bluuebunny/crossref_metadata_2025_split huggingface dataset:
Monosaccharides DriveSalmonellaGut Colonization in a Context-Dependent Manner
Authors: Schubert Christopher , Nguyen Bidong D. , Sichert Andreas , Näpflin Nicolas , Sintsova Anna , Feer Lilith , Näf Jana , Daniel Benjamin B.J. , Steiger Yves , von Mering Christian , Sauer Uwe , Hardt Wolf-Dietrich 
Published: August 2024

AbstractThe carbohydrates that fuel gut colonization byS. Typhimurium are not fully known. To investigate this, we designed a quality-controlled mutant pool to probe the metabolic capabilities of this enteric pathogen. Using WISH-barcoding, we tested 35 metabolic mutants across five different mouse models, allowing us to differentiate between context-dependent and context-independent nutrient sources. Results showed thatS. Typhimurium uses D-glucose, D-mannose, D-fructose, and D-galactose as context-independent carbohydrates across all models. The utilization of N-acetylglucosamine and hexuronates, on the other hand, was context-dependent. Furthermore, we showed that D-fructose is important in strain-to-strain competition betweenSalmonellaserovars. Complementary experiments confirmed that D-glucose, D-fructose, and D-galactose are excellent niches forS. Typhimurium to exploit during colonization. Quantitative measurements revealed sufficient amounts of D-glucose and D-galactose in the murine cecum to driveS. Typhimurium colonization. Understanding these key substrates and their context-dependent use by enteric pathogens will inform the future design of probiotics and therapeutics to prevent diarrheal infections such as non-typhoidal salmonellosis.
In-cell structural insight into the asymmetric assembly of central apparatus in mammalian sperm axoneme
Authors: Zhu Yun , Yin Guoliang , Tai Linhua , Wang Binbin , Lu Yi , Zhang Zhiyong , Chen Suren , Sun Fei 
Published: August 2024

AbstractIn motile cilia or flagella, the axoneme typically exhibits a “9+2” configuration, with the central apparatus (CA) consisting of extensively modified microtubules C1 and C2 to regulate ciliary motility. How C1 and C2 are interconnected asymmetrically remains unknown due to the lack of complete structural model of CA. Here, we utilized thein situcryo-electron tomography approach to solve the in-cell structure of intact mouse sperm CA at sub-nanometer resolution and built its near-complete atomic model with the aid of AlphaFold2. We identified 39 different CA-associated proteins with 8 never reported from isolated specimen. We assigned the long chain-like ASH-containing proteins CFAP47 and HYDIN responsible for connecting C1 and C2. Sperm fromCfap47-knockout mice displayed a hollowing bridge in the CA structure, correlating with its reduced progressive motility. Our findings elucidate the molecular mechanisms of CA components in ciliary motility, and the implications of their mutations in human ciliopathies.
Defining short linear motif binding determinants by phage-based multiplexed deep mutational scanning
Authors: Benz Caroline , Maasen Lars , Simonetti Leandro , Mihalic Filip , Lindqvist Richard , Tsitsa Ifigenia , Jemth Per , Överby Anna K. , Davey Norman E. , Ivarsson Ylva 
Published: August 2024

AbstractDeep mutational scanning (DMS) has emerged as a powerful approach for evaluating the effects of mutations on binding or function. Here, we developed a multiplexed DMS by phage display protocol to define the binding determinants of short linear motifs (SLiMs) binding to peptide binding domains. We first designed a benchmarking DMS library to evaluate the performance of the approach on well-known ligands for eleven different peptide binding domains, including the talin-1 PTB domain. Systematic benchmarking against a gold-standard set of motifs from the eukaryotic linear motif (ELM) database confirmed that the DMS by phage analysis correctly identifies known motif binding determinants. The DMS analysis further defined a non-canonical PTB binding motif, with a putative extended conformation. A second DMS library was designed aiming to provide information on the binding determinants for 19 SLiM-based interactions between human and SARS-CoV-2 proteins. The analysis confirmed the affinity determining residues of viral peptides binding to host proteins, and refined the consensus motifs in human peptides binding to five domains from SARS-CoV-2 proteins, including the non-structural protein (NSP) 9. The DMS analysis further pinpointed mutations that increased the affinity of ligands for NSP3 and NSP9. An affinity improved cell-permeable NSP9-binding peptide was found to exert stronger antiviral effects as compared to the initial wild-type peptide. Our study demonstrates that DMS by phage display can efficiently be multiplexed and applied to refine binding determinants, and shows how DMS by phage display can guide peptide-engineering efforts.
Episodic Transport of Protein Aggregates Achieves a Positive Size Selectivity in Aggresome Formation
Authors: Fang Rui , Bai Luolan , Li Boyan , Dong Kevin , Paulo Joao A. , Zhou Mengying , Chu Yi-Chi , Song Yuyu , Sherman Michael Y. , Gygi Steven , Field Christine M. , Mitchison Timothy J. , Lu Ying 
Published: August 2024

