bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hepatocyte cholesterol content modulates glucagon receptor signalling
Authors: McGlone Emma Rose , Ansell T. Bertie , Dunsterville Cecilia , Song Wanling , Carling David , Tomas Alejandra , Bloom Stephen R , Sansom Mark S. P. , Tan Tricia , Jones Ben 
Published: November 2021

SummaryGlucagon decreases liver fat, and non-alcoholic fatty liver disease (NAFLD) is associated with hepatic glucagon resistance. Increasingly it is recognised that the function of G protein-coupled receptors can be regulated by their local plasma membrane lipid environment. The aim of this study was to evaluate the effects of experimentally modulating hepatocyte cholesterol content on the function of the glucagon receptor (GCGR). We found that glucagon-mediated cAMP production is inversely proportional to cholesterol content of human hepatoma and primary mouse hepatocytes after treatment with cholesterol-depleting and loading agents, with ligand internalisation showing the opposite trend. Mice fed a high cholesterol diet had increased hepatic cholesterol and a blunted hyperglycaemic response to glucagon, both of which were partially reversed by simvastatin. Molecular dynamics simulations identified potential membrane-exposed cholesterol binding sites on the GCGR. Overall, our data suggest that increased hepatocyte membrane cholesterol could directly contribute to glucagon resistance in NAFLD.
Dominant species determine ecosystem stability across scales in Inner Mongolian grassland
Authors: Wang Yonghui , Wang Shaopeng , Zhao Liqing , Liang Cunzhu , Miao Bailing , Zhang Qing , Niu Xiaxia , Ma Wenhong , Schmid Bernhard 
Published: November 2021

AbstractThere is an urgent need to extend knowledge on ecosystem temporal stability to larger spatial scales because presently available local-scale studies generally do not provide effective guide for management and conservation decisions at the level of an entire region with diverse plant communities. We investigated temporal stability of plant biomass production across spatial scales and hierarchical levels of community organization and analyzed impacts of dominant species, species diversity and climatic factors using a multi-site survey of Inner Mongolian grassland. We found that temporal stability at a large spatial scale, i.e. a large area aggregating multiple local communities, was related to temporal stability of and asynchrony among spatially separated local communities and large-scale population dynamics of dominant species, yet not to species richness. Additionally, a lower mean and higher variation of yearly precipitation destabilized communities at local and large scales by destabilizing dominant species population dynamics. We argue that, for semi-arid temperate grassland, dynamics and precipitation responses of dominant species and asynchrony among local communities stabilize ecosystems at large spatial scales. Our results indicate that reduced amounts and increased variation of precipitation may present key threats to the sustainable provision of biological products and services to human well-being in this region.
Genome Wide Association Metanalysis Of Skull Bone Mineral Density Identifies Loci Relevant For Osteoporosis And Craniosynostosis
Authors: Medina-Gomez Carolina , Mullin Benjamin H. , Chesi Alessandra , Prijatelj Vid , Kemp John P. , Shochat-Carvalho Chen , Trajanoska Katerina , Wang Carol , Joro Raimo , Evans Tavia E. , Schraut Katharina E. , Li-Gao Ruifang , Ahluwalia Tarunveer S. , Zillikens M. Carola , Zhu Kun , Mook-Kanamori Dennis O. , Evans Daniel S. , Nethander Maria , Knol Maria J. , Thorleifsson Gudmar , Prokic Ivana , Zemel Babette , Broer Linda , van Schoor Natasja , Reppe Sjur , Pawlak Mikolaj A. , Ralston Stuart H. , van der Velde Nathalie , Lorentzon Mattias , Stefansson Kari , Adams Hieab H.H. , Wilson Scott G. , Ikram M. Arfan , Walsh John P. , Lakka Timo A. , Gautvik Kaare M. , Wilson James F , Orwoll Eric S. , van Duijn Cornelia M. , Bønnelykke Klaus , Uitterlinden Andre G. , Stykársdóttir Unnur , Spector Timothy D. , Tobias Jonathan H , Ohlsson Claes , Felix Janine F. , Bisgaard Hans , Grant Struan F.A. , Richards J. Brent , Evans David M. , van der Eerden Bram , van de Peppel Jeroen , Ackert-Bicknell Cheryl , Karasik David , Kague Erika , Rivadeneira Fernando 
Published: November 2021

