bluuebunny/crossref_metadata_2025_split huggingface dataset:
The rare DRB1*04-DQ8 haplotype is the main discriminative HLA class II genetic driver of Early-Onset Type 1 Diabetes in the Portuguese population
Authors: Caramalho Iris , Matoso Paula , Ligeiro Dário , Paixão Tiago , Sobral Daniel , Fitas Ana Laura , Limbert Catarina , Demengeot Jocelyne , Penha-Gonçalves Carlos 
Published: July 2023

AbstractBackgroundEarly-onset Type 1 diabetes (EOT1D) is considered a disease subtype with distinctive immunological and clinical features. While both Human Leukocyte Antigen (HLA) and non-HLA variants contribute to age at T1D diagnosis, detailed analyses of EOT1D-specific genetic determinants are still lacking. This study scrutinized the involvement of the HLA class II locus in EOT1D genetic control.MethodsWe conducted genetic association and regularized logistic regression analyses to evaluate genotypic, haplotypic and allelic variants inDRB1,DQA1andDQB1genes in children with EOT1D (diagnosed at ≤5 years of age; n=97), individuals with later-onset disease (LaOT1D; diagnosed 8-30 years of age; n=96) and nondiabetic control subjects (n=169), in the Portuguese population.FindingsAnalysis of EOT1D and LaOT1D unrelated patients in comparison with controls, revealed the rare DRB1*04:08-DQ8 haplotype is specifically associated with EOT1D (corrected p-value=1.4×10-5) and represents the major discriminative HLA class II genetic factor. Allelic association further indicated the DRB1*04:08 allele is a distinctive EOT1D susceptibility factor (corrected p-value=7.0×10-7). Conversely, the classical T1D risk allele DRB1*04:05 was absent in EOT1D children while was associated with LaOT1D (corrected p-value=1.4×10-2).InterpretationThis study uncovered that EOT1D holds a distinctive spectrum of HLA class II susceptibilityloci, which includes risk factors overlapping with LaOT1D and discriminative genetic configurations. These findings warrant replication studies in larger multicentric settings and may impact target screening strategies and follow-up of young children with high T1D genetic risk.FundingEuropean Foundation for the Study of Diabetes, Maratona da Saúde and Fundação para a Ciência e a Tecnologia.
Seasonal malaria chemoprevention and the spread ofPlasmodium falciparumquintuple mutant parasites resistant to sulfadoxine-pyrimethamine: a modelling study
Authors: Masserey Thiery , Lee Tamsin , Kelly Sherrie L , Hastings Ian M , Penny Melissa A 
Published: July 2023

SummaryBackgroundSeasonal malaria chemoprevention (SMC) with sulfadoxine-pyrimethamine (SP) plus amodiaquine (AQ) prevents millions of clinical malaria cases in children under five in Africa’s Sahel region. However, parasites partially resistant to SP (with “quintuple” mutations) potentially threaten SMC protective effectiveness. We evaluated its spread and clinical consequences.MethodsAn individual-based malaria transmission model with explicit parasite dynamics and drug pharmacological models, was used to identify and quantify the influence of factors driving quintuple mutant spread and predict the time needed for the mutant to spread from 1% to 50% of inoculations for several SMC deployment strategies. We estimated the impact of this spread on SMC effectiveness against clinical malaria.FindingsHigher transmission intensity, SMC coverage, and expanded age range of chemoprevention promoted mutant spread. SMC implementation in a high transmission setting (40% parasite prevalence in children aged 2-10 years) with four monthly cycles to children aged three months to five years (with 95% initial coverage declining each cycle), the mutant requires 53·1 years (95% CI 50·5–56·0) to spread from 1% to 50% of inoculations. This time increased in lower transmission settings and reduced by half when SMC was extended to children under ten, or reduced by 10-13 years when an additional monthly cycle of SMC was deployed. For the same setting, the effective reduction in clinical cases in children receiving SMC was 79·0% (95% CI 77·8–80·8) and 60·4% (95% CI 58·6–62·3) during the months of SMC implementation when the mutant was absent or fixed in the population, respectively.InterpretationSMC with SP+AQ leads to a relatively slow spread of SP-resistant quintuple mutants and remains effective at preventing clinical malaria despite the mutant spread. SMC with SP+AQ should be considered in seasonal settings where this mutant is already prevalent.FundingSwiss National Science Foundation and Marie Curie Individual Fellowship.
Antibiotics of the future are prone to resistance in Gram-negative pathogens
Authors: Daruka Lejla , Czikkely Márton Simon , Szili Petra , Farkas Zoltán , Balogh Dávid , Grézal Gábor , Maharramov Elvin , Vu Thu-Hien , Sipos Levente , Juhász Szilvia , Dunai Anett , Daraba Andreea , Számel Mónika , Sári Tóbiás , Stirling Tamás , Vásárhelyi Bálint Márk , Ari Eszter , Christodoulou Chryso , Manczinger Máté , Enyedi Márton Zsolt , Jaksa Gábor , Kovács Károly , van Houte Stineke , Pursey Elizabeth , Pintér Lajos , Haracska Lajos , Kintses Bálint , Papp Balázs , Pál Csaba 
Published: July 2023

