bluuebunny/crossref_metadata_2025_split huggingface dataset:
Type of refugee accommodation and health of residents: cross-sectional cluster analysis
Authors: Mohsenpour Amir , Dudek Verena , Bozorgmehr Kayvan , Biddle Louise , Razum Oliver , Sauzet Odile 
Published: December 2022

AbstractFew studies have assessed whether refugees’ health is associated with accommodation characteristics. We aimed to devise a typology of refugee accommodation based on number of inhabitants, degree of housing deterioration and remoteness (distance to amenities) and assess the association with health in multivariate analyses. Accommodations with a moderate occupation, lowest levels of deterioration, and a central urban location showed the best health outcomes in terms of subjective general health status, depression, and general anxiety disorder (GAD). Associations were strongest for GAD and weakest for depression. Our findings inform policymakers on layout and location of refugee collective accommodation centres.
Regions with intermediate DNA methylation are epigenomic hotspots governing behavioral adaptation to changing environments
Authors: Brindley Elizabeth , Taki Faten , Odell Shannon C. , Baker Madelyn R , Toth Judit Gal , Toth Miklos 
Published: December 2022

AbstractEpigenetic and associated gene expression changes in the brain drive animals’ ability to adapt to changing environments. However, epigenetic attributes of environmental adaptation are unknown. Here we show that exercise, unpredictable stress, and environmental enrichment, conditions that elicit adaptive changes in synaptic plasticity and spatial learning, result in CpG methylation changes in regions that exist in both methylated and unmethylated states (i.e., epigenetically bistable) in hippocampal granule cells. Sustained exposures altered both the epiallelic proportions at these regions and neuronal and behavioral adaptation, indicating their adaptive nature. These malleable regions were enriched in exons and enhancer-associated chromatin marks. Their locations were mostly unique to specific environments but converged on similar synaptic genes. Lastly, manipulating DNA methylation altered epiallelic proportions at bistable regions in granule cells and phenocopied adaptive behavior. We propose that shifts in epiallelic proportions at evolutionarily conserved bistable regions, via gene expression changes, contribute to hippocampal plasticity and behavioral adaptation to changing environments.
Genomic heterogeneity and ploidy identify patients with intrinsic resistance to PD-1 blockade in metastatic melanoma
Authors: Tarantino Giuseppe , Ricker Cora A. , Wang Annette , Ge Will , Aprati Tyler J. , Huang Amy Y. , Madha Shariq , Chen Jiajia , Shi Yingxiao , Glettig Marc , Frederick Dennie T. , Freeman Samuel , Holovatska Marta M. , Manos Michael P. , Zimmer Lisa , Rösch Alexander , Zaremba Anne , Reardon Brendan , Park Jihye , Elmarakeby Haitham A. , Schilling Bastian , Giobbie-Hurder Anita , Vokes Natalie I. , Buchbinder Elizabeth I. , Flaherty Keith T. , Haq Rizwan , Wu Catherine J. , Boland Genevieve M. , Hodi F. Stephen , Van Allen Eliezer M. , Schadendorf Dirk , Liu David 
Published: December 2022

AbstractWhile the introduction of immune checkpoint blockade (ICB) has dramatically improved clinical outcomes for patients with advanced melanoma, a significant proportion of patients develop resistance to therapy, and mechanisms of resistance are poorly elucidated in most cases. Further, while combination ICB has higher response rates and improved progression free survival compared to single agent therapy in the front line setting, there is significantly increased toxicity with combination ICB, and biomarkers to identify patients who would disproportionately benefit from combination therapy vs aPD-1 ICB are poorly characterized. To understand resistance mechanisms to single vs combination ICB therapy, we analyze whole-exome-sequencing (WES) of pre-treatment tumor and matched normals of 4 cohorts (n=140) of previously ICB-naïve aPD-1 ICB treated patients. We find that high intratumoral genomic heterogeneity and low ploidy identify patients with intrinsic resistance to aPD-1 ICB. Comparing to a melanoma cohort from a pre-targeted therapy and ICB time period (“untreated” cohort), we find that genomic heterogeneity specifically predicts response and survival in the ICB treated cohorts, but not in the untreated cohort, while ploidy is also prognostic of overall survival in the “untreated” (by targeted therapy or ICB) group. To establish clinically actionable predictions, we optimize a simple decision tree using genomic ploidy and heterogeneity to identify with high confidence (90% PPV) a subset of patients with intrinsic resistance to and significantly worse survival on aPD1 ICB treatment. We then validate this model in independent cohorts, and further show that a significant proportion of patients predicted to have intrinsic resistance to single agent aPD-1 ICB respond to combination ICB, which suggests that nominated patients may benefit disproportionately from combination ICB. We further show that the features and predictions of the model are independent of known clinical features and previously nominated molecular biomarkers. These findings highlight the clinical and biological importance of genomic heterogeneity and ploidy, and sets a concrete framework towards clinical actionability, broadly advancing precision medicine in oncology.
Sleep-like state during wakefulness induced by psychedelic 5-MeO-DMT in mice
Authors: Bréant Benjamin J B , Mengual José Prius , Hoerder-Suabedissen Anna , Patel Jasmin , Bannerman David M , Sharp Trevor , Vyazovskiy Vladyslav V 
Published: December 2022