AbstractSkull bone mineral density (SK-BMD) provides a suitable trait for the discovery of genes important to bone biology in general, and particularly for identifying components unique to intramembranous ossification, which cannot be captured at other skeletal sites. We assessed genetic determinants of SK-BMD in 43,800 individuals, identifying 59 genome-wide significant loci (4 novel), explaining 12.5% of its variance. Pathway and enrichment analyses of the association signals resulted in clustering within gene-sets involved in regulating the development of the skeleton; overexpressed in the musculoskeletal system; and enriched in enhancer and transcribed regions in osteoblasts. From the four novel loci (mapping to ZIC1, PRKAR1A, ATP6V1C1, GLRX3), two (ZIC1 and PRKAR1A) have previously been related to craniofacial developmental defects. Functional validation of skull development in zebrafish revealed abnormal cranial bone initiation that culminated in ectopic sutures and reduced BMD in mutated zic1 and atp6v1c1 fish and asymmetric bone growth and elevated BMD in mutated prkar1a fish. We confirmed a role of ZIC1 loss-of-function in suture patterning and discovered ATP6V1C1 gene associated with suture development. In light of the evidence presented suggesting that SK-BMD is genetically related to craniofacial abnormalities, our study opens new avenues to the understanding of the pathophysiology of craniofacial defects and towards the effective pharmacological treatment of bone diseases.
Serum neurofilament light as a biomarker for prognosis in patients with newly diagnosed Parkinson’s disease
Authors: Vijiaratnam Nirosen , Lawton Michael , Heslegrave Amanda , Guo Tong , Tan Manuela MX , Jabbari Edwin , Real Raquel , Woodside John , Grosset Katherine A , Chelban Viorica , Athauda Dilan , Girges Christine , Barker Roger A , Hardy John , Wood Nicholas , Houlden Henry , Williams Nigel M , Ben-Shlomo Yoav , Zetterberg Henrik , Grosset Donald G , Foltynie Thomas , Morris Huw R ,   PRoBaND clinical consortium
Published: November 2021

ABSTRACTBackgroundPatients with Parkinson’s disease (PD) have variable disease progression. More accurate prediction of progression could improve clinical trial design. Although some variance in clinical progression can be predicted by age at onset and phenotype, we hypothesise that this can be improved by blood biomarkers.ObjectiveTo determine if serum neurofilament light (NfL) is a useful biomarker for prognostic modelling in PD.MethodsWe evaluated the relationship between serum NfL and baseline and longitudinal clinical measures as well as patients’ genetic (GBA and APOE) status in a large clinical dataset. We classified patients as having a favourable or an unfavourable outcome based on a previously validated model and explored whether serum NfL could distinguish prognostic phenotypes. We compared NfL with baseline candidate predictor variables and studied the combination of clinical, serum and genetic data.ResultsSerum NfL was associated with patients’ cognitive status at baseline. Baseline NfL was associated with the progression of motor and functional impairment and with increased mortality (Survival HR 1.85, CI: 1.03-3.33, p=0.04). Baseline NfL levels predicted unfavourable progression to a similar extent as previously validated clinical predictors (AUC: 0.74 vs 0.78, p=0.22). The combination of clinical, genetic and biomarker data produced a strong predication of unfavourable outcomes as compared to age and gender alone (AUC: 0.71-age/gender vs 0.83-ALL p = 0.0076)ConclusionsBaseline serum NfL provides an objective measure of neurodegeneration in PD patients. Clinical trials of disease-modifying therapies might usefully stratify patients according using clinical, genetic and NfL status at the time of recruitment.
Muscle activation strategies of the vastus lateralis according to sex
Authors: Guo Yuxiao , Jones Eleanor J. , Inns Thomas B. , Ely Isabel A. , Stashuk Daniel W. , Wilkinson Daniel J. , Smith Kenneth , Piasecki Jessica , Phillips Bethan E. , Atherton Philip J. , Piasecki Mathew 
Published: November 2021