AbstractEukaryotic cells direct toxic misfolded proteins to various protein quality control pathways based on their chemical features and aggregation status. Aggregated proteins are targeted to selective autophagy or specifically sequestered into the “aggresome,” a perinuclear inclusion at the microtubule-organizing center (MTOC). However, the mechanism for selectively sequestering protein aggregates into the aggresome remains unclear. To investigate aggresome formation, we reconstituted MTOC-directed aggregate transport inXenopus laevisegg extract using AgDD, a chemically inducible aggregation system. High-resolution single-particle tracking revealed that dynein-mediated transport of aggregates was highly episodic, with average velocity positively correlated with aggregate size. Our mechanistic model suggests that the recurrent formation of the dynein transport complex biases larger aggregates towards the active transport state, compensating for the slowdown due to viscosity. Both episodic transport and positive size selectivity are specifically associated with aggresome-dynein adaptors. Coupling conventional dynein-activating adaptors to the aggregates perturbs aggresome formation and reverses size selectivity.
Dysfunction of telomeric Cdc13-Stn1-Ten1 simultaneously activates the DNA damage and spindle checkpoints
Authors: Grandin Nathalie , Charbonneau Michel 
Published: August 2024

AbstractTelomeres, the ends of eukaryotic linear chromosomes, are composed of repeated DNA sequences and specialized proteins, with the conserved Cdc13/CTC1-Stn1-Ten1 (CST) telomeric comple providing chromosome stability via telomere end-protection and regulation of telomerase accessibility. In the present study,SIZ1, coding for a SUMO E3 ligase, andTOP2(Top2 is a SUMO target for Siz1 and Siz2) were isolated as extragenic suppressors of temperature-sensitive mutants ofSaccharomyces cerevisiaeCST.ten1-sz, stn1-szandcdc13-szmutants were next isolated on the basis of being sensitive to intracellular Siz1 dosage. In parallel, strong negative genetic interactions between mutants of CST and septins were identified, septins being noticeably sumoylated through action of Siz1. The temperature-sensitive arrest in these new mutants of CST was dependent on the G2/M Mad2-mediated and Bub2-mediated spindle checkpoints as well as on the G2/M Mec1-mediated DNA damage checkpoint. Our data suggest the existence of yet unknown functions of the telomeric Cdc13-Stn1-Ten1 complex related with mitotic spindle positioning and/or spindle assembly that could be further elucidated by studying these newten1-sz, stn1-szandcdc13-szmutants.
Aperiodic and oscillatory systems underpinning human domain-general cognition
Authors: Lu Runhao , Dermody Nadene , Duncan John , Woolgar Alexandra 
Published: August 2024

AbstractDomain-general cognitive systems are essential for adaptive human behaviour, supporting various cognitive tasks through flexible neural mechanisms. While fMRI studies link the frontoparietal network activation to increasing demands across various tasks, the electrophysiological mechanisms underlying this domain-general response to demand remain unclear. Here, we used MEG/EEG, with aperiodic and oscillatory components separated, to examine their roles in domain-general cognition across three cognitive tasks using multivariate analysis. We found that both aperiodic (broadband power, slope, and intercept) and oscillatory (theta, alpha, and beta power) components coded task demand and content across all subtasks. Aperiodic broadband power in particular strongly coded task demand, in a manner that generalised across all subtasks. Source estimation suggested that increasing cognitive demand decreased aperiodic broadband power across the brain, with the strongest modulations overlapping with the frontoparietal network. In contrast, oscillatory activity showed more localised patterns of modulation, primarily in frontal or occipital regions. These results provide insights into the electrophysiological underpinnings of human domain-general cognition, highlighting the critical role of aperiodic broadband power.
Engineering synthetic agonists for targeted activation of Notch signaling
Authors: Perez David H. , Antfolk Daniel , Bustos Xiomar E. , Medina Elliot , Chang Shiun , Ramadan Ahmed A. , Rodriguez Paulo C. , Gonzalez-Perez David , Abate-Daga Daniel , Luca Vincent C. 
Published: August 2024

