bluuebunny/crossref_metadata_2025_split huggingface dataset:
Epigenetic age acceleration and mortality risk prediction in U.S. adults
Authors: Mendy Angelico , Mersha Tesfaye B. 
Published: August 2024

AbstractBackgroundEpigenetic clocks have emerged as novel measures of biological age and potential predictors of mortality. We aimed to test whether epigenetic age acceleration (EAA) estimated using different epigenetic clocks predict long-term overall, cardiovascular or cancer mortality.MethodsWe analyzed data from 2,105 participants to the 1999-2002 National Health and Nutrition Examination Survey aged ≥50 years old who were followed for mortality through 2019. EAAs was calculated from the residuals of Horvath, Hannum, SkinBlood, Pheno, Zhang, Lin, Weidner, Vidal-Bralo and Grim epigenetic clocks regressed on chronological age. Using cox proportional hazards regression, we estimated the hazard ratio (HR) and 95% confidence interval (CI) for the association of EAA (per 5-year) and the DunedinPoAm pace of aging (per 10% increase) with overall, cardiovascular and cancer mortality, adjusting for covariates and white blood cell composition.ResultsDuring a median follow-up of 17.5 years, 998 deaths occurred, including 272 from cardiovascular disease and 209 from cancer. Overall mortality was most significantly predicted by Grim EAA (P< 0.0001; HR: 1.50, 95% CI: 1.32-1.71) followed by Hannum (P= 0.001; HR: 1.16, 95% CI: 1.07-1.27), Pheno (P= 0.001; HR: 1.13, 95% CI: 1.05-1.21), Horvath (P= 0.007; HR: 1.13, 95% CI: 1.04-1.22) and Vidal-Bralo (P= 0.008; HR: 1.13, 95% CI: 1.03-1.23) EAAs. Grim EAA predicted cardiovascular mortality (P< 0.0001; HR: 1.55, 95% CI: 1.29-1.86), whereas Hannum (P= 0.006; HR: 1.24, 95% CI: 1.07-1.44), Horvath (P= 0.02; HR: 1.18, 95% CI: 1.02-1.35) and Grim (P= 0.049; HR: 1.37, 95% CI: 1.00-1.87) EAAs predicted cancer mortality. DunedinPoAm pace of aging was associated with overall (P= 0.003; HR: 1.23, 95% CI: 1.08-1.38) and cardiovascular (P= 0.04; HR: 1.25, 95% CI: 1.01-1.55) mortality.ConclusionsIn a U.S. representative sample, Horvath, Hannum, Pheno, Vidal-Bralo and Grim EAA all predicted overall mortality but only Grim EAA predicted cardiovascular mortality and Horvath, Hannum or Grim EAA predicted cancer mortality. Pace of aging predicted overall and cardiovascular mortality.
Ventral-to-dorsal electrocyte development in electric organs of electric eel (Electrophorus)
Authors: Senarat Sinlapachai , Matsumoto Ayako , Sakaki Shintaro , Tsuzuki Daichi , Uchida Kazuko , Kuwahara Makoto , Hondo Eiichi , Iida Atsuo 
Published: August 2024

AbstractElectric eels (Electrophorus) are renowned for their ability to generate electric discharge, which is used for prey capture and defense. Their electric organs (EOs) are located along the lateral– ventral region of the tail and contain electrocytes, which are multinucleated syncytium cells. Two major hypotheses for the electrocyte origin are proposed: (1) muscle fibers or their precursors, and (2) mesodermal cells not via muscle lineage. In this study, we demonstrate the likely molecular mechanisms and processes involved in this differentiation, supporting the second hypothesis. We report the regional differences in cell morphology within the main EO (mEO) ofElectrophorus. The cell morphology and distribution from the ventral terminal to the dorsal region of the mEO suggest the segregation of progenitors from the ventral cluster and their gradual transformation into mature multinucleated electrocytes via the layering and proliferation stages along the dorsal axis. Myosin-positive muscle cells were not included in the mEO differentiation process. Immunohistochemistry revealed strong expression of sodium-potassium adenosine triphosphatase (Na+/K+-ATPase), a key component in generating electric discharge in the mEO, across most mEO regions, except in the ventral cluster cells. Based on these observations, we propose that electrocyte progenitors develop from ventral cluster cells in the mEO and differentiate into mature multinucleated cells as they migrate dorsally. This is the first report to approach the developmental process ofElectrophoruselectrocytes from cell morphology and genetic profiles. Our findings represent a breakthrough in understanding the differentiation of electrocytes during the growth stages ofElectrophorus.
Platelets as key cells in endometriosis patients: insights from small extracellular vesicles in peritoneal fluid and endometriotic lesions analysis
Authors: Bortot Barbara , Di Florio Roberta , Merighi Simona , Peacock Ben , Lees Rebecca , Valle Francesco , Brucale Marco , Mangogna Alessandro , Di Lorenzo Giovanni , Romano Federico , Zito Gabriella , Zanconati Fabrizio , Ricci Giuseppe , Cancila Valeria , Belmonte Beatrice , Biffi Stefania 
Published: August 2024

