bluuebunny/crossref_metadata_2025_split huggingface dataset:
Activin receptor ALK4 promotes adipose tissue hyperplasia by suppressing differentiation of adipocyte precursors
Authors: Lee Ee-Soo , Guo Tingqing , Srivastava Raj Kamal , Shabbir Assim , Ibáñez Carlos F. 
Published: November 2022

AbstractAdipocyte hyperplasia and hypertrophy are the two main processes contributing to adipose tissue expansion, yet the mechanisms that regulate and balance their involvement in obesity are incompletely understood. Activin B/GDF-3 receptor ALK7 is expressed in mature adipocytes, and promotes adipocyte hypertrophy upon nutrient overload by suppressing adrenergic signaling and lipolysis. In contrast, the role of ALK4, the canonical pan-activin receptor, in adipose tissue is unknown. Here we report that, unlike ALK7, ALK4 is preferentially expressed in adipocyte precursors, where it suppresses differentiation, allowing proliferation and adipose tissue expansion. ALK4 expression in adipose tissue increases upon nutrient overload and positively correlates with fat depot mass and body weight, suggesting a role in adipose tissue hyperplasia during obesity. Mechanistically, ALK4 signaling suppresses expression of CEBPα and PPARγ, two master regulators of adipocyte differentiation. Conversely, ALK4 deletion enhances CEBPα/PPARγ expression and induces premature adipocyte differentiation, which can be rescued by CEBPα knock-down. These results clarify the function of ALK4 in adipose tissue and highlight the contrasting roles of the two activin receptors in the regulation of adipocyte hyperplasia and hypertrophy during obesity.
Paradox Found: Global Accounting of Lymphocyte Protein Synthesis
Authors: Seedhom Mina O. , Dersh Devin , Holly Jaroslav , Pavon-Eternod Mariana , Wei Jiajie , Angel Matthew , Shores Lucas , David Alexandre , Santos Jefferson , Hickman Heather D. , Yewdell Jonathan W. 
Published: November 2022

AbstractRapid lymphocyte cell division places enormous demands on the protein synthesis machinery. Flow cytometric measurement of puromycylated ribosome-associated nascent chains after treating cells or mice with translation initiation inhibitors reveals that ribosomes in resting lymphocytesin vitroandin vivoelongate at typical rates for mammalian cells. Intriguingly, elongation rates can be increased up to 30% by activationin vivoor fever temperaturein vitro. Resting and activated lymphocytes possess abundant monosome populations, most of which actively translatein vivo,whilein vitro,nearly all can be stalled prior to activation. Quantitating lymphocyte protein mass and ribosome count reveals a paradoxically high ratio of cellular protein to ribosomes insufficient to support their rapidin vivodivision, suggesting that the activated lymphocyte proteomein vivomay be generated in an unusual manner. Our findings demonstrate the importance of a global understanding of protein synthesis in lymphocytes and other rapidly dividing immune cells.
Retrospective varying coefficient association analysis of longitudinal binary traits: application to the identification of genetic loci associated with hypertension
Authors: Xu Gang , Amei Amei , Wu Weimiao , Liu Yunqing , Shen Linchuan , Oh Edwin C. , Wang Zuoheng 
Published: November 2022

AbstractMany genetic studies contain rich information on longitudinal phenotypes that require powerful analytical tools for optimal analysis. Genetic analysis of longitudinal data that incorporates temporal variation is important for understanding the genetic architecture and biological variation of complex diseases. Most of the existing methods assume that the contribution of genetic variants is constant over time and fail to capture the dynamic pattern of disease progression. However, the relative influence of genetic variants on complex traits fluctuates over time. In this study, we propose a retrospective varying coefficient mixed model association test, RVMMAT, to detect time-varying genetic effect on longitudinal binary traits. We model dynamic genetic effect using smoothing splines, estimate model parameters by maximizing a double penalized quasi-likelihood function, design a joint test using a Cauchy combination method, and evaluate statistical significance via a retrospective approach to achieve robustness to model misspecification. Through simulations, we illustrated that the retrospective varying-coefficient test was robust to model misspecification under different ascertainment schemes and gained power over the association methods assuming constant genetic effect. We applied RVMMAT to a genome-wide association analysis of longitudinal measure of hypertension in the Multi-Ethnic Study of Atherosclerosis. Pathway analysis identified two important pathways related to G-protein signaling and DNA damage. Our results demonstrated that RVMMAT could detect biologically relevant loci and pathways in a genome scan and provided insight into the genetic architecture of hypertension.
Akt activator SC79 stimulates antibacterial nitric oxide production from human nasal epithelial cells and increases macrophage phagocytosisin vitro
Authors: Lee Robert J. , Adappa Nithin D. , Palmer James N. 
Published: November 2022

