that local disturbance can impair survival of coral species even under such extreme conditions.
Geological records of transient fluid drainage into the shallow mantle wedge
Authors: Yoshida Kazuki , Oyanagi Ryosuke , Kimura Masao , Plümper Oliver , Fukuyama Mayuko , Okamoto Atsushi
Published: April 2023

Pore fluid pressure on subduction zone megathrusts is lowered by fluid drainage into the overlying plate, affecting subduction zone seismicity. However, the spatial and temporal scales of fluid flow through suprasubduction zones are poorly understood. We constrain the duration and velocity of fluid flow through a shallow mantle wedge based on the analyses of vein networks consisting of high-temperature serpentine in hydrated ultramafic rocks from the Oman ophiolite. On the basis of a diffusion model and the time-integrated fluid flux, we show that the channelized fluid flow was short-lived (2.1 × 10
−1
to 1.1 × 10
1
 years) and had a high fluid velocity (2.7 × 10
−3
to 4.9 × 10
−2
 meters second
−1
), which is close to the propagation velocities of seismic events in present-day subduction zones. Our results suggest that the drainage of fluid into the overlying plate occurs as episodic pulses, which may influence the recurrence of megathrust earthquakes.
T
STEM
-like CAR-T cells exhibit improved persistence and tumor control compared with conventional CAR-T cells in preclinical models
Authors: Meyran Deborah , Zhu Joe Jiang , Butler Jeanne , Tantalo Daniela , MacDonald Sean , Nguyen Thu Ngoc , Wang Minyu , Thio Niko , D’Souza Criselle , Qin Vicky Mengfei , Slaney Clare , Harrison Aaron , Sek Kevin , Petrone Pasquale , Thia Kevin , Giuffrida Lauren , Scott Andrew M. , Terry Rachael L. , Tran Ben , Desai Jayesh , Prince H. Miles , Harrison Simon J. , Beavis Paul A. , Kershaw Michael H. , Solomon Ben , Ekert Paul G. , Trapani Joseph A. , Darcy Phillip K. , Neeson Paul J.
Published: April 2023

Patients who receive chimeric antigen receptor (CAR)–T cells that are enriched in memory T cells exhibit better disease control as a result of increased expansion and persistence of the CAR-T cells. Human memory T cells include stem-like CD8
+
memory T cell progenitors that can become either functional stem-like T (T
STEM
) cells or dysfunctional T progenitor exhausted (T
PEX
) cells. To that end, we demonstrated that T
STEM
cells were less abundant in infused CAR-T cell products in a phase 1 clinical trial testing Lewis Y-CAR-T cells (NCT03851146), and the infused CAR-T cells displayed poor persistence in patients. To address this issue, we developed a production protocol to generate T
STEM
-like CAR-T cells enriched for expression of genes in cell replication pathways. Compared with conventional CAR-T cells, T
STEM
-like CAR-T cells had enhanced proliferative capacity and increased cytokine secretion after CAR stimulation, including after chronic CAR stimulation in vitro. These responses were dependent on the presence of CD4
+
T cells during T
STEM
-like CAR-T cell production. Adoptive transfer of T
STEM
-like CAR-T cells induced better control of established tumors and resistance to tumor rechallenge in preclinical models. These more favorable outcomes were associated with increased persistence of T
STEM
-like CAR-T cells and an increased memory T cell pool. Last, T
STEM
-like CAR-T cells and anti–programmed cell death protein 1 (PD-1) treatment eradicated established tumors, and this was associated with increased tumor-infiltrating CD8
+
CAR
+
T cells producing interferon-γ. In conclusion, our CAR-T cell protocol generated T
STEM
-like CAR-T cells with enhanced therapeutic efficacy, resulting in increased proliferative capacity and persistence in vivo.
Selective Bcl-2 inhibition promotes hematopoietic chimerism and allograft tolerance without myelosuppression in nonhuman primates
Authors: Sasaki Hajime , Hirose Takayuki , Oura Tetsu , Otsuka Ryo , Rosales Ivy , Ma David , Lassiter Grace , Karadagi Ahmad , Tomosugi Toshihide , Dehnadi Abbas , Matsunami Masatoshi , Raju Paul Susan , Reeves Patrick M. , Hanekamp Isabel , Schwartz Samuel , Colvin Robert B. , Lee Hang , Spitzer Thomas R. , Cosimi A. Benedict , Cippà Pietro E. , Fehr Thomas , Kawai Tatsuo
Published: April 2023

Hematopoietic stem cell transplantation (HSCT) has many potential applications beyond current standard indications, including treatment of autoimmune disease, gene therapy, and transplant tolerance induction. However, severe myelosuppression and other toxicities after myeloablative conditioning regimens have hampered wider clinical use. To achieve donor hematopoietic stem cell (HSC) engraftment, it appears essential to establish niches for the donor HSCs by depleting the host HSCs. To date, this has been achievable only by nonselective treatments such as irradiation or chemotherapeutic drugs. An approach that is capable of more selectively depleting host HSCs is needed to widen the clinical application of HSCT. Here, we show in a clinically relevant nonhuman primate model that selective inhibition of B cell lymphoma 2 (Bcl-2) promoted hematopoietic chimerism and renal allograft tolerance after partial deletion of HSCs and effective peripheral lymphocyte deletion while preserving myeloid cells and regulatory T cells. Although Bcl-2 inhibition alone was insufficient to induce hematopoietic chimerism, the addition of a Bcl-2 inhibitor resulted in promotion of hematopoietic chimerism and renal allograft tolerance despite using only half of the dose of total body irradiation previously required. Selective inhibition of Bcl-2 is therefore a promising approach to induce hematopoietic chimerism without myelosuppression and has the potential to render HSCT more feasible for a variety of clinical indications.
Investigation of Peptidoglycan-Associated Lipoprotein of
Acinetobacter baumannii
and Its Interaction with Fibronectin To Find Its Therapeutic Potential
Authors: Solanki Vandana , Tiwari Monalisa , Tiwari Vishvanath
Published: April 2023

Acinetobacter baumannii
causes hospital-acquired infections and is responsible for high mortality and morbidity. The interaction of this bacterium with the host is critical in bacterial pathogenesis and infection.