bluuebunny/crossref_metadata_2025_split huggingface dataset:
The predictive capacity of polygenic risk scores for disease risk is only moderately influenced by imputation panels tailored to the target population
Authors: Levi Hagai , Elkon Ran , Shamir Ron 
Published: August 2023

AbstractPolygenic risk scores (PRS) predict individuals’ genetic risk of developing complex diseases. They summarize the effect of many genetic variants discovered in genome-wide association studies (GWASs). However, to date, large GWASs exist primarily for the European population and the quality of PRS prediction declines when applied to target sets of other ethnicities. A key step in using a PRS is imputation, which is the inference of un-typed SNPs using a set of fully-sequenced individuals, called the imputation panel. The SNP genotypes called by the imputation process depend on the ethnic composition of the imputation panel. Several studies have shown that imputing genotypes using a panel that contains individuals of the same ethnicity as the genotyped individuals improves imputation accuracy. However, until now, there has been no systematic investigation into the influence of the ethnic composition of imputation panels on the accuracy of PRS predictions when applied to ethnic groups that differ from the population used in the GWAS.In this study we estimated the effect of imputation of the target set on prediction accuracy of PRS when the discovery (GWAS) and the target sets come from different ethnic groups. We analyzed twelve binary phenotypes and three populations from the UK Biobank (Europeans, South-Asians, and Africans). We generated imputation panels from several ethnic groups, imputed the target set using each panel, and generated PRS to compute individuals’ risk scores. Then, we assessed the prediction accuracy obtained from each imputation panel. Our analysis indicates that using an imputation panel matched to the ethnic group of the target population yields only a marginal improvement and only under specific conditions. Hence, while a target-matched imputation panel can potentially improve prediction accuracy of European PRSs in non-EUR populations, the improvement is limited.
High-efficiency gene editing inAnopheles sinensisusing ReMOT control
Authors: Yang Xiao-lin , Ling Xia , Sun Quan , Qiu Pin-pin , Xiang Kai , Hong Jun-feng , He Shu-lin , Chen Jie , Ding Xin , Hu Hai , He Zheng-bo , Zhou Cao , Chen Bin , Qiao Liang 
Published: August 2023

AbstractCRISPR/Cas9-mediated gene editing provides an effective method for deciphering the molecular mechanisms underlying mosquito development and mosquito-borne disease transmission, as well as for exploring genetic control strategies. However, delivering the Cas9 ribonucleoprotein complex by embryo injection to produce genetic modifications is challenging, is mostly confined to model mosquitoes and specialized laboratories, and has low editing efficiency. Here, we established an effective Receptor-Mediated Ovary Transduction of Cargo (ReMOT) control method, enabling the introduction of heritable mutations intoAnopheles sinensis, the major malaria vector in China and Southeast Asia, via the injection of female adult mosquitoes. Injection of a mixture of P2C-DsRed and saponin resulted in red fluorescence in the ovaries, with a 100% success rate. Using this system, we knocked-out the pigment synthesis genes,AswhiteandAsyellow, using injected wild-type (WT) females mated with WT males, resulting in the highest efficiency of gene editing among mosquitoes under the same mating conditions. Furthermore, the gene-editing efficiency was increased by at least 2.1-fold using injected WT females mated with mutant males. This improved ReMOT control method exhibits high editing efficiency, with important benefits in terms of functional genomics research and genetic control strategies inAn. sinensis. Moreover, this represents a convenient method for gene manipulation in laboratories that are unable to perform embryo injection or that lack embryo-injection equipment.
RdDM mutants reduce histone methylation rather than DNA methylation at the paramutated maizeb1enhancer
Authors: Hövel Iris , Bader Rechien , Louwers Marieke , Haring Max , Peek Kevin , Gent Jonathan I. , Stam Maike 
Published: August 2023