AbstractEndometriosis is a chronic inflammatory condition characterized by the presence of endometrium-like tissue outside the uterus, primarily affecting pelvic organs and tissues. In this study, we explored platelet activation in endometriosis. We utilized the STRING database to analyze the functional interactions among proteins previously identified in small extracellular vesicles (EVs) isolated from the peritoneal fluid of endometriosis patients and controls. The bioinformatic analysis indicated enriched signaling pathways related to platelet activation, hemostasis, and neutrophil degranulation. Double immunohistochemistry analysis for CD61 and MPO revealed a significant presence of neutrophils and platelets infiltrating endometriotic lesions, suggesting potential cell-cell interactions. Subsequently, we isolated small EVs from the peritoneal fluid of women diagnosed with endometriosis and from women without endometriosis who underwent surgery for non-inflammatory benign diseases. We performed single-particle phenotyping analysis based on platelet biomarkers GPIIb/IIIa and PF4 using nanoflow cytometry, as well as single-particle morphological and nanomechanical characterization through atomic force microscopy. The study demonstrated that patients with endometriosis had a notably higher proportion of particles testing positive for platelet biomarkers compared to the total number of EVs. This finding implies a potential role for platelets in the pathogenesis of endometriosis. Further research is necessary to delve into the mechanisms underlying this phenomenon and its implications for disease progression.
WHIX is a T6SS secretion domain found in polymorphic double-edged sword effectors
Authors: Fridman Chaya Mushka , Keppel Kinga , Rudenko Vladislav , Altuna-Alvarez Jon , Albesa-Jové David , Bosis Eran , Salomon Dor 
Published: August 2024

AbstractGram-negative bacteria employ the type VI secretion system (T6SS) to deliver toxic effectors into neighboring cells and outcompete rivals. Although many effectors have been identified, their secretion mechanism often remains unknown. Here, we describe WHIX, a domain that is sufficient to mediate the secretion of effectors via the T6SS. Remarkably, we find WHIX in T6SS effectors that contain a single toxic domain, as well as in effectors that contain two distinct toxic domains fused to either side of WHIX. We demonstrate that the latter, which we name double-edged sword effectors, require two cognate immunity proteins to antagonize their toxicity. Furthermore, we show that WHIX can be used as a chassis for T6SS-mediated secretion of multiple domains. Our findings reveal a new class of polymorphic T6SS cargo effectors with a unique secretion domain that can deploy two toxic domains in one shot, possibly reducing recipients’ ability to defend themselves.
Distinct checkpoint and homolog biorientation pathways regulate meiosis I inDrosophilaoocytes
Authors: Shapiro Joanatta G. , Changela Neha , Jang Janet K. , Joshi Jay N. , McKim Kim S. 
Published: August 2024

