bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of Target Gene Regulation by the Two Epstein-Barr Virus Oncogene LMP1 Domains Essential for B-cell Transformation
Authors: Mitra Bidisha , Beri Nina Rose , Guo Rui , Burton Eric M. , Murray-Nerger Laura A. , Gewurz Benjamin E. 
Published: April 2023

AbstractThe Epstein-Barr virus (EBV) oncogene latent membrane protein 1 (LMP1) mimics CD40 signaling and is expressed by multiple malignancies. Two LMP1 C-terminal cytoplasmic tail regions, termed transformation essential sites (TES) 1 and 2, are critical for EBV transformation of B lymphocytes into immortalized lymphoblastoid cell lines (LCL). However, TES1 versus TES2 B-cell target genes have remained incompletely characterized, and whether both are required for LCL survival has remained unknown. To define LCL LMP1 target genes, we profiled transcriptome-wide effects of acute LMP1 CRISPR knockout (KO) prior to cell death. To then characterize specific LCL TES1 and TES2 roles, we conditionally expressed wildtype, TES1 null, TES2 null or double TES1/TES2 null LMP1 alleles upon endogenous LMP1 KO. Unexpectedly, TES1 but not TES2 signaling was critical for LCL survival. The LCL dependency factor cFLIP, which plays obligatory roles in blockade of LCL apoptosis, was highly downmodulated by loss of TES1 signaling. To further characterize TES1 vs TES2 roles, we conditionally expressed wildtype, TES1 and/or TES2 null LMP1 alleles in two Burkitt models. Systematic RNAseq analyses revealed gene clusters that responded more strongly to TES1 versus TES2, that respond strongly to both or that are oppositely regulated. Robust TES1 effects on cFLIP induction were again noted. TES1 and 2 effects on expression of additional LCL dependency factors, including BATF and IRF4, and on EBV super-enhancers were identified. Collectively, these studies suggest a model by which LMP1 TES1 and TES2 jointly remodel the B-cell transcriptome and highlight TES1 as a key therapeutic target.ImportanceEpstein-Barr virus (EBV) causes multiple human cancers, including B-cell lymphomas. In cell culture, EBV converts healthy human B-cells into immortalized ones that grow continuously, which model post-transplant lymphomas. Constitutive signaling from two cytoplasmic tail domains of the EBV oncogene Latent Membrane Protein 1 (LMP1) is required for this transformation, yet there has not been systematic analysis of their host gene targets. We identified that only signaling from the membrane proximal domain is required for survival of these EBV-immortalized cells and that its loss triggers apoptosis. We identified key LMP1 target genes, whose abundance changed significantly with loss of LMP1 signals, or that were instead upregulated in response to switching on signaling by one or both LMP1 domains in an EBV-uninfected human B-cell model. These included major anti-apoptotic factors necessary for EBV-infected B-cell survival. Bioinformatics analyses identified clusters of B-cell genes that respond differently to signaling by either or both domains.
OGG1 and MUTYH repair activities promote telomeric 8-oxoguanine induced cellular senescence
Authors: Rosa Mariarosaria De , Barnes Ryan P. , Nyalapatla Prasanth R. , Wipf Peter , Opresko Patricia L. 
Published: April 2023

SUMMARYTelomeres are prone to formation of the common oxidative lesion 8-oxoguanine (8oxoG), and the acute production of 8oxoG damage at telomeres is sufficient to drive rapid cellular senescence. OGG1 and MUTYH glycosylases initiate base excision repair (BER) at 8oxoG sites to remove the lesion or prevent mutation. Here, we show OGG1 loss or inhibition, or MUTYH loss, partially rescues telomeric 8oxoG-induced senescence, and loss of both glycosylases results in a near complete rescue. Loss of these glycosylases also suppresses 8oxoG-induced telomere fragility and dysfunction, indicating that single-stranded break (SSB) intermediates arising downstream of glycosylase activity impair telomere replication. The failure to initiate BER in glycosylase-deficient cells suppresses PARylation at SSB intermediates and confers resistance to the synergistic effects of PARP inhibitors on damage-induced senescence. Our studies reveal that inefficient completion of 8oxoG BER at telomeres triggers cellular senescence via SSB intermediates which impair telomere replication and stability.
Diethylcarbamazine elicits Ca2+signals through TRP-2 channels that are potentiated by emodepside inBrugia malayimuscles
Authors: Williams Paul D. E. , Kashyap Sudhanva S. , Robertson Alan P. , Martin Richard J. 
Published: April 2023