AbstractParamutation is the transfer of mitotically and meiotically heritable silencing information between two alleles. With paramutation at the maizebooster1(b1) locus, the low expressedB’epiallele heritably changes the high expressedB-Iepiallele intoB’with 100% frequency. This requires specific tandem repeats and multiple components of the RNA-directed DNA methylation (RdDM) pathway, including the RNA-dependent RNA polymerase (RdRP,mediator of paramutation1, MOP1), the second-largest subunit of RNA polymerase IV and V (NRP(D/E)2a,mediator of paramutation2,MOP2), and the largest subunit of RNA Polymerase IV (NRPD1,mediator of paramutation3, MOP3). Mutations inmopgenes prevent paramutation and release silencing at theB’epiallele. In this study we investigated the effect of mutations inmop1,mop2andmop3on chromatin structure and DNA methylation at theB’epiallele, and especially the regulatory hepta-repeat 100 kb upstream of theb1gene.We show that mutations inmop1andmop3result in decreased repressive histone modifications H3K9me2 and H3K27me2 at the hepta-repeat. Associated with this decrease are partial activation of the hepta-repeat enhancer function, formation of a multi-loop structure, and elevatedb1expression. Inmop2mutants, which do not show elevatedb1expression, H3K9me2 and H3K27me2 and a single-loop structure like in wild typeB’are retained. Surprisingly, high DNA methylation levels at theB’hepta-repeat remains in all three mutants. Our results raise the possibility of MOP factors mediating RNA-directed histone methylation rather than RNA-directed DNA methylation at theb1locus.
KRASallelic imbalance drives tumour initiation yet suppresses metastasis in colorectal cancerin vivo
Authors: Najumudeen Arafath K. , Fey Sigrid K. , Millett Laura M. , Ford Catriona , Gilroy Kathryn , Gunduz Nuray , Ridgway Rachel A. , Anderson Eve , Strathdee Douglas , Clark William , Nixon Colin , Morton Jennifer P. , Campbell Andrew D. , Sansom Owen J. 
Published: August 2023

AbstractOncogenicKRASmutations are well-described functionally and are known to drive tumorigenesis. Recent reports describe a significant prevalence ofKRASallelic imbalances or gene dosage changes in human cancers, including loss of the wild-type allele inKRASmutant cancers. However, there is still much debate over the function of wild-typeKRASin tumour initiation, progression and therapeutic response. We have developed a genetically engineered mouse model which allows deletion of the wild-type copy ofKrasin the context of an intact oncogenicKrasin colorectal cancer. We observe that in the presence of oncogenicKras, wild-typeKrasacts to restrain tumour growth. Mechanistically, deletion of wild-typeKrasexacerbates oncogenic KRAS signalling through MAPK and thus drives tumour initiation. Absence of wild-typeKraspotentiates the oncogenic effect of KRASG12D, while presence of wild-typeKrasis associated with resistance to inhibition of MEK1/2 in KRASG12D driven tumours. Importantly, loss of wild-typeKrasin oncogenic KRAS-driven aggressive tumours significantly alters tumour progression, metastasis while impacting tumour immune cell infiltration. This study demonstrates a suppressive role for wild-typeKrasduring colon tumour initiation and highlights the critical impact of wild-typeKrasupon therapeutic response to MAPK and tumour progression inKrasmutant cancers.HighlightsWild-type KRAS suppresses mutant KRASG12D mediated proliferation and signalling in colorectal cancer modelsin vivoConcomitant loss of wild-type KRAS and activation of WNT signalling promotes mutant KRAS-driven tumour initiation.Wild-type KRAS promotes resistance to MAPK inhibition in KRAS mutant tumoursLoss of wild-type KRAS inhibits metastasis of late-stage mutant KRAS colorectal cancer models.
An amphipathic helix facilitates direct membrane binding of Mycoplasma FtsZ
Authors: Dutta Soumyajit , Poddar Sakshi , Chakraborty Joyeeta , Srinivasan Ramanujam , Gayathri Pananghat 
Published: August 2023