AbstractMitosis and meiosis have two mechanisms for regulating the accuracy of chromosome segregation: error correction and the spindle assembly checkpoint (SAC). We have investigated the function of several checkpoint proteins in meiosis I ofDrosophilaoocytes. Evidence of a SAC response by several of these proteins is found upon depolymerization of microtubules by colchicine. However, unattached kinetochores or errors in biorientation of homologous chromosomes does not induce a SAC response. Furthermore, the metaphase I arrest does not depend on SAC genes, suggesting the APC is inhibited even if the SAC is silenced. Two SAC proteins, ROD of the ROD-ZW10-Zwilch (RZZ) complex and MPS1, are also required for the biorientation of homologous chromosomes during meiosis I, suggesting an error correction function. Both proteins aid in preventing or correcting erroneous attachments and depend on SPC105R for localization to the kinetochore. We have defined a region of SPC105R, amino acids 123-473, that is required for ROD localization and biorientation of homologous chromosomes at meiosis I. Surprisingly, ROD removal, or “streaming”, is independent of the dynein adaptor Spindly and is not linked to the stabilization of end-on attachments. Instead, meiotic RZZ streaming appears to depend on cell cycle stage and may be regulated independently of kinetochore attachment or biorientation status. We also show that dynein adaptor Spindly is also required for biorientation at meiosis I, and surprisingly, the direction of RZZ streaming.Author SummaryThe Spindle Assembly Checkpoint (SAC) is known to delay cell cycle progression until chromosomes are properly attached to microtubules. Meiotic cells often have modified cell cycle phases, and natural arrest points such as metaphase I inDrosophila. We show that inDrosophilaoocytes, the SAC is sensitive to loss of microtubules, but not sensitive to a variety of kinetochore attachment errors. Thus, the function of the SAC appears to be limited to monitoring oocyte spindle assembly, and not required for accurate chromosome segregation. However, two of the SAC genes,rodandMps1, are required for the biorientation of homologous chromosomes during meiosis I, suggesting an error correction function. Rod is part of the RZZ complex and is notable for its property of streaming off the kinetochores. However, our results show that streaming off the kinetochore may not contribute to RZZ regulation of microtubule attachments, and only be associated with SAC function. Instead, the establishment of stable end-on attachments may occur while RZZ is still present at kinetochore. We suggest that RZZ interacts with multiple motors to promote bidirectional movement of kinetochores along microtubules, which allows chromosomes to find and attach to the correct pole.
Learning reshapes the hippocampal representation hierarchy
Authors: Chiossi Heloisa S. C. , Nardin Michele , Tkačik Gašper , Csicsvari Jozsef L. 
Published: August 2024

AbstractA key feature of biological and artificial neural networks is the progressive refinement of their neural representations with experience. In neuroscience, this fact has inspired several recent studies in sensory and motor systems. However, less is known about how higher associational cortical areas, such as the hippocampus, modify representations throughout the learning of complex tasks. Here we focus on associative learning, a process that requires forming a connection between the representations of different variables for appropriate behavioral response. We trained rats in a spatial-context associative task and monitored hippocampal neural activity throughout the entire learning period, over several days. This allowed us to assess changes in the representations of context, movement direction and position, as well as their relationship to behavior. We identified a hierarchical representational structure in the encoding of these three task variables that was preserved throughout learning. Nevertheless, we also observed changes at the lower levels of the hierarchy where context was encoded. These changes were local in neural activity space and restricted to physical positions where context identification was necessary for correct decision making, supporting better context decoding and contextual code compression. Our results demonstrate that the hippocampal code not only accommodates hierarchical relationships between different variables but also enables efficient learning through minimal changes in neural activity space. Beyond the hippocampus, our work reveals a representation learning mechanism that might be implemented in other biological and artificial networks performing similar tasks.
Magnetic Activation of Spherical Nucleic Acids for the Remote Control of Synthetic Cells
Authors: Parkes Ellen , Al Samad Assala , Mazzotti Giacomo , Newell Charlie , Ng Brian , Radford Amy , Booth Michael J. 
Published: August 2024

AbstractThe advancement of synthetic cells as drug delivery devices hinges on the development of targeting strategies, in particular the controlled synthesis of biomolecules in-situ using a deeply penetrative stimulus. To address this, we have designed spherical nucleic acids comprising DNA promoter sequences decorating magnetic nanoparticle cores. By harnessing the heat dissipated from magnetic hyperthermia (a clinically-approved anticancer therapy) we tightly controlled cell-free protein synthesis. We then deployed a tissue phantom that is impenetrable by current activation methods to demonstrate the potential of this technology for the remote control of synthetic cells using deeply tissue-penetrating magnetic fields. This paves the way for targeting and controlling the in-situ synthesis of biomolecules deep within the body.Abstract Figure
Fc-independent SARS-CoV-2 infection-enhancing antibodies decouple N-terminal and receptor-binding domains by cross-linking neighboring spikes
Authors: van Eerden Floris J. , Li Songling , Lusiany Tina , Ismanto Hendra S. , Terada Tohru , Gerle Christoph , Akamatsu Kanako , Hirose Mika , Sugihara Fuminori , Chen David Virya , Kishikawa Jun-ichi , Kato Takayuki , Liu Yafei , Okada Masato , Arase Hisashi , Standley Daron M. 
Published: August 2024