AbstractDespite the ongoing development of new antibiotics, the future evolution of bacterial resistance may render them ineffective. We demonstrate that antibiotic candidates currently under development are as prone to resistance evolution in Gram-negative pathogens as clinically employed antibiotics. Resistance generally stems from both genomic mutations and the transfer of antibiotic resistance genes from microbiomes associated with humans, both factors carrying equal significance. The molecular mechanisms of resistance overlap with those found in commonly used antibiotics. Therefore, these mechanisms are already present in natural populations of pathogens, indicating that resistance can rapidly emerge through selection of pre-existing bacterial variants. However, certain combinations of antibiotics and bacterial strains are less prone to developing resistance, emphasizing the potential of narrow-spectrum antibacterial therapies that could remain effective. Our comprehensive framework allows for predicting future health risks associated with bacterial resistance to new antibiotics.
The Arf-GAP Age2 localizes to the late-Golgi via a conserved amphipathic helix
Authors: Manzer Kaitlyn M. , Fromme J. Christopher 
Published: July 2023

AbstractArf GTPases are central regulators of the Golgi complex, which serves as the nexus of membrane trafficking pathways in eukaryotic cells. Arf proteins recruit dozens of effectors to modify membranes, sort cargos, and create and tether transport vesicles, and are therefore essential for orchestrating Golgi trafficking. The regulation of Arf activity is controlled by the action of Arf-GEFs, which activate via nucleotide exchange, and Arf-GAPs, which inactivate via nucleotide hydrolysis. The localization dynamics of Arf GTPases and their Arf-GAPs during Golgi maturation have not been reported. Here we use the budding yeast model to examine the temporal localization of the Golgi Arf-GAPs. We also determine the mechanisms used by the Arf-GAP Age2 to localize to the Golgi. We find that the catalytic activity of Age2 and a conserved sequence in the unstructured C-terminal domain of Age2 are both required for Golgi localization. This sequence is predicted to form an amphipathic helix and mediates direct binding of Age2 to membranesin vitro. We also report the development of a probe for sensing active Arf1 in living cells and use this probe to characterize the temporal dynamics of Arf1 during Golgi maturation.
Endocytic vesicles act as vehicles for glucose uptake in response to growth factor stimulation
Authors: Tsutsumi Ryouhei , Ueberheide Beatrix , Liang Feng-Xia , Neel Benjamin G. , Sakai Ryuichi , Saito Yoshiro 
Published: July 2023

AbstractGlycolysis is a fundamental cellular process, yet its regulatory mechanisms remain incompletely understood. Here, we show that a subset of glucose transporter 1 (GLUT1/SLC2A1) co-endocytoses with platelet-derived growth factor (PDGF) receptor (PDGFR) upon PDGF-stimulation. Furthermore, multiple glycolytic enzymes localize to these endocytosed PDGFR/GLUT1-containing vesicles adjacent to mitochondria. Contrary to current models, which emphasize the importance of glucose transporters on the cell surface, we find that PDGF-stimulated glucose uptake depends on receptor/transporter endocytosis. Our results suggest that growth factors generate glucose-loaded endocytic vesicles that deliver glucose to the glycolytic machinery in proximity to mitochondria, and argue for a new layer of regulation for glycolytic control governed by cellular membrane dynamics.
The epidemiological investigation of hyperlipidemia in the northern Henan Province
Authors: Lu Xing , Lin Ziyang , Yang Junzheng 
Published: July 2023