AbstractPsychedelics lead to profound changes in subjective experience and behaviour, which are typically conceptualised in psychological terms rather than corresponding to an altered brain state or a distinct state of arousal. Here, we performed chronic electrophysiological recordings from the cortex concomitant with pupillometry in freely moving adult male mice following an injection of a short-acting psychedelic 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT). We observed an acute induction of a dissociated state of arousal, characterised by prominent sleep-like slow waves in the cortex and marked pupil dilation in behaviourally awake, moving animals. REM sleep was markedly suppressed, similar to the effect of conventional antidepressants. We argue that the occurrence of a dissociated brain state combining features of waking and sleep may fundamentally underpin the known and hypothesised effects of psychedelics — from dream-like hallucinations to reopening of the critical period for plasticity.
Biasing AlphaFold2 to predict GPCRs and Kinases with user-defined functional or structural properties
Authors: Sala D. , Meiler J. 
Published: December 2022

ABSTRACTDetermining the three-dimensional structure of proteins in their native functional states has been a longstanding challenge in structural biology. While experimental methods combined with integrative structural biology has been the most effective way to get high accuracy structures and mechanistic insights for larger proteins, advances in deep machine-learning algorithms have paved the way to fully computational predictions. In this field, AlphaFold2 (AF2) pioneeredab initiohigh accuracy single chain modeling. Since then, different customizations expanded the number of conformational states accessible through AF2. Here, we further extended AF2 with the aim of enriching an ensemble of models with user-defined functional or structural features. We tackled two common protein families for drug discovery, G-protein-coupled receptors (GPCRs) and Kinases. Our approach automatically identifies the best templates satisfying the specified features and combines those with genetic information. We also introduced the possibility of shuffling the selected templates to expand the space of solutions. In our benchmark, models showed the intended bias and great accuracy. Our protocol can thus be exploited for modeling user-defined conformational states in automatic fashion.
Mesenchymal Progenitors set the homeostatic inflammatory milieu via the TAK1-NFkB axis
Authors: Marine Theret , Melina Messing , Zoe White , Wei Tung Lin , Lucas Rempel , Mark Hamer , Joshua Hashimoto , Fangfang Li , Julyanne Brasssar , Yicong Li , Elodie Sauge , Samuel Shin , Katie Day , Manjosh Uppal , Marcela Low , Christine Eisner , Sato Shintaro , Akira Shizuo , Michael Hughes , Pascal Bernatchez , McNagny Kelly M , Rossi Fabio M.V. 
Published: December 2022