AbstractAntibody dependent enhancement (ADE) is a serious concern in vaccine development. The canonical ADE pathways are dependent on the fragment crystallizable (Fc) region of the antibody. In SARS-CoV-2 several antibodies have been discovered that inflict ADE in vitro. These antibodies target the N-terminal domain (NTD) of the SARS-CoV-2 spike protein. We previously proposed that these NTD-targeting infection-enhancing antibodies (NIEAs) cross-link neighboring spike proteins via their NTDs, and that this results in a decoupling between the NTD and receptor binding domain (RBD), facilitating the “RBD down” to “up” transition. In this study we present a combination of molecular dynamics simulations and cryogenic electron microscopy data that, together, demonstrate that NIEAs are indeed able to cross-link neighboring SARS-CoV-2 spike proteins, and that this cross-linking results in a decoupling of the NTD and RBD domains. These findings provide support for an Fc region independent ADE pathway that is not only relevant for SARS-CoV-2 but also for other viruses of which the spike proteins undergo a conformational change upon host cell entry.
Cortical Excitability is Affected by Light Exposure – Distinct Effects in Adolescents and Young Adults
Authors: Sharifpour Roya , Balda Aizpurua Fermin , Paparella Ilenia , Read John , Leysens Zoé , Letot Sara , Campbell Islay , Beckers Elise , Collette Fabienne , Phillips Christophe , Zubkov Mikhail , Vandewalle Gilles 
Published: August 2024

ABSTRACTLight, particularly blue-wavelength light, exerts a broad range of non-image forming (NIF) effects including the stimulation of cognition and alertness and the regulation of mood, sleep and circadian rhythms. However, its underlying brain mechanisms are not fully elucidated. Likewise, whether adolescents show a different NIF sensitivity to light compared to adults is not established. Here, we investigated whether cortical excitability, a basic aspect of brain function that depends on sleep-wake regulation, is affected by blue light and whether the effect is similar in young adults and adolescents. To do so, we used transcranial magnetic stimulation coupled to high-density electroencephalography (TMS–EEG) in healthy young adults (N=13, 24.2y ±3.4) and in adolescents (N=15, 16.9y ±1.1). Our results showed that, in young adults, blue light affected cortical excitability following an apparent inverted-U relationship, while adolescents’ cortical excitability was not significantly impacted by blue light. In addition, although light did not affect performance on a visuomotor vigilance task completed during the TMS-EEG recordings, cortical excitability was positively correlated to task performance in both age groups. This study provides valuable insights into the complex interplay between light, cortical excitability, and behavior. Our findings highlight the role of age in NIF effects of light, suggesting that brain responses to light differ during developmental periods.
A diagnostic gap to fill: Development of molecular tools to distinguish the plant-parasitic nematode speciesHeterodera carotaeandHeterodera cruciferae
Authors: Fouville Didier , Biget Marine , Montarry Josselin , Fournet Sylvain , Grenier Eric 
Published: August 2024

ABSTRACTThe carrot-parasitic nematode,Heterodera carotae, is an important pest causing qualitative and quantitative production losses across several countries worldwide and must be carefully identified and monitored. Indeed, in culture crops,Heterodera carotaeandHeterodera cruciferae, two genetically closely related species from the Goettingiana group, can be found in mixture and are virtually morphologically non-recognizable. However, onlyH. carotaeis able to develop on carrot. To monitor carrot production and set up suitableH. carotaecontrol plans, simple and reliable diagnostic methods to detect and identify these two species are needed. In this study, we developed and successfully tested two real-time PCR protocols (SYBR Green singleplex and TaqMan multiplex real-time PCRs) against both sister species:H. carotaeandH. cruciferae. Using two specific sets of primers targeting the two species, which were designed from sequences containing microsatellite loci, we managed, whatever the methods, to distinguish the two species. Moreover, we showed a higher specificity using the TaqMan assays (test on cysts) but a better sensitivity (tests on J2 juvenile larvae) with the SYBR Green assays. In this study, we thus proposed two useful and reliable diagnostic tools to enable farmers and scientists to rapidly detect two plant-parasitic nematodes and supervise agricultural management.
Cellular and circuit features distinguish dentate gyrus semilunar granule cells and granule cells activated during contextual memory formation
Authors: Dovek Laura , Marrero Krista , Zagha Edward , Santhakumar Vijayalakshmi 
Published: August 2024