ABSTRACTNotch signaling regulates cell fate decisions and has context-dependent tumorigenic or tumor suppressor functions. Although there are several classes of Notch inhibitors, the mechanical force requirement for Notch receptor activation has hindered attempts to generate soluble agonists. To address this problem, we engineered synthetic Notch agonist (SNAG) proteins by tethering affinity-matured Notch ligands to antibodies or cytokines that internalize their targets. This bispecific format enables SNAGs to “pull” on mechanosensitive Notch receptors, triggering their activation in the presence of a desired biomarker. We successfully developed SNAGs targeting six independent surface markers, including the tumor antigens PDL1, CD19, and HER2, and the immunostimulatory receptor CD40. SNAGs targeting CD40 increase expansion of central memory γδ T cells from peripheral blood, highlighting their potential to improve the phenotype and yield of low-abundance T cell subsets. These insights have broad implications for the pharmacological activation of mechanoreceptors and will expand our ability to modulate Notch signaling in biotechnology.
Early life stress induced sex-specific changes in behavior is paralleled by altered locus coeruleus physiology in BALB/cJ mice
Authors: Savannah Brannan , Garbe Lauren , Richardson Ben D 
Published: August 2024

ABSTRACTAdverse childhood experiences have been associated with many neurodevelopmental and affective disorders including attention deficit hyperactivity disorder and generalized anxiety disorder, with more exposures increasing negative risks. Sex and genetic background are biological variables involved in adverse psychiatric outcomes due to early life trauma. Females in general have an increased prevalence of stress-related psychopathologies beginning after adolescence, indicative of the adolescent time period being a female-specific sensitive period. To understand the underlying neuronal components responsible for this relationship between genetic background, sex, stress/trauma, and cognitive/affective behaviors, we assessed behavioral and neuronal changes in a novel animal model of early life stress exposure. Male and female BALB/cJ mice that express elevated basal anxiety-like behaviors and differences in monoamine associated genes, were exposed to an early life variable stress protocol that combined deprivation in early life with unpredictability in adolescence. Stress exposure produced hyperlocomotion and attention (5 choice serial reaction time task) in male and female mice along with female-specific increased anxiety-like behavior. These behavioral changes were paralleled by reduced excitability of locus coeruleus (LC) neurons, due to resting membrane potential hyperpolarization in males and a female specific increase in action potential delay time. These data describe a novel interaction between sex, genetic background, and early life stress that results in behavioral changes in clinically-relevant domains and potential underlying mechanistic lasting changes in physiological properties of neurons in the LC.HIGHLIGHTSBALB/cJ mice exposed to early life stress are hyperactive in adolescence and displayed attention deficits in adulthood.Only female BALB/cJ mice develop increased anxiety in adolescence after early life stress.Early life stress causes reduced excitability of locus coeruleus neurons in BALB/cJ mice.Only locus coeruleus neurons from female BALB/cJ mice exposed to early life stress displayed an increase in action potential delay time upon depolarization.
Interruption of glucagon signaling augments islet non-alpha cell proliferation in SLC7A2- and mTOR-dependent manners
Authors: Coate Katie C. , Dai Chunhua , Singh Ajay , Stanley Jade , Covington Brittney A. , Bradley Amber , Oladipupo Favour , Gong Yulong , Wisniewski Scott , Spears Erick , Poffenberger Greg , Bustabad Alexandria , Rodgers Tyler , Dey Nandita , Shultz Leonard D. , Greiner Dale L. , Yan Hai , Powers Alvin C. , Chen Wenbiao , Dean E. Danielle 
Published: August 2024