AbstractFilarial nematode infections are a major health concern in several countries. Lymphatic filariasis is caused byWucheria bancroftiandBrugia spp.affecting over 120 million people. Heavy infections can lead to elephantiasis having serious effects on individuals’ lives. Although current anthelmintics are effective at killing the microfilariae in the bloodstream, they have little to no effect against adult parasites found in the lymphatic system. The anthelmintic diethylcarbamazine is one of the central pillars of lymphatic filariasis control. Recent studies have reported that diethylcarbamazine can open Transient Receptor Potential (TRP) channels on the muscles of adult femaleBrugia malayileading to contraction and paralysis. Diethylcarbamazine has synergistic effects in combination with emodepside onBrugiainhibiting motility: emodepside is an anthelmintic that has effects on filarial nematodes and is under trials for treatment of river blindness. Here we have studied the effects of diethylcarbamazine on singleBrugiamuscle cells by measuring the change in Ca2+fluorescence in the muscle using Ca2+-imaging techniques. Diethylcarbamazine interacts with the TRPC orthologue receptor TRP-2 to promote Ca2+entry into theBrugiamuscle cells which can activate SLO-1 Ca2+activated K+channels, the putative target of emodepside. A combination of diethylcarbamazine and emodepside leads to a bigger Ca2+signal than when either compound is applied alone. Our study shows that diethylcarbamazine targets TRP channels to promote Ca2+entry that is increased by emodepside activation of SLO-1 channels.
Estimating heritability explained by local ancestry and evaluating stratification bias in admixture mapping from summary statistics
Authors: Chan Tsz Fung , Rui Xinyue , Conti David V. , Fornage Myriam , Graff Mariaelisa , Haessler Jeffrey , Haiman Christopher , Highland Heather M. , Jung Su Yon , Kenny Eimear , Kooperberg Charles , Marchland Loic Le , North Kari E. , Tao Ran , Wojcik Genevieve , Gignoux Christopher R. ,   PAGE Consortium, Chiang Charleston W. K. , Mancuso Nicholas 
Published: April 2023

AbstractThe heritability explained by local ancestry markers in an admixed populationprovides crucial insight into the genetic architecture of a complex disease or trait. Estimation ofcan be susceptible to biases due to population structure in ancestral populations. Here, we present a novel approach, Heritability estimation from Admixture Mapping Summary STAtistics (HAMSTA), which uses summary statistics from admixture mapping to infer heritability explained by local ancestry while adjusting for biases due to ancestral stratification. Through extensive simulations, we demonstrate that HAMSTAestimates are approximately unbiased and are robust to ancestral stratification compared to existing approaches. In the presence of ancestral stratification, we show a HAMSTA-derived sampling scheme provides a calibrated family-wise error rate (FWER) of ∼5% for admixture mapping, unlike existing FWER estimation approaches. We apply HAMSTA to 20 quantitative phenotypes of up to 15,988 self-reported African American individuals in the Population Architecture using Genomics and Epidemiology (PAGE) study. We observein the 20 phenotypes range from 0.0025 to 0.033 (mean), which translates toranging from 0.062 to 0.85 (mean). Across these phenotypes we find little evidence of inflation due to ancestral population stratification in current admixture mapping studies (mean inflation factor of 0.99 +/-0.001). Overall, HAMSTA provides a fast and powerful approach to estimate genome-wide heritability and evaluate biases in test statistics of admixture mapping studies.
Fecal metagenomics to identify biomarkers of food intake in healthy adults: Findings from randomized, controlled, nutrition trials
Authors: Shinn Leila M. , Mansharamani Aditya , Baer David J. , Novotny Janet A. , Charron Craig S. , Khan Naiman A. , Zhu Ruoqing , Holscher Hannah D. 
Published: April 2023

