bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of novel myokines and putative protein targets that mediate functional adaptations in response to chronic contractile activity induced skeletal muscle-extracellular vesicle treatment
Authors: Obi Patience O. , Souza Tamiris F. G. , Lao Ying , McManus Kirk J. , Gordon Joseph W. , LeDuc Richard , Zahedi René P. , Saleem Ayesha 
Published: September 2024

AbstractWe have previously shown that skeletal muscle-derived extracellular vesicles (EVs) released post-chronic contractile activity (CCA) increased mitochondrial biogenesis in murine myoblasts, and decreased cell viability and induced apoptosis and senescence in non-small cell lung cancer cells. While the underlying mechanisms are unknown, the effects perpetuated were dependent on membrane-bound proteins. Here, we performed an extensive LC-MS/MS proteomic analysis on EVs from control and CCA myotubes. A total of 2900 proteins were identified in CON-EVs and CCA-EVs, including EV-associated proteins such as TSG101, tetraspanins (CD9, CD81, and CD63), flotillin-1, and annexins. Of these, 856 proteins are novel and not listed in EV databases (ExoCarta and Vesiclepedia), indicating that myotube-EVs harbor proteins not yet identified in EVs of different origin. Additionally, we identified 2062 unique proteins that have not yet been previously reported in myotube-EVs to date. Remarkably, of the 2900 total proteins identified, we observed 46 upregulated, and 25 downregulated differentially expressed proteins (DEPs) in CCA-EVsvs. control-EVs. Most of upregulated DEPs include EV-associated proteins. Comparing the 71 DEPs with proteins expressed in skeletal muscle indicated 61 of these as potential myokines. We identified actin cytoskeleton signaling, integrin signaling and muscle contraction as the most enriched pathways among the DEPs using different databases/software including FunRich, KEGG, STRING and Ingenuity Pathway Analysis. Using a relevance score that prioritized membrane-bound proteins with known function in mitochondrial biogenesis and inhibition of cancer growth, we identified top-scoring highly enriched DEPs of interest: IGF1R, ATP7A, PFN1, GJA1, PRKCA and ITGA6. We confirmed upregulation of these targets in EVs using immunoblotting. Among these top-scoring DEPs, PFN1, and ITGA6 are associated with EVs, with expression upregulated following acute exercise. In summary, we report the first comprehensive analysis of skeletal muscle-EV proteome following CCA, with identification of putative protein targets and signaling pathways that may execute the pro-metabolic and anti-tumorigenic effects of CCA-EVs.
Deficits in the knowledge of social norms and their underlying mechanisms in Alzheimer’s disease
Authors: Carrier Thomas , Rouleau Isabelle , St-Georges Marie-Anne , Montembeault Maxime 
Published: September 2024

AbstractBackgroundCompared to other components of social cognition, knowledge of social norms has received less attention, even more so in Alzheimer’s disease (AD). While semantic memory deficits have been identified early in the course of AD, no study has delved into the knowledge of social norms at these preliminary stages, although evidence suggests it shares common ground with semantic memory. In addition, it is unclear whether the knowledge of social norms in AD is associated socioemotional deficits, as seen in the behavioral variant of frontotemporal dementia (bvFTD). Finally, how social norms knowledge impairments predict behaviours in real-world settings remains unknown in the context of AD.MethodsThis study included 286 participants with mild cognitive impairment (MCI), 157 with AD, 285 with bvFTD along with 384 older healthy controls. All participants were selected from the National Alzheimer’s Coordinating Center. They completed the Social Norms Questionnaire, which assesses the tendency to break or overadhere to social norms. They also completed tests assessing executive, semantic and socioemotional functions, along with tests measuring spontaneous interpersonal behaviours.ResultsBetween-group comparisons show that individuals with AD and MCI break and overadhere to social norms significantly more than HC, while they perform better than individuals with bvFTD. Knowledge of social norms was mainly associated with semantic knowledge across groups, and predicted insensitivity and disinhibition severity in patients.ConclusionsThis study suggests that declines in semantic memory likely play a key role in social norms knowledge decreases and that these decreases predict behavioural tendencies.
Timely vaccine strain selection and genomic surveillance improves evolutionary forecast accuracy of seasonal influenza A/H3N2
Authors: Huddleston John , Bedford Trevor 
Published: September 2024