AbstractCell division in bacteria is initiated by constriction of the Z-ring comprising two essential proteins FtsZ and FtsA. Despite our knowledge about the crucial function of the Z-ring in bacterial division, the precise roles and mechanism of how FtsZ and FtsA drive cell constriction remain elusive. FtsZ/FtsA in wall-less bacteria like mycoplasmas is an ideal model system for obtaining mechanistic insights into Z-ring constriction in the absence of cell wall machinery. In this study, we have analyzed FtsZ and FtsA sequences of 113 mycoplasma species and compared with the corresponding protein sequences in cell-walled bacteria. We report a phylogenetically distinct group of 12 species that possess FtsZs without the canonical FtsA interacting conserved C-terminal peptide (CCTP) motif. Interestingly, these FtsZs contain a putative membrane-binding amphipathic helix as an N-terminal or C-terminal extension to the globular FtsZ domain. As a proof-of-concept, we experimentally show that the proposed C-terminal amphipathic helix inM. genitaliumFtsZ binds liposomesin vitroas well as localizes toE. colimembranein vivo. Additionally, we identify a putative cholesterol recognition motif within the C-terminal amphipathic helix region ofM. genitaliumFtsZ. Our study catalogues the functional variations of membrane attachment by the FtsZ and FtsA system in cell wall-less mycoplasmas and provides a new perspective to study novel functions of FtsZ/A system in cell division.ImportanceZ-ring and peptidoglycan synthesis machinery both play crucial roles in bacterial cell division. Currently, our knowledge about how FtsZ and FtsA, the two primary components of the Z-ring, function, is limited to cell-walled bacteria where ring constriction is coupled to peptidoglycan synthesis. Cell wall-less bacterial FtsZ/A system is an excellent model to study the mechanism of Z-ring constriction in the absence of cell wall synthesis machinery. Here, we analysed FtsZ protein sequences across mycoplasma species and identified their characteristic sequence features. Our study reveals a novel group of FtsZs from mycoplasma with an inherent membrane binding and probable cholesterol sensing amphipathic motif, which serves as a new paradigm to explore fundamental roles of FtsZ and FtsA in Z-ring constriction during bacterial division.
Modelling the impact of rainfall events on increasingVibrio vulnificusconcentrations in Pacific oysters (Crassostrea gigas)
Authors: Fletcher Graham C. , Taylor Roland , Hedderley Duncan 
Published: August 2023

AbstractVibrio vulnificusoccurs naturally in seawater and causes debilitating, often fatal illnesses, particularly in people with underlying health issues such as liver disease. The illness can occur when raw molluscan shellfish that have bio-accumulated the organism are consumed. New Zealand seafood is not known to have caused any illnesses, although there have been wound infections. This study sought to better understand the effect of environmental conditions on concentrations ofV. vulnificusin Pacific oysters in three harbours over the summer months of 2016–19. Fortnightly sampling at two harbours only once gave a most probable number (MPN) of >10 per g of oyster meat, while the third harbour regularly produced much higher counts (up to 220,000 per g). From 2017–19, weekly samples from three sites in this harbour (four in 2018) were tested. Eleven peaks in concentration were observed, all when seawater temperatures exceeded 20°C and after heavy rainfall had reduced the seawater salinity, usually to <25‰ from the average of 32‰. A fitted structural equation model with temperature and salinity terms accounted for 60% of the variance in concentrations and rates of decline after concentration peaks averaged 1.05 log10MPN per week.The rate of decline was highly variable so microbiological testing would be required to confirm this rate for use in food safety management. However, the results of the study will enable better risk management.ImportanceVibrio vulnificusis a deadly bacterium that naturally occurs in some seawater and can be concentrated in shellfish such as oysters. Consumers with underlying health issues who eat contaminated shellfish may suffer serious illnesses. New Zealand shellfish have never been known to cause such illnesses although the species is present in our seawater. The strains present may not be able to cause foodborne illness. We found thatV. vulnificuscould be present in high concentrations in farmed Pacific oysters in one of three studied harbours. This happened when seawater temperatures were warm and heavy rainfall reduced salinity. We developed a model based on seawater temperature and salinity that would be able to predict concentrations in shellfish, at least in this harbour. This will help industry and regulators manage the food safety risk should this organism become a public health issue.TweetWe modelled concentrations ofVibrio vulnificusin Pacific oysters after flood events and showed that seawater salinity and temperatures in previous 168 h affected them.
Intermittent fasting promotes ILC3s secreting IL-22 contributing to the beigeing of white adipose tissue
Authors: Chen Hong , Sun Lijun , Feng Lu , Han Xue , Zhang Yunhua , Zhai Wenbo , Zhang Zehe , Mulholland Michael , Zhang Weizhen , Yin Yue 
Published: August 2023