AbstractBackgroundUndigested components of the human diet affect the composition and function of the microorganisms present in the gastrointestinal tract. Techniques like metagenomic analyses allow researchers to study functional capacity, thus, revealing the potential of using metagenomic data for developing objective biomarkers of food intake.ObjectiveAs a continuation of our previous work using 16S and metabolomic datasets, we aimed to utilize a computationally intensive, multivariate, machine learning approach to identify fecal Kyoto Encyclopedia of Genes and Genomes (KEGG) Orthology (KO) categories as biomarkers that accurately classify food intake.DesignData were aggregated from five controlled feeding studies that studied the individual impact of almonds, avocados, broccoli, walnuts, barley, and oats on the adult gastrointestinal microbiota. DNA from pre-and post-intervention fecal samples underwent shotgun genomic sequencing. After pre-processing, sequences were aligned and functionally annotated with DIAMOND v2.0.11.149 and MEGAN v6.12.2, respectively. After count normalization, the log of the fold change ratio for resulting KOs between pre-and post-intervention of the treatment group against its corresponding control was utilized to conduct differential abundance analysis. Differentially abundant KOs were used to train machine learning models examining potential biomarkers in both single-food and multi-food models.ResultsWe identified differentially abundant KOs in the almond (n = 54), broccoli (n = 2,474), and walnut (n = 732) groups (q< 0.20), which demonstrated classification accuracies of 80%, 87%, and 86% for the almond, broccoli, and walnut groups, respectively, using a random forest model to classify food intake into each food group’s respective treatment and control arms. The mixed-food random forest achieved 81% accuracy.ConclusionsOur findings reveal promise in utilizing fecal metagenomics to objectively complement self-reported measures of food intake. Future research on various foods and dietary patterns will expand these exploratory analyses for eventual use in feeding study compliance and clinical settings.
Distinct interactions stabilize EGFR dimers and higher-order oligomers in cell membranes
Authors: Mudumbi Krishna C. , Burns Eric A. , Schodt David J. , Petrova Zaritza O. , Kiyatkin Anatoly , Kim Lucy W. , Mangiacapre Emma M. , Ortiz-Caraveo Irais , Ortiz Hector Rivera , Hu Chun , Ashtekar Kumar D. , Lidke Keith A. , Lidke Diane S. , Lemmon Mark A. 
Published: April 2023

AbstractThe epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase (RTK) with important roles in many cellular processes as well as cancer and other diseases. EGF binding promotes EGFR dimerization and autophosphorylation through interactions that are well understood structurally. However, it is not clear how these dimers relate to higher-order EGFR oligomers detected at the cell surface. We used single-particle tracking (SPT) and Förster resonance energy transfer (FRET) imaging to examine how each domain within EGFR contributes to receptor dimerization and the rate of its diffusion in the cell membrane. We show that the EGFR extracellular region is sufficient to drive receptor dimerization, but that the EGF-induced EGFR slow-down seen by SPT requires formation of higher order oligomers, mediated in part by the intracellular tyrosine kinase domain – but only when in its active conformation. Our data thus provide important insight into higher-order EGFR interactions required for EGF signaling.
How individualP. aeruginosacells with diverse stator distributions collectively form a heterogeneous macroscopic swarming population
Authors: de Anda Jaime , Kuchma Sherry L. , Webster Shanice S. , Boromand Arman , Lewis Kimberley A. , Lee Calvin K. , Contreras Maria , Pereira Victor F. Medeiros , Hogan Deborah A. , O’Hern Corey S. , O’Toole George A. , Wong Gerard C.L. 
Published: April 2023

