bluuebunny/crossref_metadata_2025_split huggingface dataset:
Activity in the reticulospinal tract scales with handgrip force in humans
Authors: Danielson Tyler L. , Gould Layla , DeFreitas Jason M. , MacLennan Rob J. , Ekstrand Chelsea , Borowsky Ron , Farthing Jonathan P. , Andrushko Justin W. 
Published: November 2023

AbstractIntroductionThe neural pathways that contribute to force production in humans are currently poorly understood, as the relative roles of the corticospinal tract and brainstem pathways, such as the reticulospinal tract (RST), vary substantially across species. Using functional magnetic resonance imaging (fMRI) we aimed to measure activation in the pontine reticular nuclei during different submaximal handgrip contractions to determine the potential role of the RST in force modulation.MethodsThirteen neurologically intact participants (age: 28 ± 6 years) performed unilateral handgrip contractions at 25%, 50%, 75% of maximum voluntary contraction during brain scans. We quantified the magnitude of RST activation from the contralateral and ipsilateral sides in addition to the contralateral primary motor cortex during each of the three contraction intensities.ResultsA repeated measures ANOVA demonstrated a significant main effect of force (p= 0.012, ηp2= 0.307) for RST activation, independent of side (i.e., activation increased with force for both contralateral and ipsilateral nuclei). Further analyses of these data involved calculating the linear slope between the magnitude of activation and handgrip force for each ROI at the individual-level. One-samplet-tests on the slopes revealed significant group-level scaling for the RST bilaterally, but only the ipsilateral RST remained significant after correcting for multiple comparisons.ConclusionsHere, we show evidence of task dependent activation in the RST pontine nuclei that was positively related to handgrip force. These data build on a growing body of literature that highlights the RST as a functionally relevant motor pathway for force modulation in humans.New & NoteworthyIn this short report, we used a task-based fMRI paradigm to show that activity in the reticulospinal tract, but not the contralateral motor cortex, scales linearly with increasing force during a handgrip task. These findings directly support recently proposed hypotheses that the reticulospinal tract may play an important role in modulating force production in humans.
Revisiting Y-chromosome detection methods: R-CQ and KAMY efficiently identify Y chromosome sequences in Tephritidae insect pests
Authors: Rallis Dimitris , Tsoumani Konstantina T , Krsticevic Flavia , Papathanos Philippos Aris , Mathiopoulos Kostas D , Papanicolaou Alexie 
Published: November 2023

AbstractBackgroundThe repetitive and heterochromatic nature of Y chromosomes poses challenges for genome assembly methods which can lead to fragmented or misassembled scaffolds. While new sequencing technologies and assembly techniques becoming popular, tools for improving the generation of an accurate Y chromosome are limited, especially for species, such as insects, with a frequent occurrence of heterochromatic chromosomes.ResultsTwo novel Y-detection methods are presented here, R-CQ and KAMY, that revisit the ratio-based Chromosome Quotient and kmer-based Y-Genome Scan methods, respectively. We benchmark R-CQ and KAMY methods against their predecessors, over their ability in identifying Y-derived regions in genome assemblies of two important insect pests of the Tephritidae genus: the olive fruit flyBactrocera oleaeand the Mediterranean fruit flyCeratitis capit ata.These species are characterised by different Y-chromosome morphologies and their genomes were sequenced with different methodologies. We also evaluated the efficiency and generic applicability of these methods using suitableDrosophila melanogastergenomic data, whose Y-chromosome is the best studied among insects. Furthermore, KAMY was assessed for the capability of identifying Y-derived transcripts in the absence of a reference-Y sequence and effectively identified the Tephritid maleness factorMoYin a set of mixed-sex transcriptomic data. Through our work, we describe a methodology for manually curating the computational results, through which the performance of different Y detection methods is determined, together with the size and quality of assembled Y sequences.ConclusionsWe find a variability in the performance of Y-detection methods, that is highly dependent on the sequencing approach used and on the sequence of the Y. Our benchmarking suggests an improved overall efficiency of KAMY and R-CQ compared to their predecessors, while our analysis highlights the importance for manually curating the algorithmic outputs towards describing the accuracy and quality of identified Y sequences. Based on our results, we provide some recommendations for future sequencing efforts in insects to best support downstream Y assembly steps.
Myogenic artifacts masquerade as neuroplasticity in the auditory frequency-following response (FFR)
Authors: Bidelman Gavin M. , Sisson Alexandria , Rizzi Rose , MacLean Jessica , Baer Kaitlin 
Published: November 2023