AbstractBackground/purposeHyperlipidemia is a kind of diseases with the characteristic of high level of blood lipids, it could directly result in several serious diseases including atherosclerosis and coronary heart disease to threat to human health. Therefore, to understand the epidemiological status and risk factors of hyperlipidemia is important for the prevention, diagnosis, and treatment of hyperlipidemia.MethodsThe clinical data in Xinxiang Central Hospital from 2019-2021 were collected, and those data were classified and analyzed according to the basic information of investigation subjects and risk factors.ResultsA total of 670 investigation subjects were collected in this investigation including 521 males and 149 females, accounting for 77.76% and 22.24% in the total investigation population, respectively; age range of investigation subjects was 20-97 year old; there were 390 people with a history of smoking and 346 people were never smoking, accounting for 58.21% and 51.64% in the total investigation population, respectively; in this investigation, the proportion of peasant farmers was the highest (353/670, 52.69%), followed by retire population (164/670, 24.48%); in terms of education level, the proportion of people graduating from middle school was the highest (338/670, 50.45%), followed by those graduating from primary school (249/670, 37.16%); the statistical results found that the incident of hyperlipidemia were correlated to gender (P<0.01), ethnicity (P<0.01), age (P<0.05), marital status (P<0.05), education level (P<0.001), hypertension (P<0.05) and diabetes mellitus (P<0.001), had no relation to occupation (P>0.05), cerebral hemorrhage, angina pectoris, ischemic stroke, gastrointestinal ulcers, coronary heart disease, chronic renal insufficiency, myocardial infarction, heart failure, peripheral artery disease, chronic obstructive pulmonary disease (P>0.05).ConclusionThe epidemiological status of hyperlipidemia in northern Henan Province had the specificity, the incident of hyperlipidemia was correlated to gender, ethnicity, age, marital status, education level, hypertension, and diabetes mellitus, those results may provide basis for the prevention and treatment for hyperlipidemia in northern Henan Province.
Federated analysis of the contribution of recessive coding variants to 29,745 developmental disorder patients from diverse populations
Authors: Chundru V. Kartik , Zhang Zhancheng , Walter Klaudia , Lindsay Sarah , Danecek Petr , Eberhardt Ruth Y. , Gardner Eugene J. , Malawsky Daniel S. , Wigdor Emilie M. , Torene Rebecca , Retterer Kyle , Wright Caroline F. , McWalter Kirsty , Sheridan Eamonn , Firth Helen V. , Hurles Matthew E. , Samocha Kaitlin E. , Ustach Vincent D. , Martin Hilary C. 
Published: July 2023

AbstractAutosomal recessive (AR) coding variants are a well-known cause of rare disorders. We quantified the contribution of these variants to developmental disorders (DDs) in the largest and most ancestrally diverse sample to date, comprising 29,745 trios from the Deciphering Developmental Disorders (DDD) study and the genetic diagnostics company GeneDx, of whom 20.4% have genetically-inferred non-European ancestries. The estimated fraction of patients attributable to exome-wide AR coding variants ranged from ∼2% to ∼18% across genetically-inferred ancestry groups, and was significantly correlated with the average autozygosity (r=0.99, p=5x10-6). Established AR DD-associated (ARDD) genes explained 90% of the total AR coding burden, and this was not significantly different between probands with genetically-inferred European versus non-European ancestries. Approximately half the burden in these established genes was explained by variants not already reported as pathogenic in ClinVar. We estimated that ∼1% of undiagnosed patients in both cohorts were attributable to damaging biallelic genotypes involving missense variants in established ARDD genes, highlighting the challenge in interpreting these. By testing for gene-specific enrichment of damaging biallelic genotypes, we identified two novel ARDD genes passing Bonferroni correction,KBTBD2(p=1x10-7) andCRELD1(p=9x10-8). Several other novel or recently-reported candidate genes were identified at a more lenient 5% false-discovery rate, includingZDHHC16andHECTD4. This study expands our understanding of the genetic architecture of DDs across diverse genetically-inferred ancestry groups and suggests that improving strategies for interpreting missense variants in known ARDD genes may allow us to diagnose more patients than discovering the remaining genes.
SCN9A gene therapy: Novel mechanism to inhibit cellular senescence in astrocytesin vitro
Authors: Shah Divyash , Leonardi Donna , Waldron Alyssa 
Published: July 2023