AbstractAimDespite men exhibiting greater muscle strength and fatigibility than women, it remains unclear if there are sex-based differences in muscle recruitment strategies e.g. motor unit (MU) recruitment and modulation of firing rate (FR) at normalised forces and during progressive increases in force.MethodsTwenty-nine healthy male and thirty-one healthy female participants (18-35 years) were studied. Intramuscular electromyography was used to record individual motor unit potentials (MUPs) and near fibre MUPs from the vastus lateralis (VL) during 10% and 25% maximum isometric voluntary contractions (MVC), and spike-triggered averaging was used to obtain motor unit number estimates (MUNE) of the VL. Multilevel mixed-effects linear regression models were used to investigate the effects of sex at each contraction level.ResultsMen exhibited greater muscle strength (p<0.001) and size (p<0.001) than women, with no difference in force steadiness at 10% or 25% MVC. Women had smaller MUs and higher FR at 10% MVC (both p<0.02), similar to that at 25% MVC in MU size (p=0.062) and FR (p=0.031). However, both sexes showed similar increases in MU size and FR when moving from low-to mid-level contractions. There were no sex differences in any near fibre MUP parameters or in MUNE.ConclusionIn the vastus lateralis, women produce muscle force via different neuromuscular recruitment strategies to men which is characterised by smaller MUs discharging at higher rates. However, similar strategies are employed to increase force production from low to moderate contractions. These findings of similar proportional increases between sexes support the use of mixed sex cohorts in studies of this nature.Key pointsIncreases in muscle force production are mediated by motor unit (MU) recruitment, and MU firing rate (FR).Women are underrepresented in studies of human neuromuscular research and markedly differ to men in a number of aspects of neuromuscular function, yet little is known of the recruitment strategies of each.Here we demonstrate men and women have similar vastus lateralis MU number estimates, yet women recruit smaller MUs with higher FR than men at normalised contraction levels. However, increases in force are achieved via similar trajectories of MU recruitment and MU FR in men and women.Although men and women exhibit divergent neuromuscular recruitment strategies to achieve normalised forces, increases in force are achived similarly and support the inclusion of mixed sex cohorts in studies of this nature.
Repetition Probability Effects for Chinese Characters and German Words in the Visual Word Form Area
Authors: Li Chenglin , Kovács Gyula 
Published: November 2021

AbstractThe magnitude of repetition suppression (RS), measured by fMRI, is modulated by the probability of repetitions (P(rep)) for various sensory stimulus categories. It has been suggested that for visually presented simple letters this P(rep) effect depends on the prior practices of the participants with the stimuli. Here we tested further if previous experiences affect the neural mechanisms of RS, leading to the modulatory effects of stimulus P(rep), for more complex lexical stimuli as well. We measured the BOLD signal in the Visual Word Form Area (VWFA) of native Chinese and German participants and estimated the P(rep) effects for Chinese characters and German words. The results showed a significant P(rep) effect for stimuli of the mother tongue in both participant groups. Interestingly, Chinese participants, learning German as a second language, also showed a significant P(rep) modulation of RS for German words while the German participants who had no prior experiences with the Chinese characters showed no such effects. Our findings suggest that P(rep) effects on RS are manifest for visual word processing as well, but only for words of a language with which participants are highly familiar. These results support further the idea that predictive processes, estimated by P(rep) modulations of RS, require prior experiences.
Less efficacy of valproic acid monotherapy may be caused by neural excitatory rebound in focal seizures
Authors: Zou Xiang , Zhu Zilu , Guo Yu , Zhang Hongmiao , Liu Yuchen , Cui Zhengyu , Ke Zunji , Jiang Shize , Tong Yusheng , Wu Zehan , Mao Ying , Chen Liang , Wang Deheng 
Published: November 2021

