bluuebunny/crossref_metadata_2025_split huggingface dataset:
The central role of pyruvate metabolism on the epigenetic and molecular maturation of bovine cumulus-oocytes complexes
Authors: da Silva João Vitor Alcantara , Ispada Jessica , da Fonseca Junior Aldcejam Martins , de Lima Camila Bruna , dos Santos Erika Cristina , Chiaratti Marcos Roberto , Nociti Ricardo Perecin , Milazzotto Marcella Pecora 
Published: November 2022

AbstractPyruvate, the end-product of glycolysis in aerobic conditions, is produced by cumulus cells, and is converted in Acetyl-CoA into the mitochondria of both cumulus cells (CCs) and oocytes as a master fuel input for the tricarboxylic acid cycle (TCA). The citrate generated in the TCA cycle can be directed to the cytoplasm and converted back to acetyl-CoA, being driven to lipid synthesis or, still, being used as the substrate for histones acetylation. This work aimed to verify the impact of pyruvate metabolism on the dynamic of lysine 9 histone 3 acetylation (H3K9ac) and RNA transcription in bovine cumulus-oocyte complexes during in vitro maturation (IVM). Bovine oocytes were IVM for 24h in three experimental groups: Control [IVM medium], sodium dichloroacetate [DCA, a stimulator of pyruvate oxidation in acetyl-CoA] or sodium iodoacetate [IA, a glycolysis inhibitor]. Our results show that both treatments change the metabolic profile of oocytes and CCs, stimulating the use of lipids for energy metabolism in the gamete. This leads to changes in the dynamics of H3K9ac during the IVM in both oocytes and CCs with impact on the synthesis of new transcripts in CCs. A total of 148 and 356 differentially expressed genes were identified in DCA and IA oocytes groups, respectively, when compared to the control group. In conclusion, disorders in pyruvate metabolism during maturation stimulate the beta-oxidation pathway, altering the mitochondrial metabolism, with consequences for the mRNA content of bovine oocytes.
Statistically unbiased prediction enables accurate denoising of voltage imaging data
Authors: Eom Minho , Han Seungjae , Kim Gyuri , Cho Eun-Seo , Sim Jueun , Park Pojeong , Lee Kang-Han , Kim Seonghoon , Rózsa Márton , Svoboda Karel , Choi Myunghwan , Kim Cheol-Hee , Cohen Adam E. , Chang Jae-Byum , Yoon Young-Gyu 
Published: November 2022

ABSTRACTHere we report SUPPORT (Statistically Unbiased Prediction utilizing sPatiOtempoRal information in imaging daTa), a self-supervised learning method for removing Poisson-Gaussian noise in voltage imaging data. SUPPORT is based on the insight that a pixel value in voltage imaging data is highly dependent on its spatially neighboring pixels in the same time frame, even when its temporally adjacent frames do not provide useful information for statistical prediction. Such spatiotemporal dependency is captured and utilized to accurately denoise voltage imaging data in which the existence of the action potential in a time frame cannot be inferred by the information in other frames. Through simulation and experiments, we show that SUPPORT enables precise denoising of voltage imaging data while preserving the underlying dynamics in the scene.
Vibrio parahaemolyticusT6SS2 effector repertoires
Authors: Tchelet Daniel , Keppel Kinga , Bosis Eran , Salomon Dor 
Published: November 2022

AbstractAll strains of the marine bacteriumVibrio parahaemolyticusharbor a type VI secretion system (T6SS) named T6SS2, suggesting that this system plays an important role in the life cycle of this emerging pathogen. Although T6SS2 was recently shown to play a role in interbacterial competition, its effector repertoire remains unknown. Here, we employed proteomics to investigate the T6SS2 secretome of twoV. parahaemolyticusstrains, and we identified several antibacterial effectors encoded outside of the main T6SS2 gene cluster. We revealed two T6SS2-secreted proteins that are conserved in this species, indicating that they constitute the core secretome of T6SS2; other identified effectors are found only in subsets of strains, suggesting that they comprise an accessory effector arsenal of T6SS2. Remarkably, a conserved Rhs repeat-containing effector serves as a quality control checkpoint and is required for T6SS2 activity. Our results reveal the effector repertoire of a conserved T6SS, some of which have no known activity and have not been previously associated with T6SSs.
Familial Alzheimer’s disease mutation undermines axonal transport by enhancing dynactin recruitment to the APP motor assemblies
Authors: Feole Monica , Stokin Gorazd B. 
Published: November 2022