AbstractCellular aging, also known as senescence, is a form of proliferation arrest that occurs in cells with age. In individuals, this process occurs due to telomere degradation and consequent dysfunction. In the nervous system, senescence of astrocytes, the most common neuronal support cells, has been associated with inflammation and forms of neurodegeneration associated with various disease pathologies. Thus, studying senescence may be a unique approach to understanding brain and aging and consequential diseases as well. Studies have shown that transcription downregulation of SCN9A led to reversal of senescence in epithelial cells. So, this study explores the role of SCN9A in astrocytes.In silicopatient gene analysis reveals multiple significant pathways associated with neuronal aging including ion channel regulation. Subsequent analysis shows the downregulation of SCN9A is associated with genes in the neuronal senescence pathway.In vitrostudies showed that astrocytes with knockdowned SCN9A did not undergo senescence as significantly as regular astrocytes. Furthermore, protein analysis presented a novel role for SCN9A in the astrocyte senescence pathway and an association with preventing DNA leakage. This study suggests SCN9A plays a large role in neurodegeneration and it should be studied in reversing senescence and even treatment plans for brain aging.
Downregulation of a cell polarity protein potentiates Chikungunya Virus infection in host cells
Authors: Kumar Ramesh , Tatiya Pushkar , Dey Debajit , Ratra Yashika , Mian Syed Yusuf , Chaudhary Shikha , Suhag Kirti , Basak Soumen , Banerjee Manidipa 
Published: July 2023

AbstractDownregulation of the host cell pro-apoptotic pathways confers a selective advantage to viral pathogens, and many viruses interfere with such regulatory mechanisms in order to enhance their propagation in infected cells. The Scribble cell polarity complex, which is composed of multiple adapter proteins including human Scribble, Dlg and MAGI, controls a variety of host cell functionalities including apoptosis, morphology, polarity, signaling and migration. In the recent years, components from several viral pathogens, including oncogenic viruses, have been found to associate with and modulate the activities of this complex, particularly that of the proapoptotic protein Scribble. Here, we establish a critical role for the downregulation of Scribble expression for the potentiation of Chikungunya Virus (CHIKV) infection. CHIKV is a well-known mosquito-borne alphavirus, which has caused outbreaks in more than 100 countries and constitutes a global health hazard. While the majority of the CHIKV proteome is well characterized, the role of a small structural protein 6K, and its transframe variant, TF, which is generated from the 6K sequence by ribosomal slippage and frameshifting, is not established as yet. We show that TF triggers the punctation, ubiquitination and degradation of Scribble during CHIKV infection, and that the downregulation of Scribble during CHIKV infection. We show that the association of TF with the PDZ domains of Scribble is mediated through a PDZ-domain binding motif at the C-terminus of TF. Thus, our work establishes a role for the downregulation of Scribble in alphavirus infections for the first time, while allocating a novel role in host modulation to the mysterious 6K/TF component of alphaviruses.
Evolution of cullin E3 ubiquitin ligases and function in trypanosomes
Authors: del Pino Ricardo Canavate , Zoltner Martin , Yamada Kayo , Butterfield Erin R. , Field Mark C. 
Published: July 2023

AbstractPost-translational modifications (PTMs) modulate protein function, with ubiquitylation a pre-eminent example with major roles in protein turnover. Ubiquitylation utilises a ligase enzyme cascade for conjugation of ubiquitin to client proteins and cullin-RING ligases are amongst the most complex known. We reconstructed evolution of cullin-RING E3 ubiquitin ligases across eukaryotes and experimentally characterised two cullin complexes in trypanosomatids, a taxon highly divergent from animals and fungi. We find considerable diversity within cullins and, in particular, trypanosomatids share only a minority of cullins with other lineages. Furthermore, we identify expansions in cullin client adaptor protein families, novel client adaptors and demonstrate client specificity. Finally we show that ornithine decarboxylase (TbODC), an important target of the drug trypanosome eflornithine, is a substrate for TbCul-A and overturn earlier models for eflornithine specificity. These studies highlight lineage-specific roles for cullin E3s and their contributions towards eukaryotic complexity.
Characterization of Pik1 function in fission yeast reveals its conserved role in lipid synthesis and not cytokinesis
Authors: Willet Alaina H. , Turner Lesley A. , Park Joshua S. , Ren Liping , Snider Chloe E. , Gould Kathleen L. 
Published: July 2023