AbstractThe frequency-following response (FFR) is an evoked potential that provides a neural index of complex sound encoding in the brain. FFRs have been widely used to characterize speech and music processing, experience-dependent neuroplasticity (e.g., learning, musicianship), and biomarkers for hearing and language-based disorders that distort receptive communication abilities. It is widely assumed FFRs stem from a mixture of phase-locked neurogenic activity from brainstem and cortical structures along the hearing neuraxis. Here, we challenge this prevailing view by demonstrating upwards of ∼50% of the FFR can originate from a non-neural source: contamination from the postauricular muscle (PAM) vestigial startle reflex. We measured PAM, transient auditory brainstem responses (ABRs), and sustained frequency-following response (FFR) potentials reflecting myogenic (PAM) and neurogenic (ABR/FFR) responses in young, normal-hearing listeners with varying degrees of musical training. We first establish PAM artifact is present in all ears, varies with electrode proximity to the muscle, and can be experimentally manipulated by directing listeners’ eye gaze toward the ear of sound stimulation. We then show this muscular noise easily confounds auditory FFRs, spuriously amplifying responses by 3-4x fold with tandem PAM contraction and even explaining putative FFR enhancements observed in highly skilled musicians. Our findings expose a new and unrecognized myogenic source to the FFR that drives its large inter-subject variability and cast doubt on whether changes in the response typically attributed to neuroplasticity/pathology are solely of brain origin.
Motivational context determines the impact of aversive outcomes on mental effort allocation
Authors: Fahey Mahalia Prater , Yee Debbie M. , Leng Xiamin , Tarlow Maisy , Shenhav Amitai 
Published: November 2023

AbstractIt is well known that people will exert effort on a task if sufficiently motivated, but how they distribute these efforts across different strategies (e.g., efficiency vs. caution) remains uncertain. Past work has shown that people invest effort differently for potential positive outcomes (rewards) versus potential negative outcomes (penalties). However, this research failed to account for differences in the context in which negative outcomes motivate someone - either as punishment or reinforcement. It is therefore unclear whether effort profiles differ as a function of outcome valence, motivational context, or both. Using computational modeling and our novel Multi-Incentive Control Task, we show that the influence of aversive outcomes on one’s effort profile is entirely determined by their motivational context. Participants (N:91) favored increased caution in response to larger penalties for incorrect responses, and favored increased efficiency in response to larger reinforcement for correct responses, whether positively or negatively incentivized.Statement of RelevancePeople have to constantly decide how to allocate their mental effort, and in doing so can be motivated by both the positive outcomes that effort accrues and the negative outcomes that effort avoids. For example, someone might persist on a project for work in the hopes of being promoted or to avoid being reprimanded or even fired. Understanding how people weigh these different types of incentives is critical for understanding variability in human achievement as well as sources of motivational impairments (e.g., in major depression). We show that people not only consider both potential positive and negative outcomes when allocating mental effort, but that the profile of effort they engage under negative incentives differs depending on whether that outcome is contingent on sustaining good performance (negative reinforcement) or avoiding bad performance (punishment). Clarifying the motivational factors that determine effort exertion is an important step for understanding motivational impairments in psychopathology.
Characterization of anOsmrConditional Knockout Mouse Model
Authors: Schwartz Logan S. , Saxl Ruth L. , Stearns Tim , Trowbridge Jennifer J. 
Published: November 2023