ABSTRACTExperiments in flies, mice and humans suggest a significant role of impaired axonal transport in the pathogenesis of Alzheimer’s disease (AD), however, the underlying mechanisms remain unknown1,2. We report that the Swedish familial AD (FAD) mutation perturbs fast anterograde axonal transport of the amyloid precursor protein (APP) by altering directionality of its movement. APP thus spends more time in retrograde movement and accumulates in the soma. We found that the Swedish mutation enhances recruitment of dynactin 1 to the APP transport assemblies. Given that dynactin 1 activates the retrograde motor dynein3, this hampers physiological anterograde axonal transport of APP. We last show that the Swedish mutation perturbs also the axonal transport of early endosomes, which rely on the same molecular motors as APP. Our findings reveal extensive impairment of the axonal transport pathways by a FAD mutation, which reflects dysregulation of the cargo motor assemblies.
Whole genome error-corrected sequencing for sensitive circulating tumor DNA cancer monitoring
Authors: Cheng Alexandre Pellan , Widman Adam J. , Arora Anushri , Rusinek Itai , Hooper William F. , Murray Rebecca , Halmos Daniel , Langanay Theophile , Inghirami Giorgio , Germer Soren , Marton Melissa , Manaa Dina , Helland Adrienne , Furatero Rob , McClintock Jaime , Winterkorn Lara , Steinsnyder Zoe , Wang Yohyoh , Rajagopalan Srinivas , Alimohamed Asrar I. , Malbari Murtaza S. , Saxena Ashish , Callahan Margaret K. , Frederick Dennie T. , Spain Lavinia , Jaimovich Ariel , Lipson Doron , Turajlic Samra , Zody Michael C. , Altorki Nasser K. , Wolchok Jedd D. , Postow Michael A. , Robine Nicolas , Boland Genevieve , Landau Dan A. 
Published: November 2022

ABSTRACTCirculating cell-free DNA (ccfDNA) sequencing for low-burden cancer monitoring is limited by sparsity of circulating tumor DNA (ctDNA), the abundance of genomic material within a plasma sample, and pre-analytical error rates due to library preparation, and sequencing errors. Sequencing costs have historically favored the development of deep targeted sequencing approaches for overcoming sparsity in ctDNA detection, but these techniques are limited by the abundance of ccfDNA in samples, which imposes a ceiling on the maximal depth of coverage in targeted panels. Whole genome sequencing (WGS) is an orthogonal approach to ctDNA detection that can overcome the low abundance of ccfDNA by supplanting sequencing depth with breadth, integrating signal across the entire tumor mutation landscape. However, the higher cost of WGS limits the practical depth of coverage and hinders broad adoption. Lower sequencing costs may thus allow for enhanced ctDNA cancer monitoring via WGS. We therefore applied emerging lower-cost WGS (Ultima Genomics, 1USD/Gb) to plasma samples at ∼120x coverage. Copy number and single nucleotide variation profiles were comparable between matched Ultima and Illumina datasets, and the deeper WGS coverage enabled ctDNA detection at the parts per million range. We further harnessed these lower sequencing costs to implement duplex error-corrected sequencing at the scale of the entire genome, demonstrating a ∼1,500x decrease in errors in the plasma of patient-derived xenograft mouse models, and error rates of ∼10−7in patient plasma samples. We leveraged this highly de-noised plasma WGS to undertake cancer monitoring in the more challenging context of resectable melanoma without matched tumor sequencing. In this context, duplex-corrected WGS allowed us to harness known mutational signature patterns for disease monitoring without matched tumors, paving the way for de novo cancer monitoring.
Adaptation toex vivoculture drives human haematopoietic stem cell loss of repopulation capacity in a cell cycle independent manner
Authors: Johnson Carys S. , Sham Kendig , Belluschi Serena , Wang Xiaonan , Lau Winnie , Kaufmann Kerstin B. , Krivdova Gabriela , Calderbank Emily F. , Mende Nicole , McLeod Jessica , Mantica Giovanna , Williams Matthew J. , Grey-Wilson Charlotte , Drakopoulos Michael , Sinha Shubhankar , Diamanti Evangelia , Basford Christina , Green Anthony R. , Wilson Nicola K. , Howe Steven J. , Dick John E. , Göttgens Bertie , Francis Natalie , Laurenti Elisa 
Published: November 2022