AbstractPhosphatidylinositol (PI)-4-phosphate (PI4P) is a lipid found at the plasma membrane (PM) and Golgi in cells from yeast to humans. PI4P is generated from PI by PI4-kinases and can be converted to PI-4,5-bisphosphate [PI(4,5)P2].Schizosaccharomyces pombehave 2 essential PI4-kinases: Stt4 and Pik1. Stt4 localizes to the PM and its loss from the PM results in a decrease of PM PI4P and PI(4,5)P2. As a result, cells divide non-medially due to disrupted cytokinetic ring-PM anchoring. However, the localization and function ofS. pombePik1 has not been thoroughly examined. Here, we found that Pik1 localizes exclusively to the trans-Golgi and is required for Golgi PI4P production. We determined that Ncs1 regulates Pik1, but unlike in other organisms, it is not required for Pik1 Golgi localization. When Pik1 function was disrupted, PM PI4P but not PI(4,5)P2levels were reduced, a major difference with Stt4. We conclude that Stt4 is the chief enzyme responsible for producing the PI4P that generates PI(4,5)P2. Also, that cells with disrupted Pik1 do not divide asymmetrically highlights the specific importance of PM PI(4,5)P2for cytokinetic ring-PM anchoring.Summary statementFission yeast Pik1 localizes exclusively to the trans-Golgi independently of Ncs1, where it contributes to PI4P but not PI(4,5)P2synthesis. Pik1 does not affect cytokinesis.
How to believe? Building trust in food businesses' consumers based on psychological contracts
Authors: Wang Weihua , Yang Dong , Zheng Yaqin 
Published: July 2023

PurposeThe purpose of this study is to understand the psychological mechanism that affects consumer trust by focusing on the formation and influence process of psychological contracts, and taking this opportunity, explore the influence paths of food quality, food safety and service quality on consumer trust in the online food market, and provide theoretical suggestions for building trust in food businesses' consumers.Design/methodology/approachThis study is based on an empirical investigation and uses partial least square structural equation modeling for analysis. Survey data were collected online from 359 APP users of online food transaction platforms in China.FindingsFood quality, food safety and service quality influence consumer trust through the mediating effects of relational and transactional psychological contracts. However, the differences between these influencing paths are obvious and shift with changes in the marketing channels.Practical implicationsThis study contributes to the body of consumer trust research by exploring online food transactions as an emerging trend in China. Some optimization strategies for food quality, food safety and service quality are provided for enterprises involved in online food transactions.Originality/valueThis is a pioneering study revealing psychological contracts as a missing but significant mediator between consumer trust and its antecedents.
Implementing the principles of circular economy in the construction industry: exploratory and confirmatory factor analyses of strategies
Authors: Amudjie Judith , Agyekum Kofi , Adinyira Emmanuel , Amos-Abanyie Samuel , Botchway Edward Ayebeng 
Published: July 2023

Purpose
This study aims to examine the strategies that can be adopted to enhance the practice of circular economy (CE) principles among built environment (BE) firms operating in the Ghanaian Construction Industry (GCI).

Design/methodology/approach
A structured questionnaire survey was used to solicit the views of 162 BE professionals working in construction, consulting, and developer firms on the issue under investigation. The questionnaire was developed through a review of related literature and complemented with a pilot review. Data were analysed by descriptive and inferential statistics.

Findings
The findings revealed four major categories of strategies (i.e. systems and technical related strategies, market orientation and operational strategies, knowledge dissemination and awareness-related strategies, and environmental and regulatory strategies) to promote the practice of the principles of CE among BE professionals in the GCI.

Originality/value
This study’s findings provide insights into an under-investigated topic in the construction industry, especially, in a developing country such as Ghana, and offer new and additional information and insights into the current state-of-the-art on CE implementation.
Farmer education and adoption of sustainable and chemical pesticide-free agriculture: evidence from rural Burkina Faso
Authors: Maré Tobignaré Florent , Zahonogo Pam , Savadogo Kimseyinga 
Published: July 2023

PurposeIn a context where the promotion of a more sustainable agriculture is clearly aimed at, the paradoxical combination of sustainable agricultural practices (SAP) with chemical pesticides use instead of biological pest management techniques is recurrent in Sub-Saharan African (SSA) countries like Burkina Faso. Chemical pesticides are harmful to the environment and health. This paper aims to analyze the role of farmer education on the mode of adoption of SAP.Design/methodology/approachAn endogenous treatment effect model is used with survey data on 1,898 rural households in Burkina Faso.FindingsThe results show a positive causal effect of farmer education on sustainable and chemical pesticide-free agriculture adoption.Research limitations/implicationsFormal education appears to be general. This research could be extended to consider the role of training or extension services. More detailed results, focusing on spatial effects, could reinforce those of the present research.Originality/valueUnlike previous studies, this paper addresses for the first time the paradoxical behavior of combining SAP with chemical pesticides use. It shows that farmer education contributes to explain it and is therefore a determining factor for a more sustainable agriculture.