AbstractThe dentate gyrus is critical for spatial memory formation and shows task related activation of cellular ensembles considered as memory engrams. Semilunar granule cells (SGCs), a sparse dentate projection neuron subtype distinct from granule cells (GCs), were recently reported to be enriched among behaviorally activated neurons. However, the mechanisms governing SGC recruitment during memory formation and their role in engram refinement remains unresolved. By examining neurons labeled during contextual memory formation in TRAP2 mice, we empirically tested competing hypotheses for GC and SGC recruitment into memory ensembles. In support of the proposal that more excitable neurons are preferentially recruited into memory ensembles, SGCs showed greater sustained firing than GCs. Additionally, SGCs labeled during memory formation showed less adapting firing than unlabeled SGCs. Our recordings did not reveal glutamatergic connections between behaviorally labeled SGCs and GCs, providing evidence against SGCs driving local circuit feedforward excitation in ensemble recruitment. Contrary to a leading hypothesis, there was little evidence for individual SGCs or labeled neuronal ensembles supporting lateral inhibition of unlabeled neurons. Instead, pairs of GCs and SGCs within labeled neuronal cohorts received more temporally correlated spontaneous excitatory synaptic inputs than labeled-unlabeled neuronal pairs, validating a role for correlated afferent inputs in neuronal ensemble selection. These findings challenge the proposal that SGCs drive dentate GC ensemble refinement, while supporting a role for intrinsic active properties and correlated inputs in preferential SGC recruitment to contextual memory engrams.Impact StatementEvaluation of semilunar granule cell involvement in dentate gyrus contextual memory processing supports recruitment based on intrinsic and input characteristics while revealing limited contribution to ensemble refinement.
Grin1Y647S/+Mice: A Preclinical Model ofGRIN1-Related Neurodevelopmental Disorder
Authors: Sullivan Megan T. , Tidball Patrick , Yan Yuanye , Intson Katheron , Chen Wenjuan , Xu Yuchen , Venkatesan Sridevi , Horsfall Wendy , Georgiou John , Finnie Peter S.B. , Lambe Evelyn K. , Traynelis Stephen F. , Salahpour Ali , Yuan Hongjie , Collingridge Graham L. , Ramsey Amy J. 
Published: August 2024

ABSTRACTObjectiveGRIN1-related neurodevelopmental disorder (GRIN1-NDD) is characterized by clinically significant variation in theGRIN1gene, which encodes the obligatory GluN1 subunit of N-methyl-D-aspartate receptors (NMDARs). The identified p.Tyr647Ser (Y647S) variant — carried by a 33-year-old female with seizures and intellectual disability — is located in the M3 helix in the GluN1 transmembrane domain. This study builds upon initialin vitroinvestigations of the functional impacts of theGRIN1Y647S variant and examines itsin vivoconsequences in a mouse model.MethodsTo investigatein vitrofunctional impacts of NMDARs containing GluN1-Y647S variant subunits, GluN1-Y647S was co-expressed with wildtype GluN2A or GluN2B subunits inXenopus laevisoocytes and HEK cells.Grin1Y647S/+mice were created by CRISPR-Cas9 endonuclease-mediated transgenesis and the molecular, electrophysiological, and behavioural consequences of the variant were examined.ResultsIn vitro, NMDARs containing GluN1-Y647S show altered sensitivity to endogenous agonists and negative allosteric modulators, and reduced cell surface trafficking.Grin1Y647S/+mice displayed a reduction in whole brain GluN1 levels and deficiency in NMDAR-mediated synaptic transmission in the hippocampus. Behaviourally,Grin1Y647S/+mice exhibited spontaneous seizures, altered vocalizations, muscle strength, sociability, and problem-solving.InterpretationThe Y647S variant confers a complexin vivophenotype, which reflects largely diminished properties of NMDAR function. As a result,Grin1Y647S/+mice display atypical behaviour in domains relevant to the clinical characteristics ofGRIN1-NDD and the individual carrying the variant. Ultimately, the characterization ofGrin1Y647S/+mice accomplished in the present work expands our understanding of the mechanisms underlyingGRIN1-NDD and provides a foundation for the development of novel therapeutics.