AbstractLoss of long-term haematopoietic stem cell function (LT-HSC) hampers the success ofex vivoHSC gene therapy and expansion procedures, but the kinetics and the mechanisms by which this occurs remain incompletely characterized. Here through time-resolved scRNA-Seq, matchedin vivofunctional analysis and the use of a reversiblein vitrosystem of early G1arrest, we define the sequence of transcriptional and functional events occurring during the firstex vivodivision of human LT-HSCs. We demonstrate that contrary to current assumptions, loss of long-term repopulation capacity during culture is independent of cell cycle progression. Instead it is a rapid event that follows an early period of adaptation to culture, characterised by transient gene expression dynamics and constrained global variability in gene expression. Cell cycle progression however contributes to the establishment of differentiation programmes in culture. Our data have important implications for improving HSC gene therapy and expansion protocols.
ACC neural ensemble dynamics are structured by strategy prevalence
Authors: Proskurin Mikhail , Manakov Maxim , Karpova Alla Y. 
Published: November 2022

AbstractMedial frontal cortical areas are thought to play a critical role in the brain’s ability to flexibly deploy strategies that are effective in complex settings. Still, the specific circuit computations that underpin this foundational aspect of intelligence remain unclear. Here, by examining neural ensemble activity in rats that sample different strategies in a self-guided search for latent task structure, we demonstrate a robust tracking of individual strategy prevalence in the anterior cingulate cortex (ACC), especially in an area homologous to primate area 32D. Prevalence encoding in the ACC is wide-scale, independent of reward delivery, and persists through a substantial ensemble reorganization that tags ACC representations with contextual content. Our findings argue that ACC ensemble dynamics is structured by a summary statistic of recent behavioral choices, raising the possibility that ACC plays a role in estimating – through statistical learning – which actions promote the occurrence of events in the environment.
Spatially-embedded recurrent neural networks reveal widespread links between structural and functional neuroscience findings
Authors: Achterberg Jascha , Akarca Danyal , Strouse DJ , Duncan John , Astle Duncan E 
Published: November 2022

ABSTRACTBrain networks exist within the confines of resource limitations. As a result, a brain network must overcome metabolic costs of growing and sustaining the network within its physical space, while simultaneously implementing its required information processing. To observe the effect of these processes, we introduce the spatially-embedded recurrent neural network (seRNN). seRNNs learn basic task-related inferences while existing within a 3D Euclidean space, where the communication of constituent neurons is constrained by a sparse connectome. We find that seRNNs, similar to primate cerebral cortices, naturally converge on solving inferences using modular small-world networks, in which functionally similar units spatially configure themselves to utilize an energetically-efficient mixed-selective code. As all these features emerge in unison, seRNNs reveal how many common structural and functional brain motifs are strongly intertwined and can be attributed to basic biological optimization processes. seRNNs can serve as model systems to bridge between structural and functional research communities to move neuroscientific understanding forward.
Evolutionary insights from profiling LINE-1 activity at allelic resolution in a single human genome
Authors: Yang Lei , Metzger Genevieve A. , Del Valle Ricky Padilla , Rubalcaba Diego Delgadillo , McLaughlin Richard N. 
Published: November 2022

AbstractTransposable elements including LINE-1 (Long INterspersed Element-1) impact genome variation, function, regulation, and disease. LINE-1s seem to have expanded as distinct consecutive lineages, but the drivers of lineage emergence and disappearance are unknown. Reference genomes provide a snapshot of LINE-1 evolution; however, the ongoing retrotransposition of LINE-1s in humans is not evident in these mosaic assemblies. Utilizing long-read-based haploid assemblies, we identified the sequence and location of all the youngest LINE-1s in these genomes at allelic resolution. We cloned and assayed thein vitroretrotransposition activity of the subset of LINE-1s with intact open reading frames and found 34 were measurably active. Yet, among individuals, these same LINE-1s varied in their presence, allelic sequences, and activity. Using a measure ofin vivoretrotransposition of closely related groups of LINE-1, we found that recently retrotransposed LINE-1s tend to be activein vitroand polymorphic in the population. However, for a considerable number of LINE-1s, their measuredin vitroactivity and inferredin vivofitness were uncorrelated, regardless of their frequency in the population. Some of these unexpected patterns come from rare allelic forms of old LINE-1s that retain activity, suggesting older LINE-1 lineages can persist much longer than expected. Finally, some LINE-1s showed mutations that were potentially adaptive, increasing their replication in the genome. These key mutations specific to LINE-1s with bothin vitroactivity andin vivofitness represent promising candidates for the future mechanistic investigation of the drivers of LINE-1 evolution which may contribute to disease susceptibility.
Branched germline cysts and female-specific cyst fragmentation facilitate oocyte determination in mice
Authors: Ikami Kanako , Shoffner Suzanne , Weh Malgorzata Gosia Tyczynska , Schnell Santiago , Ma Jingqun , Yoshida Shosei , Miranda Edgar Diaz , Ko Sooah , Lei Lei 
Published: November 2022