AbstractSwarming is a macroscopic phenomenon in which surface bacteria organize into a motile population. The flagellar motor that drives swarming inPseudomonas aeruginosais powered by stators MotAB and MotCD. Deletion of the MotCD stator eliminates swarming, whereas deletion of the MotAB stator enhances swarming. Interestingly, we measured a strongly asymmetric stator availability in the WT strain, with MotAB stators produced ∼40-fold more than MotCD stators. However, recruitment of MotCD stators in free swimming cells requires higher liquid viscosities, while MotAB stators are readily recruited at low viscosities. Importantly, we find that cells with MotCD stators are ∼10x more likely to have an active motor compared to cells without, so wild-type, WT, populations are intrinsically heterogeneous and not reducible to MotAB-dominant or MotCD-dominant behavior. The spectrum of motility intermittency can either cooperatively shut down or promote flagellum motility in WT populations. InP. aeruginosa, transition from a static solid-like biofilm to a dynamic liquid-like swarm is not achieved at a single critical value of flagellum torque or stator fraction but is collectively controlled by diverse combinations of flagellum activities and motor intermittencies via dynamic stator recruitment. Experimental and computational results indicate that the initiation or arrest of flagellum-driven swarming motility does not occur from individual fitness or motility performance but rather related to concepts from the ‘jamming transition’ in active granular matter.ImportanceAfter extensive study, it is now known that there exist multifactorial influences on swarming motility inP. aeruginosa, but it is not clear precisely why stator selection in the flagellum motor is so important or how this process is collectively initiated or arrested. Here, we show that forP. aeruginosaPA14, MotAB stators are produced ∼40-fold more than MotCD stators, but recruitment of MotCD over MotAB stators requires higher liquid viscosities. Moreover, we find the unanticipated result that the two motor configurations have significantly different motor intermittencies, the fraction of flagellum-active cells in a population on average, with MotCD active ∼10x more often than MotAB. What emerges from this complex landscape of stator recruitment and resultant motor output is an intrinsically heterogeneous population of motile cells. We show how consequences of stator recruitment led to swarming motility, and how they potentially relate to surface sensing circuitry.
Comparative analysis of myoglobin in Cetaceans and humans reveals novel regulatory elements and evolutionary flexibility
Authors: Sackerson Charles , Garcia Vivian , Medina Nicole , Maldonado Jessica E. , Daly John , Cartwright Rachel 
Published: April 2023

AbstractCetacea and other diving mammals have undergone numerous adaptations to their aquatic environment, among them high levels of the oxygen-carrying intracellular hemoprotein myoglobin in skeletal muscles, especially those responsible for swimming. Hypotheses regarding the mechanisms leading to these high myoglobin levels often invoke exercise, hypoxia, and other physiological pathways that impact gene regulation, and increase myoglobin gene expression. Here we explore an alternative hypothesis: that Cetacean myoglobin genes have evolved high levels of transcription driven by the intrinsic developmental mechanisms that drive muscle cell differentiation. We have used luciferase assays in differentiated C2C12 cells to test this hypothesis. Contrary to our hypothesis, we find that the myoglobin gene from the minke whale,Balaenoptera acutorostrata, has a low level of expression, less than 10% that of humans. This low expression level is broadly shared among Cetaceans, and Artiodactylans. Previous work on regulation of the human gene has identified a core muscle-specific enhancer comprised of two regions, the “AT element” and a C-rich sequence 5’ of the AT element termed the “CCAC-box”. Comparative analysis of the minke whale gene supports the importance of the AT element, but the minke whale CCAC-box ortholog has little effect. Instead, critical positive input has been identified in a G-rich region 3’ of the AT element. Also, a conserved E-box in exon 1 positively affects expression, despite having been assigned a repressive role in the human gene. Last, a novel region 5’ of the core enhancer has been identified, which we hypothesize may function as a boundary element. These results illustrate regulatory flexibility during evolution. They also support the hypothesis that the induction of transcription by physiological signaling pathways, and evolved protein stability are important in leading to the high myoglobin protein levels found in Cetaceans.
The Intestinal Clock Regulates Host Metabolism through the Fiber-Dependent Microbiome and Macronutrient Transcriptome
Authors: Heddes Marjolein , Niu Yunhui , Altaha Baraa , Kleigrewe Karin , Meng Chen , Haller Dirk , Kiessling Silke 
Published: April 2023

AbstractCircadian disruption, e.g. through shift work, causes microbial dysbiosis and increases the risk of metabolic diseases. Microbial rhythmicity in mice depends on a functional intestinal clock and frequent jetlag as well as high-caloric energy intake induces loss of these oscillations. Similarly, arrhythmic microbiota was found in obese and T2D populations. However, the interplay between the intestinal circadian clock, the microbiome, diet and host metabolism is poorly understood.In intestinal-specificBmal1knockout mice (Bmal1IEC-/-) we demonstrate the relevance of the intestinal clock in microbiome oscillations and host and microbial nutrient metabolism. Microbiota transfer fromBmal1IEC-/-mice into germ-free recipients led to obesity, reflected by increased bodyweight and fat mass. Western diet-fedBmal1IEC-/-miceincreased bodyweight likely through mechanisms involving the intestinal clock-control of lipid and hexose transporters. Additionally, we identified dietary fiber as novel link between circadian microbial rhythmicity, intestinal clock functioning and host physiology. Thus, revealing the potential of fiber-rich diet intervention as a non-invasive strategy targeting microbial oscillations in metabolic disease prevention.
Temperature-dependent modulation of odor-dependent behavior in three drosophilid fly species of differing thermal preference
Authors: Baleba Steve B. S. , Mahadevan Venkatesh Pal , Knaden Markus , Hansson Bill S 
Published: April 2023