AbstractValproic acid (VPA) represents one of the most efficient antiepileptic drugs (AEDs) with either general or focal seizures, but a certain percentage of patients are not recovered or even worse, the mechanism under this phenomenon remains unclear. Here, we retrospectively reviewed 16 patients who received awake craniotomy surgery. Intro-operative high density electrocorticogram (ECoG) was used to record the local field potential (LFP) response to VPA treatment. We found the less efficacy of VPA monotherapy was associated with ECoG spectrum power shift from higher to lower frequency after VPA injection, together with increased synchronization of the LFP. Furthermore, we established the computational model to testify the hypothesis that the ineffectivity of VPA may be caused by excitatory dynamic rebound during the inhibitory power increasing. In addition to test the hypothesis, we employed the mice with Kanic Acid (KA)-induced epileptic model to confirm that it would be inhibited by VPA on behavior and neural activity. Also, the neural activity shows significant rebound on spike firing. Then we discovered that the LFP would increase the power spectral density in multiple wave bands after the VPA delivers. These findings suggest that less efficacy of valproic acid monotherapy in focal seizures may be caused by neural excitatory rebound which mediated by elevated inhibitory power.
Dephosphorylation of the pre-initiation complex during S-phase is critical for origin firing
Authors: Jenkinson Fiona , Tan Kang Wei , Schöpf Barbara , Santos Miguel M , Phanada Ivan , Zegerman Philip 
Published: November 2021

AbstractGenome stability requires complete DNA duplication exactly once before cell division. In eukaryotes, cyclin-dependent kinase (CDK) plays a dual role in this regulation by inhibiting helicase loading factors before also activating origin firing. CDK activates initiation by phosphorylation of two substrates, Sld2 and Sld3, forming a transient and limiting intermediate – the pre-initiation complex (pre-IC). The importance and mechanism of dissociation of the pre-IC from origins is not understood. Here we show in the budding yeast Saccharomyces cerevisiae that CDK phosphorylation of Sld3 and Sld2 is specifically and rapidly turned over during interphase by the PP2A and PP4 phosphatases. Inhibiting dephosphorylation of Sld3/Sld2 causes dramatic defects in replication initiation genome-wide, retention of the pre-IC at origins and cell death. These studies not only provide a mechanism to guarantee that Sld3 and Sld2 are dephosphorylated before helicase loading factors but also uncover a novel positive role for phosphatases in eukaryotic origin firing.
Volatility in coral cover erodes niche structure, but not diversity, in reef fish assemblages
Authors: Tsai Cheng-Han , Sweatman Hugh PA , Thibaut Loïc M , Connolly Sean R 
Published: November 2021

AbstractEnvironmental fluctuations are becoming increasingly volatile in many ecosystems, highlighting the need to better understand how stochastic and deterministic processes shape patterns of commonness and rarity, particularly in high-diversity systems like coral reefs. Here, we analyze reef fish time-series across the Great Barrier Reef to show that approximately 75% of the variance in relative species abundance is attributable to deterministic, intrinsic species differences. Nevertheless, the relative importance of stochastic factors is markedly higher on reefs that have experienced stronger coral cover volatility. By contrast, α-diversity and species composition are independent of coral cover volatility but depend on environmental gradients. Our findings imply that increased environmental volatility on coral reefs erodes assemblage’s niche structure, an erosion that is not detectable from static measures of biodiversity.One-Sentence SummaryCoral cover volatility modulates how stochastic and deterministic processes shape commonness and rarity in coral reef fishes.
Outside-in thinking, value chain collaboration and business model innovation in manufacturing firms
Authors: Wu Liang , Liu Heng , Bao Yongchuan 
Published: November 2021

Purpose
This paper aims to explore how manufacturing firms pursue business model innovation (BMI) through their use of outside-in thinking.

Design/methodology/approach
Survey data were collected on 175 Chinese manufacturing firms. A regression model was used to verify the research results.

Findings
Manufacturing firms rely on outside-in thinking to develop BMI under different market and institutional environments. From a whole-value-chain perspective, interacting with customers and sharing information with suppliers are two key ways to develop BMI.