AbstractDuring mouse gametogenesis, germ cells derived from the same progenitor are connected via intercellular bridges forming germline cysts, within which asymmetrical or symmetrical cell fate occurs in female and male germ cells respectively. Here, we have identified branched cyst structures in mice, and investigated their formation and function in oocyte determination. In fetal female cysts, 16.8% of the germ cells are connected by three or four bridges, namely branching germ cells. These germ cells are preferentially protected from cell death and cyst fragmentation, and to accumulate organelles and cytoplasm from sister germ cells to become primary oocytes. Changes in cyst structure and single-cell mRNA profiles suggested that cytoplasmic transport in germline cysts is conducted in a directional manner, in which cellular content is first transported locally between peripheral germ cells and further enriched in branching germ cells, a process causing selective germ cell loss in cysts. Cyst fragmentation occurs extensively in female cysts, but not in male cysts. Male cysts in fetal and adult testes have branched cyst structures, without differential cell fates between germ cells. During cyst formation, E-cadherin junctions between germ cells position intercellular bridges to form branched cysts. Disrupted junction formation in E-cadherin-depleted cysts led to an altered ratio in branched cysts. Germ cell-specific E-cadherin knockout resulted in reductions in primary oocyte number and oocyte size. These findings shed light on the mechanism of how the size of the ovarian reserve, the number of primary oocytes available to sustain adult ovarian function, is determined during ovary formation.
Measuring the non-selective effects of motor inhibition using isometric force recordings
Authors: Rangel Benjamin O. , Novembre Giacomo , Wessel Jan R. 
Published: November 2022

AbstractInhibition is a key cognitive control mechanism. When rapidly exerted, inhibitory control has broad, non-selective motor effects, typically demonstrated using cortico-spinal excitability measurements (CSE) elicited by transcranial magnetic stimulation (TMS). For example, during rapid action-stopping, CSE is suppressed at both stopped and task-unrelated muscles. While such TMS-based CSE measurements provide crucial insights into the fronto-basal ganglia circuitry underlying non-selective inhibition, they have several downsides. TMS is contraindicated in many populations (e.g., epilepsy, deep-brain stimulation patients), has limited temporal resolution, produces distracting auditory and haptic stimulation, is difficult to combine with other imaging methods, and necessitates expensive, immobile equipment. Here, we attempted to measure the non-selective motor effects of inhibitory control using a method unaffected by these shortcomings. 30 participants exerted isometric force on a hand-held force transducer while performing a foot-response stop-signal task. Indeed, when foot movements were stopped, force output at the task-irrelevant hand was suppressed as well. Moreover, this non-selective reduction of isometric force was highly correlated with stop-signal performance and showed frequency dynamics similar to established inhibitory signatures typically found in neural and muscle recordings. Together, we demonstrate that isometric force recordings capture the non-selective effects of motor inhibition, enabling many applications that are impossible with TMS.
IκBα controls dormancy induction in Hematopoietic stem cell development via retinoic acid
Authors: Thambyrajah Roshana , Fadlullah Zaki , Proffitt Martin , Neo Wen Hao , Guillén Yolanda , Casado-Pelaez Marta , Herrero-Molinero Patricia , Brujas Carla , Castelluccio Noemi , González Jessica , Iglesias Arnau , Marruecos Laura , Ruiz-Herguido Cristina , Esteller Manel , Mereu Elisabetta , Lacaud Georges , Espinosa Lluis , Bigas Anna 
Published: November 2022