AbstractFor the last decade, evolutionary forecasting models have influenced seasonal influenza vaccine design. These models attempt to predict which genetic variants circulating at the time of vaccine strain selection will be dominant 12 months later in the influenza season targeted by vaccination campaign. Forecasting models depend on hemagglutinin (HA) sequences from the WHO’s Global Influenza Surveillance and Response System to identify currently circulating groups of related strains (clades) and estimate clade fitness for forecasts. However, the average lag between collection of a clinical sample and the submission of its sequence to the Global Initiative on Sharing All Influenza Data (GISAID) EpiFlu database is ∼3 months. Submission lags complicate the already difficult 12-month forecasting problem by reducing understanding of current clade frequencies at the time of forecasting. These constraints of a 12-month forecast horizon and 3-month average submission lags create an upper bound on the accuracy of any long-term forecasting model. The global response to the SARS-CoV-2 pandemic revealed that modern vaccine technology like mRNA vaccines can reduce how far we need to forecast into the future to 6 months or less and that expanded support for sequencing can reduce submission lags to GISAID to 1 month on average. To determine whether these recent advances could also improve long-term forecasts for seasonal influenza, we quantified the effects of reducing forecast horizons and submission lags on the accuracy of forecasts for A/H3N2 populations. We found that reducing forecast horizons from 12 months to 6 or 3 months reduced average absolute forecasting errors to 25% and 50% of the 12-month average, respectively. Reducing submission lags provided little improvement to forecasting accuracy but decreased the uncertainty in current clade frequencies by 50%. These results show the potential to substantially improve the accuracy of existing influenza forecasting models by modernizing influenza vaccine development and increasing global sequencing capacity.
Pyjacker identifies enhancer hijacking events in acute myeloid leukemia includingMNX1activation via deletion 7q
Authors: Sollier Etienne , Riedel Anna , Toprak Umut H. , Wierzbinska Justyna A. , Weichenhan Dieter , Schmid Jan Philipp , Hakobyan Mariam , Touzart Aurore , Jahn Ekaterina , Vick Binje , Brown-Burke Fiona , Kelly Katherine , Kelekci Simge , Pejkovska Anastasija , Goyal Ashish , Bähr Marion , Breuer Kersten , Chen Mei-Ju May , Llamazares-Prada Maria , Hartmann Mark , Schönung Maximilian , Correia Nádia , Trumpp Andreas , Abdullah Yomn , Klingmüller Ursula , Mughal Sadaf S. , Brors Benedikt , Westermann Frank , Schlesner Matthias , Vosberg Sebastian , Herold Tobias , Greif Philipp A. , Pfeifer Dietmar , Lübbert Michael , Fischer Thomas , Heidel Florian H. , Gebhard Claudia , Walter Wencke , Haferlach Torsten , Eisfeld Ann-Kathrin , Mrózek Krzysztof , Nicolet Deedra , Bullinger Lars , Smeenk Leonie , Erpelinck Claudia , Mulet-Lazaro Roger , Delwel Ruud , Ernst Aurélie , Scherer Michael , Lutsik Pavlo , Jeremias Irmela , Döhner Konstanze , Döhner Hartmut , Lipka Daniel B. , Plass Christoph 
Published: September 2024

AbstractAcute myeloid leukemia with complex karyotype (ckAML) is characterized by high genomic complexity, including frequentTP53mutations and chromothripsis. We hypothesized that the numerous genomic rearrangements could reposition active enhancers near proto-oncogenes, leading to their aberrant expression. We developed pyjacker, a computational tool for the detection of enhancer hijacking events, and applied it to a cohort of 39 ckAML samples. Pyjacker identifiedmotor neuron and pancreas homeobox 1(MNX1), a gene aberrantly expressed in 1.4% of AML patients, often as a result of del(7)(q22q36) associated with hijacking of aCDK6enhancer.MNX1-activated cases show significant co-occurrence withBCORmutations and a gene signature shared with t(7;12)(q36;p13) pediatric AML. We demonstrated thatMNX1is a dependency gene, as its knockdown in a xenograft model reduces leukemia cell fitness. In conclusion, enhancer hijacking is a frequent mechanism for oncogene activation in AML.Statement of significanceThis study examines the consequences of structural alterations and demonstrates that proto-oncogene activation by enhancer hijacking is an overlooked pathomechanism in AML.MNX1overexpression demonstrates that deletions on chromosome 7q can not only lead to haploinsufficiency, but also to activation of oncogenes by enhancer hijacking, providing a novel leukemogenic mechanism.
Timing of starvation determines its effects on susceptibility to infection inDrosophila melanogasterfemales independent of host evolutionary history
Authors: Basu Aabeer , Singh Aparajita , Prasad Nagaraj Guru 
Published: September 2024