ABSTRACTObjectiveDysregulated glucagon secretion and inadequate functional beta cell mass are hallmark features of diabetes. While glucagon receptor (GCGR) antagonism ameliorates hyperglycemia and elicits beta cell regeneration in pre-clinical models of diabetes, it also promotes alpha and delta cell hyperplasia. We sought to investigate the mechanism by which loss of glucagon action impacts pancreatic islet non-alpha cells, and the relevance of these observations in a human islet context.MethodsWe used zebrafish, rodents, and transplanted human islets comprising six different models of interrupted glucagon signaling to examine their impact on delta and beta cell proliferation and mass. We also used models with global deficiency of the cationic amino acid transporter, SLC7A2, and mTORC1 inhibition via rapamycin, to determine whether amino acid-dependent nutrient sensing was required for islet non-alpha cell growth.ResultsInhibition of glucagon signaling stimulated delta cell proliferation in mouse and transplanted human islets, and in mouse islets. This was rapamycin-sensitive and required SLC7A2. Likewise,gcgrdeficiency augmented beta cell proliferation via SLC7A2- and mTORC1-dependent mechanisms in zebrafish and promoted cell cycle engagement in rodent beta cells but was insufficient to drive a significant increase in beta cell mass in mice.ConclusionOur findings demonstrate that interruption of glucagon signaling augments islet non-alpha cell proliferation in zebrafish, rodents, and transplanted human islets in a manner requiring SLC7A2 and mTORC1 activation. An increase in delta cell mass may be leveraged for future beta cell regeneration therapies relying upon delta cell reprogramming.
SLC27A2as a molecular marker of impaired epithelium in chronic rhinosinusitis with nasal polyps
Authors: Park Jaewoo , Jang Jung Yeon , Kim Jeong Heon , Yi Se Eun , Lee Yeong Ju , Yu Myeong Sang , Chung Yoo-Sam , Jang Yong Ju , Kim Ji Heui , Kang Kyuho 
Published: August 2024

ABSTRACTBackgroundChronic rhinosinusitis with nasal polyps (CRSwNP) is a complex disease characterized by multiple inflammatory endotypes. Although recent progress has been made in endotype-based classification, developing tailored therapeutic strategies for CRSwNP remains challenging. This study aimed to optimize therapeutic outcomes in CRSwNP by identifying potential molecular markers.MethodsWe utilized an integrated approach that combined bulk and single-cell RNA sequencing (scRNA-seq) to delineate the molecular signatures inherent to the cellular components of nasal polyp (NP) tissue. The levels of C11-BODIPY (as a marker of lipid peroxidation) andSLC27A2/FATP2 were assessed using quantitative PCR and immunofluorescence (IF) staining. The effects of lipofermata, a FATP2 inhibitor, were examined in air-liquid interface (ALI) cultured epithelial cells derived from CRSwNP patients and healthy controls.ResultsDeconvolution analysis of NP tissue revealed an upregulation of genes associated with lipid metabolism in the NP epithelium. In CRSwNP patients, we observed a significant increase in lipid peroxidation andSLC27A2/FATP2 expression in the NP epithelium. A marked expression of genes critical to metabolic pathways involved in lipid peroxidation was identified inSLC27A2-positive epithelial cells. Additionally, FATP2 and lipid peroxidation staining patterns exhibited a positive correlation in their respective % Area levels. ElevatedSLC27A2expression was associated with disease pathogenesis and correlated with disease severity. Treatment with lipofermata resulted in decreased mRNA levels ofALOX15, a key mediator of inflammation and lipid peroxidation, andFOXJ1, a marker of abnormal ciliogenesis.ConclusionElevatedSLC27A2expression in the NP epithelium correlates with the severity of CRSwNP, highlighting its potential as a therapeutic target for managing advanced CRSwNP cases.
RIGHT SEPSIS CLASSIFICATION- MUST FOR ANTIMICROBIAL STEWARDSHIP: A LONGITUDINAL OBSERVATIONAL STUDY
Authors: Pilania Jaideep , Panda Prasan Kumar , Das Ananya , Chauhan Udit , Kant Ravi 
Published: August 2024