Research limitations/implications
Firms focus on customer needs, sense the dynamics of external markets and technology and seize market opportunities to measure outside-in thinking. Empirical results suggest using other measures of outside-in thinking. BMI itself can be multidimensional, so scholars could consider BMI’s diverse dimensions and measurements, which may demand different kinds of outside-in thinking.

Practical implications
Manufacturing firms can use outside-in thinking to overcome inertia and rigidity and increase their knowledge, information and technology. Managers should develop outside-in thinking to respond quickly to emerging economies. Managers should use value chain collaboration and improve the firm’s capacity to interact with customers and suppliers to apply the benefits of outside-in thinking to their BMI.

Originality/value
The study explores how outside-in thinking is a key driver of BMI. Applying the whole-value-chain view, it finds that interacting with customers and suppliers connects outside-in thinking with BMI. It also highlights the effects of intense market competition and volatile government regulation on BMI.
Mediating role of attitude in halal cosmetics purchase intention: an ELM perspective
Authors: Anubha  
Published: November 2021

Purpose
The purpose of this study is to examine the role of attitude as a mediator in exploring the Halal cosmetics purchase intention of Indian Muslim women. Various drivers of electronic word of mouth (eWOM) (quality, quantity, consistency and quantity) have been tested as antecedents of purchase intention through the lenses of the elaboration likelihood model (ELM).

Design/methodology/approach
The positivist paradigm approach has been used to test the proposed mediation model using structural equation modelling. Responses of 313 Indian Muslim women who read reviews shared on various social media platforms before making any halal cosmetics purchase intention have been used for the final analysis. Mediation was tested using bootstrapping.

Findings
The findings of the study revealed that attitude towards halal cosmetics mediates the relationships of various drivers of eWOM with halal cosmetics purchase intention. However, it was observed that this mediation was partial in the context of eWOM quality, eWOM valence and eWOM consistency. Furthermore, for eWOM quantity, the mediation effect was full as the direct impact of eWOM quality on halal cosmetics purchase intention was not significant but its indirect impact on the latter via attitude was found to be significant.

Research limitations/implications
This study adds to the marketing communication literature, especially in the context of eWOM. The study also validates ELM theory in explaining the attitude that shapes the halal cosmetics purchase intention, thus the current study enriches the ELM literature.

Practical implications
The current study offers several implications for halal cosmetics marketers. It offers various suggestions to them on how to capitalize on eWOM as it influences Indian Muslim women’s purchasing intention for halal cosmetics by shaping their attitude towards such cosmetics favourably.

Originality/value
With reference to halal cosmetics, the current study offers a new perspective by examining the purchasing intention for such cosmetics based on various drivers of eWOM. The attitude towards halal cosmetics as a mediator has helped in better explaining the purchase intention for halal cosmetics.
Patient safety and leadership style in the government general hospitals in Kuwait: a multi-method study
Authors: ALFadhalah Talal , Elamir Hossam 
Published: November 2021

Purpose
This study aims to evaluate the relationships between leadership style and reported incidents, reporting practices and patient safety initiatives in Kuwaiti hospitals.

Design/methodology/approach
This cross-sectional and retrospective quantitative multi-centre study was conducted in a secondary care setting. The multifactor leadership questionnaire and the patient safety questionnaire were distributed in six general hospitals to a sample of physicians, nurses and pharmacists. Incident reports were reviewed in each hospital to assess reporting practices.

Findings
The hospital with the most safety incident reports scored the highest on good reporting practices, whereas the hospital with the lowest score of poor reporting practices had reported fewer incidents. Reporting was better if an error reached the patient but caused no harm. Overall, reporting practices and implementation of patient safety initiatives in the hospitals were suboptimal. Nevertheless, a transformational leadership style had a positive effect on patient safety and reporting practices.

Practical implications
This study represents a baseline for researchers to assess the relationship between leadership style and patient safety. Moreover, it highlights significant considerations to be addressed when planning patient safety improvement programmes. More investment is needed to understand how to raise transformational leaders who are more effective on patient safety. Further studies that include primary and tertiary health-care settings and the private sector are required.

Originality/value
To the best of the authors’ knowledge, this study is the first in Kuwait to report on the relationship between transformational leadership and safety practices.