AbstractAn organism’s susceptibility to pathogens is contingent on various environmental factors, including the availability of nutrition. Starvation can alter host susceptibility to infections, either directly via depletion of resources essential for proper functioning of the immune system, or indirectly via the various physiological changes it induces within the host body. We tested if the susceptibility ofDrosophila melanogasterpopulations toEnterococcus faecalisinfection is affected by (a) whether the hosts are starved before or after the infection, and (b) the evolutionary history of the host. Hosts from laboratory fly populations that have been experimentally evolved to be more resistant toE. faecalis, and their corresponding control populations, were subjected to infection with or without being starved prior to and after being infected. We found that the effect of starvation on susceptibility toE. faecalischanged with the timing of starvation: starvation after infection improved survival of infected hosts, irrespective of how they were treated before infection, while starving only prior to infection (and not after) compromised post-infection survival. The changes in infection susceptibility were uniform in both the evolved and the control populations, suggesting that the effects of starvation are not dependent on pre-existing resistance to the infecting pathogen.
Synergistic cross-kingdom host cell damage betweenCandida albicansandEnterococcus faecalis
Authors: Kapitan Mario , Niemiec Maria Joanna , Millet Nicolas , Brandt Philipp , Chowdhury Md Estiak Khan , Czapka Anna , Abdissa Ketema , Hoffmann Franziska , Lange Anna , Veleba Mark , Nietzsche Sandor , Mosig Alexander S. , Löffler Bettina , Marquet Mike , Makarewicz Oliwia , Kline Kimberly A. , Vylkova Slavena , Swidergall Marc , Jacobsen Ilse D. 
Published: September 2024

AbstractThe fungusCandida albicansand the Gram-positive bacteriumEnterococcus faecalisshare mucosal niches in the human body. As opportunistic pathogens, both are found to expand population size during dysbiosis, and can cause severe systemic infections in susceptible individuals. Here, we show that the presence ofC. albicansresults in increased host cell damage byE. faecalis. Furthermore,E. faecalisaggravates oropharyngeal candidiasis in mice. Increased damage is mediated by enterococcal cytolysin, and involves both physical interaction and altered glucose availability. Physical interaction promotes accumulation of bacteria on host cells, facilitating contact of cytolysin with host cells. Glucose depletion by the metabolic activity of the fungus sensitized host cells to cytolysin. This work illustrates how a complex interplay between fungi and bacteria can result in detrimental consequences for the host.
Glyco-phenotyping of mutants ofLacticaseibacillus paracaseiby lectin microarray
Authors: Suzuki Emi , Serata Masaki , Sako Tomoyuki , Sato Sumie , Iino Tohru , Tateno Hiroaki , Hirabayashi Jun 
Published: September 2024

ABSTRACTWe previously identified a gene cluster ofLacticaseibacillus paracaseistrain Shirota (YIT 9029) for cell surface long-chain polysaccharides (LCPS-1) biosynthesis, which modulates YIT 9029 activity to induce cytokine production in immune cells, and showed that a lectin microarray can be useful for distinguishing the profile of bacterial cell-surface polysaccharide (PS) structures. Therefore, we isolated disruptive mutant strains of 51 genes predicted to be involved in cell wall PS biosynthesis in YIT 9029. Their binding profiles to lectins in conjunction with their binding abilities to YIT 9029-specific monoclonal antibody (MAb) were compared. The mutants defective in binding to the MAb all had defects within thecps1gene cluster. Some mutants partially bound to MAb, indicating that these genes may influence the synthesis and maturation of LCPS-1. Advanced lectin microarray analyzed the cell surface glycosylation properties of YIT 9029 and its mutants. YIT 9029 bound to a rhamnose-specific lectin CSA, and three additional lectins including an O-glycan binder (rDiscoidin II) and two mannose binders (rOrysata and rBanana). Lectin binding specificity was confirmed by a gene complementation assay for thecps1Cgene and a carbohydrate inhibition assay. When the binding profiles of individualcps1Athroughcps1Jknockout mutants were compared, typical and specific binding profiles patterns were observed, in which some similarities in the functions of each gene could be predicted. In conclusion, the combined use of lectin microarray and a YIT 9029 mutant strain library is a powerful tool for identifying unknown bacterial gene functions related to cell surface glycome.IMPORTANCEPreviously, only a limited number of methods have been available for studying mutations in bacterial cell surface polysaccharide structures in relation to gene function. In this study, we focused on the lectin-binding properties ofLacticaseibacillus paracaseiYIT 9029 (wild-type; WT) and investigated the lectin-binding capabilities of 51 cell wall biosynthesis gene disruption strains using lectin microarrays. The results indicated that lectin-binding properties in gene-disrupted strains varied significantly with the presence or absence of LCPS-1, ranging from similar to WT to distinctly different. The use of lectin microarrays in conjunction with the YIT 9029 mutant library has been shown to be a highly effective method for identifying the functions of unknown bacterial genes related to cell-surface glycomes. This innovative approach to glycophenotyping allows for the determination of cell wall glycomes associated with bacterial gene functions using lectin microarrays.
Developing and validating modular surveys for vector-borne diseases: a study protocol
Authors: Finucane Skyler , Renault Alexandria , Hayden Mary H. , Ernst Kacey , Yeo Sarah 
Published: September 2024