AbstractRapid and ongoing climate change increases global temperature and impacts both feeding and reproduction in insects. The sense of smell plays an important underlying role in these behaviors in most insect species. Here, we aimed to investigate how changing temperatures affect odor detection and ensuing behavior in three drosophilid flies:Drosophila novamexicana,D. virilisandD. ezoana, species that have adapted to life in desert, global and subarctic climates, respectively. Using a series of thermal preference assays, we confirmed that the three species indeed exhibit distinct temperature preferences. Next, using single sensillum recording technique, we classified olfactory sensory neurons (OSNs) present in basiconic sensilla on the antenna of the three species and thereby identified ligands for each OSN type. In a series of trap assays we proceeded to establish the behavioral valence of the best ligands and chose guaiacol, methyl salicylate and isopropyl benzoate as representatives of a repellent, attractant and neutral odor. Next, we assessed the behavioral valence of these three odors in all three species across a thermal range (10-35 C), with flies reared at 18°C and 25°C. We found that both developmental and experimental temperatures affected the behavioral performance of the flies. Our study thus reveals temperature-dependent changes in odor-guided behavior in drosophilid flies.
Impact of difficult coworkers on employees' turnover intention: the mediating roles of perceived organizational support and affective commitment
Authors: To Wai Ming , Yu Billy T.W. 
Published: April 2023

PurposeThis study explores the impact of difficult coworkers on employees' turnover intention. Additionally, this study investigates the roles of employees' attitude toward difficult coworkers, perceived organizational support and affective commitment in the relationship between difficult coworkers and turnover intention.Design/methodology/approachBased on the stimulus-organism-response theory, a theoretical model was established that linked difficult coworkers to employees' attitude toward the, then to turnover intention directly and indirectly through perceived organizational support and affective commitment. The model was validated using responses from 343 Chinese employees in Macao's banking industry.FindingsResults of the partial least squares-structural equation modeling (PLS-SEM) showed that difficult coworkers significantly influenced employees' attitude toward them. Employees' attitude toward difficult coworkers had a small and significant effect on turnover intention while perceived organizational support and affective commitment mediated the relationship between attitude toward difficult coworkers and turnover intention.Originality/valueThe study is the first empirical study to employ the stimulus-organism-response theory to characterize the impact of difficult coworkers on turnover intention. Fortunately, perceived organizational support and affective commitment were able to lessen the impact of difficult coworkers on turnover intention.
Identifying critical challenges to lean construction adoption
Authors: Singh Arpit , Kumar Vimal , Mittal Ankesh , Verma Pratima 
Published: April 2023

Purpose
This study aims to set out to identify and evaluate potential obstacles to successfully implementing lean construction (LC) as a result.

Design/methodology/approach
Several indicators were recognized as major obstacles following an exhaustive assessment of the literature and a multicriteria decision analysis based on the analytic hierarchy process (AHP) of information obtained from a questionnaire survey that was directed to practitioners in the Indian construction industry.

Findings
The results of this AHP model suggest that “Managerial” and “Inadequate resources” categories with a priority weight of “0.361” and “0.309” have the highest levels of influence, respectively, while “Inadequate knowledge” and “just in time (JIT)” categories with a priority weight of “0.053” and “0.034” have the lowest levels of influence, respectively.

Research limitations/implications
Construction companies can use the study’s findings as a guide to determine whether they are ready to embrace LC, learn more about the components needed for implementation or investigate any challenges that may arise. These businesses can then create plans to promote the adoption and application of the lean philosophy.

Originality/value
The Indian construction industry may see great success with LC management initiatives. LC concepts have been adopted by many nations, but during the past 20 years, there has only appeared to be a limited amount of lean implementation in the Indian construction industry. It seems that several structural and cultural barriers are preventing its effective implementation. Organizations will not be able to determine what improvement efforts are required, where these efforts should be directed or which initiatives could provide the best outcomes if they are unaware of the elements that influence the effective implementation of LC.