SummaryThe ability of mesenchymal stromal cells to modulate inflammation is at the basis of the ongoing interest in their therapeutic potential. Yet, reliable success in clinical trials is limited, possibly due to a limited understanding of their impact on the inflammatory milieu in physiological conditions. Here we show that, at steady state, mesenchymal progenitors regulate the balance between type 1 and type 2 inflammatory milieus by acting on innate immune cells through the TAK1-NFkB pathway. Suppressing the constitutive activity of this pathway in MPs leads to skewing of the immune system toward systemic Type 2 inflammation (Th2). These changes have significant effects on diseases with an important inflammatory component, leading to a worsening of disease in a preclinical model of Th2-dependent Asthma, and a reduction of symptoms associated with Th1/Th17-dependent experimental autoimmune encephalitis.
TRAP1S-nitrosylation as a model of population-shift mechanism to study the effects of nitric oxide on redox-sensitive oncoproteins
Authors: Papaleo Elena , Tiberti Matteo , Arnaudi Matteo , Pecorari Chiara , Faienza Fiorella , Cantwell Lisa , Degn Kristine , Pacello Francesca , Battistoni Andrea , Lambrughi Matteo , Filomeni Giuseppe 
Published: December 2022

AbstractS-nitrosylation is a post-translational modification in which nitric oxide (NO) binds to the thiol group of cysteine, generating anS-nitrosothiol (SNO) adduct.S-nitrosylation has different physiological roles, and its alteration has also been linked to a growing list of pathologies, including cancer. SNO can affect the function and stability of different proteins, such as the mitochondrial chaperone TRAP1. Interestingly, the SNO site (C501) of TRAP1 is in the proximity of another cysteine (C527). This feature suggests that theS-nitrosylated C501 could engage in a disulfide bridge with C527 in TRAP1, resembling the well-known ability ofS-nitrosylated cysteines to resolve in disulfide bridge with vicinal cysteines. We used enhanced sampling simulations and in-vitro biochemical assays to address the structural mechanisms induced by TRAP1S-nitrosylation. We showed that the SNO site induces conformational changes in the proximal cysteine and favors conformations suitable for disulfide-bridge formation. We explored 4172 knownS-nitrosylated proteins using high-throughput structural analyses. Furthermore, we carried out coarse-grain simulations of 44 proteins to account for protein dynamics in the analyses. This resulted in the identification of up to 1248 examples of proximal cysteines which could sense the redox state of the SNO site, opening new perspectives on the biological effects of redox switches. In addition, we devised two bioinformatic workflows (https://github.com/ELELAB/SNO_investigation_pipelines) to identify proximal or vicinal cysteines for a SNO site with accompanying structural annotations. Finally, we analyzed mutations in tumor suppressor or oncogenes in connection with the conformational switch induced byS-nitrosylation. We classified the variants as neutral, stabilizing, or destabilizing with respect to the propensity to beS-nitrosylated and to undergo the population-shift mechanism. The methods applied here provide a comprehensive toolkit for future high-throughput studies of new protein candidates, variant classification, and a rich data source for the research community in the NO field.
Sketch the Organoids from Birth to Death – Development of an Intelligent OrgaTracker System for Multi-Dimensional Organoid Analysis and Recreation
Authors: Du Xuan , Cui Wenhao , Song Jiaping , Cheng Yanping , Qi Yuxin , Zhang Yue , Li Qiwei , Zhang Jing , Sha Lifeng , Ge Jianjun , Li Yanhui , Chen Zaozao , Gu Zhongze 
Published: December 2022

AbstractOrganoids are three-dimensionalin vitromodels that recreate the structure and physiology of their source organs or tissues in remarkable detail. Due to the diversity of organoids in shape and size and the three-dimensional growth environment, it is challenging to observe and analyze organoids periodically in the microscope to obtain their morphological or growth characteristics, especially in high-throughput experiments. Here, this paper first proposes OrgaTracker, a novel assembled architecture combining Yolov5 for object detection and U-net for semantic segmentation. The deep learning algorithm can track and segment organoids over time and effectively avoid the influence of bubbles and accurately capture and analyze organoid fusion. A two-stage object detection methodology was performed to achieve the crypt count of each mouse small intestinal organoid, and the skeleton of intestinal organoids was further extracted to describe the structural relationship between the absorption villi and the crypt. Next, we used the “sketch” to convey visual concepts, which led to the clear identification of organoids at different growth/treatment stages. Lastly, based on our designed GAN network, various organoid images could be generated by drawing sketches, which for the first time provided a direct and practical approach for biologists and researchers to create “artificial organoids” simulating organoid morphology and allowing the exchange of ideas on organoid development. In sum, this research reported and provided a comprehensive novel organoid analysis and generation methodology for organoid research.HighlightsOrgaTracker can track organoids and capture and analyze the integration of organoids. The system was also able to identify the number of crypts in each intestinal organoid, as well as extract the skeleton of the organoid. It also allowed, for the first time, recreating “artificial organoids” from hand-drawn sketches.
Genetically engineered mesenchymal stem cells as a nitric oxide reservoir for acute kidney injury therapy
Authors: Huang Haoyan , Qian Meng , Liu Yue , Chen Shang , Li Huifang , Han Zhibo , Han Zhong-Chao , Chen Xiang-Mei , Zhao Qiang , Li Zongjin 
Published: December 2022