ABSTRACTOncostatin M (OSM) is a member of the interleukin-6 (IL-6) family of cytokines and has been found to have distinct anti-inflammatory and pro-inflammatory properties in various cellular and disease contexts. OSM signals through two receptor complexes, one of which includes OSMRβ. To investigate OSM-OSMRβ signaling in adult hematopoiesis, we utilized the readily available conditionalOsmrfl/flmouse model B6;129-Osmrtm1.1Nat/J, which is poorly characterized in the literature. This model contains loxP sites flanking exon 2 of theOsmrgene. We crossedOsmrfl/flmice to interferon-inducibleMx1-Cre, which is robustly induced in adult hematopoietic cells. We observed complete recombination of theOsmrflallele and loss of exon 2 in hematopoietic (bone marrow) as well as non-hematopoietic (liver, lung, kidney) tissues. Using a TaqMan assay with probes downstream of exon 2,Osmrtranscript was lower in the kidney but equivalent in bone marrow, lung, and liver fromOsmrfl/flMx1-Cre versusMx1-Cre control mice, suggesting that transcript is being produced despite loss of this exon. Western blots show that liver cells fromOsmrfl/flMx1-Cre mice had complete loss of OSMR protein, while bone marrow, kidney, and lung cells had reduced OSMR protein at varying levels. RNA-seq analysis of a subpopulation of bone marrow cells (hematopoietic stem cells) finds that some OSM-stimulated genes, but not all, are suppressed inOsmrfl/flMx1-Cre cells. Together, our data suggest that the B6;129-Osmrtm1.1Nat/J model should be utilized with caution as loss ofOsmrexon 2 has variable and tissue-dependent impact on mRNA and protein expression.
Robust reprogramming of glia into neurons by inhibition of Notch signaling and NFI factors in adult mammalian retina
Authors: Le Nguyet , Vu Trieu-Duc , Palazzo Isabella , Pulya Ritvik , Kim Yehna , Blackshaw Seth , Hoang Thanh 
Published: November 2023

SummaryGeneration of neurons through direct reprogramming has emerged as a promising therapeutic approach for neurodegenerative diseases. Despite successful applicationsin vitro,in vivoimplementation has been hampered by low efficiency. In this study, we present a highly efficient strategy for reprogramming retinal glial cells into neurons by simultaneously inhibiting key negative regulators. By suppressing Notch signaling through the removal of its central mediatorRbpj,we induced mature Müller glial cells to reprogram into bipolar and amacrine neurons in uninjured adult mouse retinas, and observed that this effect was further enhanced by retinal injury. We found that specific loss of function ofNotch1andNotch2receptors in Müller glia mimicked the effect ofRbpjdeletion on Müller glia-derived neurogenesis. Integrated analysis of multiome (scRNA- and scATAC-seq) and CUT&Tag data revealed that Rbpj directly activates Notch effector genes and genes specific to mature Müller glia while also indirectly represses the expression of neurogenic bHLH factors. Furthermore, we found that combined loss of function ofRbpjandNfia/b/xresulted in a robust conversion of nearly all Müller glia to neurons. Finally, we demonstrated that inducing Müller glial proliferation by AAV (adeno-associated virus)-mediated overexpression of dominant- active Yap supports efficient levels of Müller glia-derived neurogenesis in bothRbpj- andNfia/b/x/Rbpj- deficient Müller glia. These findings demonstrate that, much like in zebrafish, Notch signaling actively represses neurogenic competence in mammalian Müller glia, and suggest that inhibition of Notch signaling andNfia/b/xin combination with overexpression of activated Yap could serve as an effective component of regenerative therapies for degenerative retinal diseases.
Genomic-inferred cross-selection metrics for multi-trait improvement in a recurrent selection breeding program
Authors: Atanda Sikiru Adeniyi , Bandillo Nonoy 
Published: November 2023

AbstractThe major drawback to the implementation of genomic selection in a breeding program is the reduction of additive genetic variance in the long term, primarily due to the Bulmer effect. Increasing genetic gain and retaining additive genetic variance requires optimizing the trade-off between the two competing factors. Our approach integrated index selection in the genomic infer cross-selection (GCS) methods. With this strategy, we identified optimal crosses that simultaneously maximize progeny performance and maintain genetic variance for multiple traits. Using a stochastic simulated recurrent breeding program over a 40-year period, we evaluated different GCS metrics with other factors, such as the number of parents, crosses, and progenies per cross, that influence genetic gain in a breeding program. Across all breeding scenarios, the posterior mean-variance consistently enhances genetic gain when compared to other metrics such as the usefulness criterion, optimal haploid value, mean genomic estimated breeding value, and mean index selection value of the superior parents. In addition, we provide a detailed strategy to optimize the number of parents, crosses, and progenies per cross that maximizes short- and long-term genetic gain in a breeding program.
Spatiotemporal Profiling Unveiling the Cellular Organization Patterns and Local Protumoral Immune Microenvironment Remodeling in Early Lung Adenocarcinoma Progression
Authors: Chen Haojie , Peng Yizhou , Li Yana , Zheng Qiang , Zhao Yue , Liu Pengcheng , Wu Zhigang , Wo Yang , Hong Hui , Sun Yihua , Shao Zhen 
Published: November 2023