AbstractMechanism underlying the metabolic benefit of intermittent fasting remains largely unknown. Here, we reported that intermittent fasting promoted IL-22 production by ILC3s and subsequent beigeing of subcutaneous white adipose tissue. Adoptive transfer of intestinal ILC3s increased beigeing of white adipose tissue in diet-induced-obese mice. Exogenous IL-22 significantly increased the beigeing of subcutaneous white adipose tissue. Deficiency of IL-22 receptor attenuated the beigeing induced by intermittent fasting. Single-cell sequencing of sorted intestinal immune cells revealed that intermittent fasting increased aryl hydrocarbon receptor signaling in ILC3s. Analysis of cell‒cell ligand receptor interactions indicated that intermittent fasting may stimulate the interaction of ILC3s with dendritic cells (DCs) and macrophages. These results establish the role of intestinal ILC3s in beigeing of white adipose tissue, suggesting that ILC3/IL-22/IL-22R axis contributes to the metabolic benefit of intermittent fasting.
FOXC1 and FOXC2 maintain mitral valve endothelial cell junctions, extracellular matrix, and lymphatic vessels to prevent myxomatous degeneration
Authors: Tan Can , Kurup Shreya , Dyakiv Yaryna , Kume Tsutomu 
Published: August 2023

AbstractBackgroundMitral valve (MV) disease including myxomatous degeneration is the most common form of valvular heart disease with an age-dependent frequency. Genetic evidence indicates mutations of the transcription factorFOXC1are associated with MV defects, including mitral valve regurgitation. In this study, we sought to determine whether murineFoxc1and its closely related factor,Foxc2, are required in valvular endothelial cells (VECs) for the maintenance of MV leaflets, including VEC junctions and the stratified trilaminar extracellular matrix (ECM).MethodsAdult mice carrying tamoxifen-inducible, endothelial cell (EC)-specific, compoundFoxc1;Foxc2mutations (i.e., EC-Foxc-DKO mice) were used to study the function ofFoxc1andFoxc2in the maintenance of mitral valves. The EC-mutations ofFoxc1/c2were induced at 7 – 8 weeks of age by tamoxifen treatment, and abnormalities in the MVs of EC-Foxc-DKO mice were assessed via whole-mount immunostaining, immunohistochemistry, and Movat pentachrome/Masson’s Trichrome staining.ResultsEC-deletions ofFoxc1andFoxc2in mice resulted in abnormally extended and thicker mitral valves by causing defects in regulation of ECM organization with increased proteoglycan and decreased collagen. Notably, reticular adherens junctions were found in VECs of control MV leaflets, and these reticular structures were severely disrupted in EC-Foxc1/c2mutant mice. PROX1, a key regulator in a subset of VECs on the fibrosa side of MVs, was downregulated in EC-Foxc1/c2mutant VECs. Furthermore, we determined the precise location of lymphatic vessels in murine MVs, and these lymphatic vessels were aberrantly expanded in EC-Foxc1/c2mutant mitral valves.ConclusionsOur results indicate thatFoxc1andFoxc2are required for maintaining the integrity of the MV, including VEC junctions, ECM organization, and lymphatic vessels to prevent myxomatous mitral valve degeneration.
Waiting for the punch(line): the circuit of culture and internal public relations at Netflix
Authors: Kazmi Saima , Heisten Mark , St John III Burton 
Published: August 2023

PurposeThis study is concerned with the dynamics of the internal communications at Netflix following the release of The Closer and the public debate that followed, testing Netflix's long-standing reputation for promoting diverse content and supporting a progressive organizational culture.Design/methodology/approachUsing the circuit of culture (CoC) as a theoretical framework, this study applies a case study approach to analyze internal communication and strategic public relations in addressing this crisis.FindingsThis study's findings illustrate that by failing to interpret two of the five moments of the CoC, production and identity, Netflix negated the very values that constitute its brand. These findings have implications for how public relations' long-standing focus on two-way symmetrical communication is problematic, especially in the workplace.Originality/valueThe findings situate how the exertion of power within an organization, particularly in moments of identity and production, problematize the role of two-way symmetrical communication within an organization in crisis.
Mining safely: examining the moderating role of safety climate on mineworkers' mental health and safety behavior nexus
Authors: Amoako Emmanuel Kodwo , Nubuor Saviour Ayertey , Suleman Abdul-Razak , Abdul Bawa Amin , Akwetey-Siaw Bridget 
Published: August 2023