AbstractVector-borne diseases are an increasing threat to human health and well-being in the United States. Understanding public perception and practices taken to reduce vector abundance and vector-human contact can guide effective interventions that can mitigate health risks. Nevertheless, vector-borne disease surveys, which are widely used in the field to understand public perception and practices, are often inconsistent in terms of structure and implementation. This protocol is designed to provide guidance for public health professionals and researchers in the development of future KAP studies by ensuring uniformity in design and structure. This manuscript describes a rigorous three-phase protocol for the development of standardized vector-borne disease survey modules that can be used throughout the United States to generate data that are comparable across diverse regions. During phase one, a workshop with subject matter experts and a comprehensive literature review will be conducted to identify survey domains and generate items of interest. Survey items will also be mapped based on two theoretical frameworks, the Health Belief Model and the Risks, Attitudes, Norms, Abilities and Self-Regulation framework, to help gauge individual perceptions of risk severity and self-efficacy. During phase two, a group of expert judges will evaluate survey items based on content relevance, representativeness, and technical quality. During the final phase, cognitive interviews and surveys with target audience groups will be conducted to ensure the face validity of the modules. Participants will be drawn from a diverse range of educational and geographic locations, and computer-assisted personal interviewing will be implemented. The surveys developed through this protocol will be available to researchers aiming to gain deeper insights into the public’s knowledge, attitudes, and practices concerning vector-borne diseases, facilitating the collection of more comparable data across various regions in the United States.
Oral-motor complexity influences center of pressure patterns in adults with stroke-related communication disorders
Authors: Pressler Daria , Dugan Sarah , De Silva Amu , Riley Michael A. , Schwab-Farrell Sarah M. 
Published: September 2024

ABSTRACTPeople with stroke (PwS) often exhibit altered postural control, and concomitant stroke-related communication disorders (e.g., aphasia, dysarthria) may be an underrecognized risk factor for post-stroke falls. This heightened fall risk may be related to alterations in postural control that emerge during different speaking and listening conditions. This study evaluated how variations in the relative articulatory demands during speech production—termed “oral-motor complexity”—affect postural center of pressure (COP) patterns among PwS, both with communication disorders (PwS-CDis) and without (PwS). Three groups of adults (PwS, PwS-CDis, and a nondisabled Control group) stood on a force platform while completing four 30-second quiet stance trials, followed by twelve 30-second trials randomized across three experimental conditions of varying oral-motor complexities (“ba”, “puh tuh kuh”, “rah shah lah nah”). COP variability (SD) was significantly higher during experimental conditions compared to quiet stance, regardless of group and movement plane. Differences in nonlinear time-dependent metrics were found across oral-motor task conditions, particularly among PwS-CDis, suggesting oral-motor complexity may influence underlying postural-motor organization. Distinct temporal-dynamical patterns observed in PwS-CDis indicate a possible link between pathology, postural control, and speech motor tasks, which is relevant when evaluating postural control in individuals with stroke-related communication disorders.
ARF degradation defines a deeply conserved step in auxin response
Authors: de Roij Martijn , Hernández García Jorge , Das Shubhajit , Borst Jan Willem , Weijers Dolf 
Published: September 2024