AbstractSpatial cellular organization patterns (COPs) in tumor microenvironment influence the tumor progression and therapeutic response, however, little is known about the cellular composition and functional potential of these multicellular structures during lung adenocarcinoma progression. Here, we integrate spatial transcriptomics with single cell RNA sequencing to characterize the local tumor and immunological landscape of samples from 8 patients with early-stage lung adenocarcinoma at different pathological stages. We identified ten COPs that show distinct associations with local immune states and clinical outcomes, including survival and therapy response. The local infiltration levels of regulatory and dysfunctional immune cells are increased with pathological progression. Cell-to-cell interactions between malignant cells and tumor microenvironment (TME) cells were involved in protumor immune state remodeling. Finally, we detected a group of malignant cells that were specifically located at the tumor boundary, representing a more aggressive state, were involved in the invasion of invasive adenocarcinoma (IAC). Altogether, these results can improve our understanding of the local microenvironment characteristics that underlie LUAD progression and may facilitate the identification of drug targets to prevent invasive progression and biomarkers for diagnosis.
CZ CELL×GENE Discover: A single-cell data platform for scalable exploration, analysis and modeling of aggregated data
Authors:   CZI Single-Cell Biology Program, Abdulla Shibla , Aevermann Brian , Assis Pedro , Badajoz Seve , Bell Sidney M. , Bezzi Emanuele , Cakir Batuhan , Chaffer Jim , Chambers Signe , Michael Cherry J. , Chi Tiffany , Chien Jennifer , Dorman Leah , Garcia-Nieto Pablo , Gloria Nayib , Hastie Mim , Hegeman Daniel , Hilton Jason , Huang Timmy , Infeld Amanda , Istrate Ana-Maria , Jelic Ivana , Katsuya Kuni , Kim Yang Joon , Liang Karen , Lin Mike , Lombardo Maximilian , Marshall Bailey , Martin Bruce , McDade Fran , Megill Colin , Patel Nikhil , Predeus Alexander , Raymor Brian , Robatmili Behnam , Rogers Dave , Rutherford Erica , Sadgat Dana , Shin Andrew , Small Corinn , Smith Trent , Sridharan Prathap , Tarashansky Alexander , Tavares Norbert , Thomas Harley , Tolopko Andrew , Urisko Meghan , Yan Joyce , Yeretssian Garabet , Zamanian Jennifer , Mani Arathi , Cool Jonah , Carr Ambrose 
Published: November 2023

AbstractHundreds of millions of single cells have been analyzed to date using high throughput transcriptomic methods, thanks to technological advances driving the increasingly rapid generation of single-cell data. This provides an exciting opportunity for unlocking new insights into health and disease, made possible by meta-analysis that span diverse datasets building on recent advances in large language models and other machine learning approaches. Despite the promise of these and emerging analytical tools for analyzing large amounts of data, a major challenge remains the sheer number of datasets and inconsistent format, data models and accessibility. Many datasets are available via unique portals platforms that often lack interoperability. Here, we present CZ CellxGene Discover(cellxgene.cziscience.com), a data platform that provides curated and interoperable data. This single-cell data resource, available via a free-to-use online data portal, hosts a growing corpus of community contributed data that spans more than 50 million unique cells. Curated, standardized, and associated with consistent cell-level metadata, this collection of interoperable single-cell transcriptomic data is the largest of its kind. A suite of tools and features enables accessibility and reusability of the data via both computational and visual interfaces to allow researchers to rapidly explore individual datasets and perform cross-corpus analysis. This functionality is enabling meta-analyses of tens of millions of cells across studies and tissues and providing global views of human cells at the resolution of single cells.
Fatty acid synthesis promotes inflammasome activation through NLRP3 palmitoylation
Authors: Leishman Stuart , Aljadeed Najd M. , Qian Liyunhe , Cockcroft Shamshad , Behmoaras Jacques , Anand Paras K. 
Published: November 2023