SummaryRecent findings are challenging the classical hematopoietic model in which long-term hematopoietic stem cells (LT-HSC) are the base of the hematopoietic system. Clonal dynamics analysis of the hematopoietic system indicate that LT-HSC are not the main contributors of normal hemapoiesis in physiological conditions and the hematopoietic system is mainly maintained by multipotent progenitors (MPPs, hereafter HPC) and LT-HSCs are mostly in a non-active state. The first HSCs emerge from the aorta-gonad and mesonephros (AGM) region along with hematopoietic progenitors (HPC) within hematopoietic clusters. Molecular pathways that determine the HSC fate instead of HPC are still unknown, although inflammatory signaling, including NF-κB has been implicated in the development of HSCs. Here, we identify a chromatin binding function for IκBα (also known as the inhibitor of NF-κB) that is Polycomb repression complex 2 (PRC2)-dependent and specifically determines dormant vs proliferating HSCs from the onset of their emergence in the AGM. We find a specific reduction of LT-HSCs in the IκBα knockout new-born pups. This defect is manifested at the FL stage already, and traceable to the first emerging HSCs in the E11.5 AGM, without affecting the general HPC population. IκBα deficient LT-HSCs express dormancy signature genes, are less proliferative and can robustly respond to activation stimuli such asin vitroculture and serial transplantation. At the molecular level, we find decreased PRC2-dependent H3K27me3 at the promoters of several retinoic acid signaling elements in the IκBα - deficient aortic endothelium and E14.5 FL LT-HSCs. Additionally, IκBα binding itself is found in the promoters of retinoic acid receptors rarα in the AGM, and rarγ in the LT-HSC of FL. Overall, we demonstrate that the retinoic acid pathway is over-activated in the hematopoietic clusters of IκBα-deficient AGMs leading to premature dormancy of LT-HSCs that persists in the FL LT-HSCs.
Potently neutralizing human monoclonal antibodies against the zoonotic pararubulavirus Sosuga virus
Authors: Parrington Helen M. , Kose Nurgun , Armstrong Erica , Handal Laura , Diaz Summer , Reidy Joseph , Dong Jinhui , Stewart-Jones Guillaume B. E. , Shrivastava-Ranjan Punya , Jain Shilpi , Albariño César G. , Carnahan Robert H. , Crowe James E. 
Published: November 2022

AbstractSosuga virus (SOSV) is a recently discovered paramyxovirus with a single known human case of disease. There has been little laboratory research on SOSV pathogenesis or immunity, and no approved therapeutics or vaccines are available. Here, we report the discovery of human monoclonal antibodies (mAbs) from the circulating memory B cells of the only known human case and survivor of SOSV infection. We isolated six mAbs recognizing the functional attachment protein (HN) and 18 mAbs against the fusion (F) protein. The anti-HN mAbs all target the globular head of the HN protein and can be organized into 4 competition-binding groups that exhibit epitope diversity. The anti-F mAbs can be divided into pre- or post-fusion conformation-specific categories and further into 8 competition-binding groups. Generally, pre-fusion conformation-specific anti-F mAbs showed higher potency in neutralization assays than did mAbs only recognizing the post-fusion conformation of F protein. Most of the anti-HN mAbs were more potently neutralizing than the anti-F mAbs, with mAbs in one of the HN competition-binding groups possessing ultra-potent (<1 ng/mL) half maximal inhibitory (IC50) virus neutralization values. These findings provide insight into the molecular basis for human antibody recognition of paramyxovirus surface proteins and the mechanisms of SOSV neutralization.
Cellular Maturation of Oligodendrocytes is Governed by Transient Gene Melting
Authors: Allan Kevin C. , Miller Tyler E. , Morton Andrew R. , Scavuzzo Marissa A. , Elitt Matthew S. , Clayton Benjamin L.L. , Hu Lucille R. , Vrabic Jost K. , Olsen Hannah E. , Factor Daniel C. , Henninger Jonathan E. , Young Richard A. , Lin Charles Y. , Scacheri Peter C. , Tesar Paul J. 
Published: November 2022

SUMMARYPluripotent stem cells (PSCs) provide an unlimited source for generating somatic cell types. However, generating fully mature cells constitutes a bottleneck for realizing their full potential in research and medicine. Here, we report a transcriptional mechanism that governs the timing of cellular maturation in post-mitotic oligodendrocytes. During differentiation of PSCs to oligodendrocytes, the transcription factor SOX6 redistributes from nearly all super enhancers in proliferating oligodendrocyte progenitor cells to cluster across specific gene bodies in immature oligodendrocytes. These sites exhibit ‘gene melting’, a process of extensive chromatin decondensation and transcription, which abruptly turns off upon maturation. Suppression of SOX6 deactivates these immaturity loci, resulting in rapid transition to mature myelinating oligodendrocytes. Cells harboring this immature oligodendrocyte SOX6 gene signature are specifically enriched in multiple sclerosis patient brains, suggestive that failed maturation may contribute to limited myelin regeneration in disease. Collectively, our finding that maturation rate is controlled by transient transcriptional clusters may inform approaches to accelerate the generation and regeneration of mature cell types.HIGHLIGHTSTranscription factors (TFs) can act as gatekeepers of post-mitotic cellular maturationIn oligodendrocytes, clustering of SOX6 controls the immaturity program through transient gene meltingSuppressing SOX6 deactivates immaturity genes and unlocks oligodendrocyte maturationSOX6 immaturity signature is enriched in oligodendrocytes in multiple sclerosis patients