AbstractAuxin response critically depends on the concentrations and stoichiometry of competing A- and B-class AUXIN RESPONSE FACTOR (ARF) proteins. InMarchantia polymorpha, both A- and B-ARFs are unstable, and here we identify a minimal necessary and sufficient region for ARF degradation that is critical for development, and auxin response. Through comparative analysis, we find that ARF instability likely preceded the emergence of the auxin response system.
A small signaling domain controls PPIP5K phosphatase activity in phosphate homeostasis
Authors: Raia Pierre , Lee Kitaik , Bartsch Simon M. , Rico-Resendiz Felix , Portugal-Calisto Daniela , Vadas Oscar , Panse Vikram Govind , Fiedler Dorothea , Hothorn Michael 
Published: September 2024

AbstractInositol pyrophosphates (PP-InsPs) are highly phosphorylated nutrient messengers. The final step of their biosynthesis is catalyzed by diphosphoinositol pentakisphosphate kinase (PPIP5K) enzymes, which are conserved among fungi, plants, and animals. PPIP5Ks contain an N-terminal kinase domain that generates the active messenger 1,5-InsP8and a C-terminal phosphatase domain that participates in PP-InsP catabolism. The balance between kinase and phosphatase activities controls the cellular levels and signaling capacity of 1,5-InsP8. Here, we present crystal structures of the apo and substrate-bound Vip1 phosphatase domain from S.cerevisiae(ScVip1PD). ScVip1PDis a phytase-like inositol 1-pyrophosphate phosphatase with two conserved histidine phosphatase catalytic motifs. The enzyme has a strong preference for 1,5-InsP8and is inhibited by inorganic phosphate. ScVip1PDhas an α-helical insertion domain stabilized by a structural Zn2+binding site, and a unique GAF signaling domain that exists in an open and closed state, allowing channeling of the 1,5-InsP8substrate to the active site. Mutations that alter the active site, that restrict the movement of the GAF domain or that modify the charge of the substrate channel, significantly inhibit the activity of the yeast enzymein vitro, and the function of the Arabidopsis PPIP5K VIH2in planta. Structural analyses of full-length PPIP5Ks suggest that the kinase and phosphatase are independent enzymatic modules. Taken together, our work reveals the structure, enzymatic mechanism and regulation of eukaryotic PPIP5K phosphatases.
Multiple mechanisms of action of an extremely painful venom
Authors: Borjon Lydia J. , de Assis Ferreira Luana C. , Trinidad Jonathan C. , Šašić Sunčica , Hohmann Andrea G. , Tracey W. Daniel 
Published: September 2024

SummaryEvolutionary arms races between predator and prey can lead to extremely specific and effective defense mechanisms. Such defenses include venoms that deter predators by targeting nociceptive (pain-sensing) pathways. Through co-evolution, venom toxins can become extremely efficient modulators of their molecular targets. The venom of velvet ants (Hymenoptera: Mutillidae) is notoriously painful. The intensity of a velvet ant sting has been described as “Explosive and long lasting, you sound insane as you scream. Hot oil from the deep fryer spilling over your entire hand.” [1] The effectiveness of the velvet ant sting as a deterrent against potential predators has been shown across vertebrate orders, including mammals, amphibians, reptiles, and birds [2–4]. The venom’s low toxicity suggests it has a targeted effect on nociceptive sensory mechanisms [5]. This leads to the hypothesis that velvet ant venom targets a conserved nociception mechanism, which we sought to uncover usingDrosophila melanogasteras a model system.Drosophilalarvae have peripheral sensory neurons that sense potentially damaging (noxious) stimuli such as high temperature, harsh mechanical touch, and noxious chemicals [6–9]. These polymodal nociceptors are called class IV multidendritic dendritic arborizing (cIV da) neurons, and they share many features with vertebrate nociceptors, including conserved sensory receptor channels [10,11]. We found that velvet ant venom strongly activatedDrosophilanociceptors through heteromeric Pickpocket/Balboa (Ppk/Bba) ion channels. Furthermore, we found a single venom peptide (Do6a) that activated larval nociceptors at nanomolar concentrations through Ppk/Bba.DrosophilaPpk/Bba is homologous to mammalian Acid Sensing Ion Channels (ASICs) [12]. However, the Do6a peptide did not produce behavioral signs of nociception in mice, which was instead triggered by other non-specific, less potent, peptides within the venom. This suggests that Do6a is an insect-specific venom component that potently activates insect nociceptors. Consistent with this, we showed that the velvet ant’s defensive sting produced aversive behavior in a predatory praying mantis. Together, our results indicate that velvet ant venom evolved to target nociceptive systems of both vertebrates and invertebrates, but through different molecular mechanisms.