PurposeThe study aims to investigate the impact of anxiety and depression (dimensions of mental health) on mineworkers' safety behaviors (safety compliance and safety participation) while examining the moderating role of safety climate on these relationships.Design/methodology/approachA quantitative research approach with an explanatory cross-sectional survey research design was adopted. A total of 274 purposively selected mineworkers participated in the study. Responses were obtained from participants through a structured questionnaire which was analyzed using the partial least square structural equation modeling.FindingsAnxiety had a significant negative effect on safety compliance but not participation. However, depression was found to have a significant negative effect on both mineworkers' safety compliance and participation behaviors. The findings of the study also show that safety climate moderates the relationships between the dimensions of mental health and mineworkers' safety behavior except for the relationship between anxiety and mineworkers' safety participation behavior.Originality/valueThe study offers an account of the negative effect of mental health on mineworkers' safety behavior whiles highlighting that safety climate is an important construct to mitigate the negative effects of mental illness on the safety behaviors of mineworkers.
Resilient banking: model-based assessment of business continuity policies on commercial banks
Authors: Bastan Mahdi , Tavakkoli-Moghaddam Reza , Bozorgi-Amiri Ali 
Published: August 2023

PurposeCommercial banks face several risks, including credit, liquidity, operational and disruptive risks. In addition to these risks that are challenging for banks to control and manage, crises and disasters can exert substantially more destructive shocks. These shocks can exacerbate internal risks and cause severe damage to the bank's performance, leading banks to bankruptcy and closure. This study aims to facilitate achieving resilient banking policies through a model-based assessment of business continuity management (BCM) policies.Design/methodology/approachBy applying a system dynamics (SD) methodology, a systemic model that includes a causal structure of the banking business is presented. To build a simulation model, data are collected from a commercial bank in Iran. By presenting the simulation model of the bank's business, the consequences of some given crises on the bank's performance are tested, and the effectiveness of risk and crisis management policies is evaluated. Vensim Personal Learning Edition (PLE) software is used to construct the simulation model.FindingsResults indicate that the current BCM policies do not show appropriate resilience in the face of various crises. Commercial banks cannot create sustainable value for the banks' shareholders despite the possibility of profitability, as the shareholders lack adequate resilience and soundness. These commercial banks do not have the appropriate resilience for the next pandemic after coronavirus disease 2019 (COVID-19). Moreover, the robustness of the current banking business model is very fragile for the banking run crisis.Practical implicationsA forward-looking view of resilient banking can be obtained by combining liquidity coverage, stable funding, capital adequacy and insights from stress tests. Resilient banking requires a balanced combination of robustness, soundness and profitability.Originality/valueThe present study is a combination of bank business management, risk and resilience management and SD simulation. This approach can analyze and simulate the dynamics of bank resilience. Additionally, present of a decision support system (DSS) to analyze and simulate the outcomes of different crisis management policies and solutions is an innovative approach to developing effective and resilient banking policies.
Exploring local job seekers perception toward employment in the private and public sectors in Qatar: implications for workforce nationalization policies
Authors: Elsharnouby Tamer H. , Elbanna Said , Obeidat Shatha M. , Mauji Nasrina Issa 
Published: August 2023

PurposeThe influx of expatriates to the Gulf Cooperation Council (GCC) countries has led to labor imbalance inducing these countries to initiate workforce nationalization policies. However, despite the policies' emphasis on increasing the presence of nationals in all sectors, employing nationals in the private sector is still a critical challenge for policymakers. This paper explores local job seekers' and employees' perceptions of employment choices in the private and public sectors.Design/methodology/approachAdopting a qualitative approach, data were collected through in-depth interviews with 28 local job seekers, either not currently employed or employed but seeking another job.FindingsThe data revealed a contextualized understanding of positive and negative connotations pertaining to employment in the private and public sectors in Qatar.Research limitations/implicationsUnderstanding nationals' negative preconceived notions against working in the private sector and the perceived benefits of public sector employment lays the groundwork for developing measures to help policymakers to create labor market-oriented policies that stimulate mobility between the public and private sectors.Originality/valueThis study contributes to the workforce nationalization literature in the GCC countries by examining local job seekers' perceptions associated with employment in the private sector and the public sector. A closer examination of why nationals are hesitant to enter the private sector can propel the pendulum towards higher success rates of workforce nationalization.