AbstractBackgroundThe role of the Akt serine/threonine kinase family in airway innate immunity is relatively unstudied compared with other pathways. Akt can phosphorylate and activate the endothelial nitric oxide synthase (eNOS) isoform expressed in airway epithelial ciliated cells. NO production by nasal epithelial cells often has antibacterial and antiviral effects. Increasing nasal epithelial NO production may be a useful anti-pathogen strategy for respiratory infections in diseases like chronic rhinosinusitis. We hypothesized that a small molecule Akt activator, SC79, might induce nasal epithelial cell NO production with bactericidal effects.MethodsWe tested the antibacterial-stimulatory effects of SC79 in primary nasal epithelial cells isolated from residual surgical material and grown at air-liquid interface. Because macrophages also use NO signaling to enhance phagocytosis, we also tested effects of SC79 in human macrophages differentiated from monocytes obtained from healthy apheresis donors.ResultsLive cell imaging of an NO-sensitive fluorescent dye revealed that SC79 induced dose-dependent NO production. Pharmacology and genetic knockdown revealed that this NO production is dependent on eNOS and Akt. The NO released into the airway surface liquid was sufficient to kill both lab and clinical strains ofP. aeruginosain a co-culture bacterial killing assay. SC79 enhanced bacterial phagocytosis in a NO-dependent and Akt-dependent manner. No overt toxicity (LDH release) or inflammatory effects (IL8 transcription) were observed in nasal cells or macrophages over 24 hrs.ConclusionsTogether, these data suggest that multiple innate immune pathways might be stimulated by SC79 delivered via topical nasal rinse or spray. Activating Akt using SC79 or another compound might have beneficial antipathogen effects in respiratory infections.
Optimization of genomewide CRISPR screens using AsCas12a and multi-guide arrays
Authors: Petiwala Sakina , Modi Apexa , Anton Tifani , Murphy Erin , Kadri Sabah , Hu Hengcheng , Lu Charles , Flister Michael J , Verduzco Daniel 
Published: November 2022

ABSTRACTGenomewide loss-of-function (LOF) screening using CRISPR (clustered regularly interspaced short palindromic repeats) has facilitated the discovery of novel gene functions across diverse physiological and pathophysiological systems. A challenge with conventional genomewide CRISPR/Cas9 libraries is the unwieldy size (60,000 to 120,000 constructs), which is resource intensive and prohibitive in some experimental contexts. One solution to streamlining CRISPR screening is by multiplexing two or more guides per gene on a single construct, which enables functional redundancy to compensate for suboptimal gene knockout by individual guides. In this regard, AsCas12a (Cpf1) and its derivatives, e.g., enhanced AsCas12a (enAsCas12a), have enabled multiplexed guide arrays to be specifically and efficiently processed for genome editing. Prior studies have established that multiplexed CRISPR/Cas12a libraries perform comparably to the larger equivalent CRISPR/Cas9 libraries, yet the most efficient CRISPR/Cas12a library design remains unresolved. Here, we demonstrate that CRISPR/Cas12a genomewide LOF screening performed optimally with three guides arrayed per gene construct and could be adapted to robotic cell culture without noticeable differences in screen performance. Thus, the conclusions from this study provide novel insight to streamlining genomewide LOF screening using CRISPR/Cas12a and robotic cell culture.
Genome editing in plants using the compact editor CasΦ
Authors: Li Zheng , Zhong Zhenhui , Wu Zhongshou , Pausch Patrick , Al-Shayeb Basem , Amerasekera Jasmine , Doudna Jennifer A. , Jacobsen Steven E. 
Published: November 2022