ABSTRACTNitric oxide (NO), as a gaseous therapeutic agent, shows great potential for the treatment of many kinds of diseases. Although various NO delivery systems have emerged, the immunogenicity and long-term toxicity of artificial carriers hinder the potential clinical translation of this gas therapeutics. Mesenchymal stem cells (MSCs), with the capacities of self-renewal, differentiation, and low immunogenicity, have been used as living carriers. However, MSCs as gaseous signaling molecule (GSM) carriers have not been reported. In this study, MSCs were genetically modified to produce mutant β-galactosidase (β-GALH363A). Furthermore, a new NO prodrug, 6-methyl-galactose-benzyl-oxy NONOate (MGP), was designed. MGP can entrance into cell and selectively trigger the NO release from genetically engineered MSCs (eMSCs) in the presence of β-GALH363A. Moreover, our results revealed that eMSCs can release NO when MGP is systemically administered in a mouse model of acute kidney injury (AKI), which can achieve NO release in a precise spatiotemporal manner and augment the therapeutic efficiency of MSCs. This eMSC and NO prodrug system provides a unique and tunable platform for GSM delivery and holds promise for regenerative therapy by enhancing the therapeutic efficiency of stem cells.SignificanceGaseous signaling molecules (GSMs), such as nitric oxide (NO), hold tremendous potential in regenerative medicine and tissue engineering. However, the delivery of GSMs with stem cells to target tissues or organs in response to demand has never been reported. This study designed engineered mesenchymal stem cells (eMSCs) that produce mutant β-galactosidase (β-GALH363A) and trigger NO release when the NO prodrug is systemically administered, which can achieve NO release in a precise spatiotemporal manner and augment the therapeutic efficiency of MSCs in a mouse model of acute kidney injury (AKI). This eMSC and NO prodrug system provides a unique and tunable platform for GSM delivery and holds promise for regenerative therapy by enhancing the therapeutic efficiency of stem cells.Graphical abstract
ATP-dependent restriction enzyme SauUSI fromStaphylococcus aureusis also abona fidesingle strand DNA endonuclease
Authors: Tumuluri Vinayak Sadasivam , Saikrishnan Kayarat 
Published: December 2022

AbstractRestriction endonucleases cleave exogenous DNA thus restricting horizontal gene transfer and phage infection of host bacterium. This nucleolytic activity occurs on double-stranded DNA (dsDNA) and is target site specific. Here we report that the Type IV ATP-dependent restriction endonuclease SauUSI fromStaphylococcus aureusalso possesses a hitherto unknown single-stranded DNA (ssDNA) endonuclease activity. We demonstrate that, unlike the dsDNA cleavage activity, ssDNA cleavage by SauUSI does not require divalent cation or ATP hydrolysis and is target-site and DNA methylation-status independent. Furthermore, we show that SauUSI can cut ssDNA gaps, overhangs, bubbles and loops but not ssRNA. The activity is inhibited at higher concentrations of magnesium ion, ATP, and the presence of single strand DNA binding protein. The ssDNA nuclease activity is thus tightly regulated and may protect the host DNA from damage by SauUSI.
Moving toward sustainability and circularity in hill road construction: a study of barriers, practices and performance
Authors: Khural Ram Asra , Shashi  , Ertz Myriam , Cerchione Roberto 
Published: December 2022