ABSTRACTBackgroundSepsis is a critical medical condition characterized by life-threatening organ dysfunction triggered by a dysregulated response to infection. It poses a substantial global health burden, with significant morbidity, mortality, and economic costs, particularly pronounced in low- and middle-income countries. Effective management of sepsis relies on early recognition and appropriate intervention, underscoring the importance of accurate classification to guide treatment decisions.ObjectiveThis longitudinal observational study aimed to assess the distribution of sepsis categories and the use of empirical antibiotics classified by the WHO AWaRe system in a tertiary care hospital in Northern India. The study also aimed to highlight implications for antimicrobial stewardship by examining the use of AWaRe group antibiotics and their correlation with sepsis classifications.MethodsA total of 1867 patients admitted with suspected sepsis were screened, with 230 meeting inclusion criteria. Patients were categorized into different sepsis classes (Asepsis, Possible Sepsis, Probable Sepsis, Confirm Sepsis) and followed until discharge or Day-28. Descriptive statistical analysis was employed to assess sepsis categories and empirical antibiotic usage classified by Access, Watch, and Reserve categories according to the WHO AWaRe system.ResultsAmong the study cohort (mean age 40.70 ± 14.49 years, 50.9% female), initial sepsis classification predominantly included Probable Sepsis (51.3%) and Possible Sepsis (35.7%), evolving to Asepsis (57.8%) upon final classification. Empirical antibiotic use showed a concerning predominance of Watch group antibiotics (92.5%), with Ceftriaxone (45.7%) and piperacillin-tazobactam (31.7%) being the most commonly prescribed.ConclusionThe dynamic nature of sepsis classification underscores the complexity of diagnosing and managing this condition. Accurate categorization is pivotal for clinical decision-making, optimizing antibiotic use, and combating antimicrobial resistance. The majority of the asepsis category was levelled as probable or possible sepsis and given antibiotics. The high reliance on Watch group antibiotics in empirical therapy signals a need for enhanced diagnostic strategies to refine treatment initiation, potentially reducing unnecessary antibiotic exposure. Future efforts should focus on establishing sepsis classification checklists and promoting adherence to antimicrobial stewardship principles to mitigate the global threat of antimicrobial resistance.
Strategic positioning and asymmetric cost behavior
Authors: Banker Rajiv , Flasher Renee , Zhang Daqun 
Published: August 2024

PurposeThis paper explores if the firm’s strategic orientation can be associated with differences in cost behavior activity.Design/methodology/approachUsing Compustat data from 1979 to 2012, the archival study examines if there are differences between differentiation and cost leadership strategies on the firm’s cost stickiness.FindingsThe main finding provides evidence that firms pursuing a differentiation strategy exhibit greater cost stickiness, on average, as compared to firms pursuing a cost leadership strategy. This relationship is moderated by the optimistic or pessimistic expectations of managers for future sales.Originality/valueThis paper contributes to the literature on cost management by explaining how strategic positioning affects firms’ cost behavior using the framework of asymmetric cost behavior. The study encompasses both product and period costs and documents the impact on earnings.
Quality and safety nexus: exploring critical factors in global food security
Authors: Qazi Abroon , Al-Mhdawi M.K.S. 
Published: August 2024

PurposeThis study aims to explore the interrelationships among quality and safety metrics within the Global Food Security Index (GFSI). Its primary objective is to identify key indicators and their respective influences on food security outcomes, thereby enriching comprehension of the intricate dynamics within global food security.Design/methodology/approachThe analysis encompasses data from 113 countries for the year 2022, utilizing Bayesian Belief Network (BBN) models to identify significant drivers of both the GFSI and quality and safety dimensions. This methodological approach enables the examination of probabilistic connections among different indicators, providing a structured framework for investigating the complex dynamics of food security.FindingsThe study highlights the critical role of regulatory frameworks, access to clean drinking water, and food safety mechanisms in fostering food security. Key findings reveal that “nutrition monitoring and surveillance” has the highest probability (75%) of achieving a high-performance state, whereas “national dietary guidelines” have the highest probability (41%) of achieving a low-performance state. High GFSI performance is associated with excelling in indicators such as “access to drinking water” and “food safety mechanisms”, while low performance is linked to underperformance in “national dietary guidelines” and “nutrition labeling”. “Protein quality” and “dietary diversity” are identified as the most critical indicators affecting both the GFSI and quality and safety dimensions.Originality/valueThis research operationalizes a probabilistic technique to analyze the interdependencies among quality and safety indicators within the GFSI. By uncovering the probabilistic connections between these indicators, the study enhances understanding of the underlying dynamics that influence food security outcomes. The findings highlight the critical roles of regulatory frameworks, access to clean drinking water, and food safety mechanisms, offering actionable insights that empower policymakers to make evidence-based decisions and allocate resources effectively. Ultimately, this research significantly contributes to the advancement of food security interventions and the achievement of sustainable development goals related to food quality and safety.