AbstractCRISPR-Cas systems have been developed as important tools for plant genome engineering. Here, we demonstrate that the hypercompact CasΦ nuclease is able to generate stably inherited gene edits inArabidopsis, and that CasΦ guide RNAs can be expressed with either the Pol-III U6 promoter or a Pol-II promoter together with ribozyme mediated RNA processing. Using theArabidopsis fwaepiallele we show that CasΦ displays higher editing efficiency when the target locus is not DNA methylated, suggesting that CasΦ is sensitive to chromatin environment. Importantly, two CasΦ protein variants, vCasΦ and nCasΦ, both showed much higher editing efficiency relative to the wildtype CasΦ enzyme, and yielded more offspring plants with inherited edits. Extensive genomic analysis of gene edited plants showed no off-target editing, suggesting that CasΦ is highly specific. The hypercompact size, T-rich minimal PAM and wide range of working temperatures make CasΦ an excellent supplement to existing plant genome editing systems.Significance StatementPlant genome engineering with CRISPR-Cas systems is frequently used in both research and agriculture. Here, we demonstrate that the hypercompact CasΦ-2 nuclease is able to generate heritable gene edits inArabidopsis. Two CasΦ protein variants vCasΦ and nCasΦ increased the editing efficiency in plants. CasΦ also has a wide range of working temperatures and the editing by CasΦ is highly specific. We also observed that editing by CasΦ is sensitive to chromatin environment. The hypercompact size, T-rich minimal PAM and wide range of working temperatures make CasΦ an excellent supplement to existing plant genome editing systems.
Reemergence of cholera in Haiti
Authors: Rubin Daniel H. F. , Zingl Franz G. , Leitner Deborah R. , Ternier Ralph , Compere Valusnor , Marseille Samson , Slater Damien , Harris Jason B. , Chowdhury Fahima , Qadri Firdausi , Boncy Jacques , Ivers Louise C. , Waldor Matthew K. 
Published: November 2022

SummaryCholera was absent from Haiti until an inadvertent introduction by United Nations security forces in October 2010. The ensuing epidemic sickened 820,000 and caused 9,792 reported deaths1. The last cholera case in Haiti was recorded in January 2019, and in February 2022, Haiti was declared to have eliminated cholera2. In late September of 2022, a new outbreak began in Port-au-Prince and rapidly expanded to 964 suspected cases by mid-October of which 115 were confirmed by culture.3Here, we present genomic and phenotypic analysis of theVibrio choleraeisolated from a stool sample collected on September 30th, 2022 of an index case – a 10-year-old girl who presented with watery diarrhea and severe dehydration – to address the origins of the epidemic.
I am more inclined to buy online–novel social media engagement stimulated purchase intentions post-COVID-19: a case of Pakistani market
Authors: Fatima Tehreem , Bilal Ahmad Raza , Khan Shahid Iqbal 
Published: November 2022

PurposeThis study sheds light on the differential impact of social media brand engagement on two distinct types of purchase intentions, i.e. online and physical, in the special context of the post-COVID-19 situation in Pakistan. It has shed light on the factor (trust in online purchases during COVID-19) that has shaped the post-pandemic purchasing attitude. The above-stated association is unlocked based on the mediating role of brand equity.Design/methodology/approachThe people who followed the social media pages of major sellers (apparel, grocery, food items and medical supplies) in Pakistan were included as the target population. A time-lagged web-based survey method was employed to collect primary data which generated 308 responses. Quantitative data were analyzed using SPSS 26.0. After checks for validity and reliability, mediation and moderation analysis were run by Hayes PROCESS model 4 and 14 respectively.FindingsResults show that brand equity mediates the relationship of social media engagement with both online and physical purchase intentions. Further, results confirm that trust in online purchases during COVID-19 19 weakens the relationship of social media engagement with physical purchase intentions but strengthens with online purchase intentions.Originality/valueThis study attempts to unveil the moderation of trust in online purchases during COVID-19 on the relationship of social media engagement with online and physical purchase intentions through the mediation of brand equity.
Corporate integrity, external assurance and sustainability reporting quality: evidence from the Malaysian public listed companies
Authors: Elaigwu Moses , Abdulmalik Salau Olarinoye , Talab Hassnain Raghib 
Published: November 2022