PurposeThis study explores the relationships among sustainability implementation barriers (resource, managerial and regulatory barriers), sustainability practices (sustainable construction materials, sustainable construction design, modern construction methods and environmental provisions and reporting) and sustainability performance (environmental, economic and social) in hill road construction (HRC).Design/methodology/approachPrimary data were collected from the 313 HRC practitioners with the help of a questionnaire, and research hypotheses were tested employing structural equation modeling.FindingsThe findings reveal a mixed effect of sustainability implementation barriers. Resource (managerial) barriers are negatively related to all practices except environmental provisions and reporting (sustainable construction materials), while regulatory barriers only negatively impact modern construction methods. On the other hand, all sustainability practices positively impact environmental performance, whereas economic (social) performance is positively influenced by all practices, except environmental provisions and reporting (modern construction methods), and positively affects economic performance.Originality/valueIn order to transform HRC toward sustainability, the barriers to sustainability implementation, sustainability practices and performance need to be understood by practitioners; however, the relationships have not previously been empirically assessed in extant literature. Besides, past research appears to be predominantly focused on the environmental aspect, thereby neglecting economic and social aspects. This study is a modest attempt to bridge these research gaps.
Critical factors influencing the failure of joint ventures in the South African construction industry: a confirmatory factor analysis approach
Authors: Ikuabe Matthew Osivue , Aigbavboa Clinton Ohis , Thwala Wellington Didibhuku , Chiyangwa Donald , Oke Ayodeji Emmanuel 
Published: December 2022

PurposeJoint ventures (JVs) serve as a viable tool in mitigating some of the challenges posed to the effective delivery of construction projects. However, JVs are highly susceptible to failure in most developing countries. Therefore, this study seeks to unravel the critical factors influencing the failure of JVs in the South African construction industry.Design/methodology/approachA quantitative approach was adopted for the study using a well-structured questionnaire as the instrument for data collection. Respondents for the study were built environment professionals in Gauteng province in South Africa. Data elicited from respondents were analyzed using a four-pronged process which included descriptive statistics, one sample t-test, exploratory factor analysis and confirmatory factor analysis.FindingsResulting from the analysis conducted, four critical components emerged as the major factors influencing the failure of JVs in the South African construction industry, which are inefficient financial framework, divergent organizational culture, poor project governance and inadequacies from project stakeholders.Practical implicationsThe outcome of this study presents a roadmap for stakeholders in the construction industry with the requisite knowledge of the critical factors leading to the failure of JVs, consequently providing a clear path for the successful delivery of JV mandates.Originality/valueEvidence from literature suggests that several studies have been conducted on the various aspects of JVs in the South African construction industry; however, none has focused on the leading factors attributed to the failure of JVs. Also, the findings of this study cultivate a good theoretical platform for future studies on JVs.
Research on the construction safety risk assessment of prefabricated subway stations in China
Authors: Luo Zhenhua , Guo Juntao , Han Jianqiang , Wang Yuhong 
Published: December 2022

PurposePrefabricated technology is gradually being applied to the construction of subway stations due to its characteristic of mechanization. However, the prefabricated subway station in China is in the initial stage of development, which is prone to construction safety issues. This study aims to evaluate the construction safety risks of prefabricated subway stations in China and formulate corresponding countermeasures to ensure construction safety.Design/methodology/approachA construction safety risk evaluation index system for the prefabricated subway station was established through literature research and the Delphi method. Furthermore, based on the structure entropy weight method, matter-element theory and evidence theory, a hybrid evaluation model is developed to evaluate the construction safety risks of prefabricated subway stations. The basic probability assignment (BPA) function is obtained using the matter-element theory, the index weight is calculated using the structure entropy weight method to modify the BPA function and the risk evaluation level is determined using the evidence theory. Finally, the reliability and applicability of the evaluation model are verified with a case study of a prefabricated subway station project in China.FindingsThe results indicate that the level of construction safety risks in the prefabricated subway station project is relatively low. Man risk, machine risk and method risk are the key factors affecting the overall risk of the project. The evaluation results of the first-level indexes are discussed, and targeted countermeasures are proposed. Therefore, management personnel can deeply understand the construction safety risks of prefabricated subway stations.Originality/valueThis research fills the research gap in the field of construction safety risk assessment of prefabricated subway stations. The methods for construction safety risk assessment are summarized to establish a reliable hybrid evaluation model, laying the foundation for future research. Moreover, the construction safety risk evaluation index system for prefabricated subway stations is proposed, which can be adopted to guide construction safety management.