PurposeThis paper aims to examine the effect of corporate integrity and external assurance on Sustainability Reporting Quality (SRQ) of Malaysian public listed companies.Design/methodology/approachThe study uses a longitudinal sample of 2,463 firm-year observations of non-financial firms listed on the main board of Bursa Malaysia from 2015 to 2019. The study employed panel regression that is, Fixed Effect (FE) Robust Standard Error estimation technique to test its hypotheses.FindingsThe panel regression results reveal that corporate integrity and external assurance positively and significantly influence the quality of sustainability reporting. Though the positive association shows an improvement in the SRQ of the sampled firms, it needs an improvement as the disclosure is more general and qualitative than quantitative. The present improvement in SRQ might result from some regulatory changes like the Sustainability Practice Note 9 Updates of Bursa Malaysia 2017 and the Revised MCCG Principle A to C within the same period.Research limitations/implicationsThe study adopts a purely quantitative approach and call for a qualitative investigation in the area in the future.Practical implicationsThe study has policy implication for the government and regulators to strengthen compliance with the sustainability reporting guide and the Practice Note 9 Updates. It also has implication for corporate integrity and external assurance for companies, to enhance SRQ and achieve sustainable development.Originality/valueThe study bridged literature gaps by offering new insights and empirical evidence on the role of corporate integrity in SRQ, which has received no empirical attention in the Malaysian context.
Risk analysis of agricultural input management and its drivers and obstacles: a case study of vegetable production enterprises in Beijing
Authors: Ding Junqi , Li Bo , Zhang Lingxian 
Published: November 2022

PurposeThe quantitative understanding of the safe input management practices of vegetable producers is essential for both food safety and environmental protection. The purpose of this study is to investigate the current status of safe production in vegetable enterprises and examine the key risk factors affecting the safe production of vegetables from the perspective of agricultural inputs.Design/methodology/approachBased on the theory of risk analysis, a framework of safe vegetable production risk analysis is constructed from the perspective of production input behaviour. Based on 202 valid questionnaires in Beijing, China, this paper identifies direct risks in input management through statistical descriptive analysis; determines weights through an expert elicitation process and calculates weighted safety values accordingly; and finally uses a categorical regression model to explore the indirect risks affecting corporate safety production.FindingsThe results show that direct risk factors include seed treatment risk, pesticide and fertilizer use criteria risk, pesticide and fertilizer operation risk, and pesticide application object risk. The production safety value of Beijing's enterprises is found to be high in the north and south regions, and low in the central region. Finally, some indirect risk factors, namely the cognition of agricultural product safety laws, the cognition of pesticide safety intervals, the cognition of prohibited pesticides and the possession of brands, are found to have positive and significant impacts on the safe production behaviour of enterprises.Originality/valueThese findings provide entry points for interventions aimed at reducing dependence on pesticides and fertilizers and promoting input management for safe vegetable production in enterprises, thus avoiding vegetable safety incidents due to improper practices in the production chain.
Drug use patterns, harm reduction strategies and use of drug checking services in boom festival patrons
Authors: Valente Helena , Martins Daniel , Pinto Marta , Fernandes José Luis , Barratt Monica J. 
Published: November 2022

Purpose
Recent studies have shown that people who attend electronic dance music events and use drug checking services (DCS) are a predominantly white male, highly educated middle-class population. However, there is still a lack of data beyond sociodemographic characteristics that must be addressed. This paper aims to describe the drug use patterns and protective behavior strategies (PBS) used by testers and nontesters at Boom Festival 2018 and analyze the relationship between these behaviors and the decision to use the DCS.

Design/methodology/approach
This is an exploratory research based on a cross-sectional design using baseline data collected at the Boom Festival from testers (N = 343) and nontesters (N = 115).

Findings
Nontesters presented, in general, slightly higher frequencies of use for most drugs, whereas testers tended to adopt PBS more frequently. Moreover, testers planned their drug use more often than nontesters and set more limits on the amount of drugs they used in one session. Both of these behaviors work as predictors for using the DCS.

Practical implications
Our data suggest that DCS might not be easily accessible to all people who use drugs, reaching almost exclusively highly educated people that already apply several harm reduction strategies. Actions should be taken to promote service accessibility.

Originality/value
To the best of the authors’ knowledge, this paper is the first to compare the demographics, drug use and PBS adoption of DCS users with nonusers who attended the same festival.
Nurturing focused motivation: leadership development in Indonesia
Authors: Gozali Charlina , Paik Susan J. 
Published: November 2022

Purpose
The present study aims to examine how a group of young leaders in Indonesia developed their leadership throughout their early and later years. In particular, the study examined focused motivation (“undeterred, intentional perseverance”), which is a common trait found in high-achieving individuals (Paik, 2013, p. 106). The study further investigated the nurturance of focused motivation through key support networks in home and school environments.

Design/methodology/approach
Using the productive giftedness model (Paik, 2013, 2015) as its theoretical framework, the study used a mixed-method design comprising a structured interview and survey. The final sample included 38 high-achieving Indonesian leaders.

Findings
Findings from the study demonstrate that focused motivation can be cultivated through a combination of opportunities, support and resources. More specifically, the home and school are integral in the development of characteristics contributing to focused motivation, such as resilience and mastery-orientation. In the study, positive characteristics and support networks of young leaders enabled them to overcome a variety of personal and professional challenges, including overcoming social barriers experienced by some of the leaders.

Social implications
Findings from the study can inform practice and policy efforts in creating nurturing home and school environments that will help children and young adults achieve their leadership potential, especially in developing countries where access to education and resources is often limited.

Originality/value
The study highlights the sociocultural context in Indonesia to discuss the opportunities and barriers in talent and leader development.
Developing social entrepreneurship through public procurement: a wicked problem!
Authors: Aitken Alan 
Published: November 2022

PurposeThis paper explores attempts to deliver socioeconomic benefit by developing social enterprise within the public sector supply chain.Design/methodology/approachA case study approach is adopted which focusses on the implementation of public procurement policy intended to support social entrepreneurs (SEs) in the delivery of social care in Scotland. Socio-technical systems theory (STST) is adopted as a lens through which to explore the case.FindingsWhile acknowledging the contextual limits of the case study, the empirical findings recognise partial implementation of the measures intended to develop social entrepreneurship in the supply chain. The results, however, suggest that both the engagement levels of SEs and the expected socio economic benefits are yet to accrue fully.Social implicationsThe paper concludes that in order to achieve the expected social benefits further progress is required in engaging SEs in formal collaborations with larger, potentially for profit, organisations and also in their increased involvement in the design and commissioning of public services.Originality/valueThe innovative, cross-sectional research design uses a survey based, gap analysis to provide a nuanced comparison between the views of local authority procurement officers and the opinions prevalent within social enterprise care providers and thereby to assesses the effectiveness of public policy.
Machine learning-based failure prediction in industrial maintenance: improving performance by sliding window selection
Authors: Leukel Joerg , González Julian , Riekert Martin 
Published: November 2022

PurposeMachine learning (ML) models are increasingly being used in industrial maintenance to predict system failures. However, less is known about how the time windows for reading data and making predictions affect performance. Therefore, the purpose of this research is to assess the impact of different sliding windows on prediction performance.Design/methodology/approachThe authors conducted a factorial experiment using high dimensional machine data covering two years of operation, taken from a real industrial case for the production of high-precision milled and turned parts. The impacts of different reading and prediction windows were tested for three ML algorithms (random forest, support vector machines and logistic regression) and four metrics (accuracy, precision, recall and F-score).FindingsThe results reveal (1) the critical role of the prediction window contingent upon the application domain, (2) a non-monotonic relationship between the reading window and performance, and (3) how sliding window selection can systematically be used to improve different facets of performance.Originality/valueThe study's findings advance the knowledge of ML-based failure prediction, by highlighting how systematic variation of two important but yet understudied factors contributes to the development of more useful prediction models.