ABSTRACTInflammasomes are multi-protein complexes assembled by NOD-like receptor (NLR) family of proteins, which play critical roles in infectious, inflammatory and metabolic diseases. The assembly of the NLRP3 inflammasome is triggered upon recognition of an apt stimulus by the sensor protein, resulting in binding to pro-caspase-1 via the adaptor protein ASC. Inflammasome activation results in the maturation of the precursor forms of cytokines IL-1βand IL-18, along with caspase-1-dependent pyroptosis, a pro-inflammatory form of cell death. Emerging evidence suggests the involvement of lipid metabolism in inflammasome activation; however, the precise mechanisms by which lipids regulate the NLRP3 inflammasome remain ambiguous. A multi-enzyme protein, fatty acid synthase (FASN) is a central regulator of lipid metabolism partaking an essential role in fatty acid biosynthesis pathway by catalysing the production of palmitic acid. Palmitic acid acts as a precursor to long-chain fatty acids and additionally regulates cellular functions by palmitoylation, a process in which palmitate is reversibly added to cysteine residues of target proteins, modifying protein localization and function. Here, we undertook a pharmacological approach to investigate the roles of fatty acid biosynthetic pathway in NLRP3 inflammasome activation. Our results demonstrated that inhibition of FASN in primary mouse and human macrophages abrogates the activation of the NLRP3 inflammasome, resulting in blunted caspase-1 activation. Furthermore, this phenomenon relied on protein palmitoylation asin vitroandin vivoabrogation of palmitoylation similarly reduced NLRP3 activation, which could be restored by exogenously supplementing palmitate in cultured cells. Consequently, an acyl biotin exchange assay corroborated NLRP3 palmitoylation. Notably, activation of the dsDNA sensing AIM2 inflammasome remained unaltered when either FASN or palmitoylation was blocked. These results therefore highlight the pivotal role of FASN and palmitoylation, shedding new mechanistic insights into the activation of the NLRP3 inflammasome.
The hypermorphic PLCγ2 S707Y variant dysregulates microglial cell function – insight into PLCγ2 activation in brain health and disease, and opportunities for therapeutic modulation
Authors: Bull Daniel , Matte Julie C , Navarron Carmen M , McIntyre Rebecca , Whiting Paul , Katan Matilda , Ducotterd Fiona , Magno Lorenza 
Published: November 2023

AbstractPhospholipase C-gamma 2 (PLCγ2) is highly expressed in hematopoietic and immune cells, where it is a key signalling node enabling diverse cellular functions. Within the periphery, gain-of-function (GOF) PLCγ2 variants, such as the strongly hypermorphic S707Y, cause severe immune dysregulation. The milder hypermorphic mutation PLCγ2 P522R increases longevity and confers protection in central nervous system (CNS) neurodegenerative disorders, implicating PLCγ2 as a novel therapeutic target for treating these CNS indications. Currently, nothing is known about what consequences strong PLCγ2 GOF has on CNS functionality, and more precisely on the specific biological functions of microglia. Using the PLCγ2 S707Y variant as a model of chronic activation we investigated the functional consequences of strong PLCγ2 GOF on human microglia. PLCγ2 S707Y expressing human inducible pluripotent stem cells (hiPSC)-derived microglia exhibited hypermorphic enzymatic activity under both basal and stimulated conditions, compared to PLCγ2 wild type. Despite the increase in PLCγ2 enzymatic activity, the PLCγ2 S707Y hiPSC-derived microglia display diminished functionality for key microglial processes including phagocytosis and cytokine secretion upon inflammatory challenge. RNA sequencing revealed a downregulation of genes related to innate immunity and response, providing molecular support for the phenotype observed. Our data suggests that chronic activation of PLCγ2 elicits a detrimental phenotype that is contributing to unfavourable CNS functions, and informs on the therapeutic window for targeting PLCγ2 in the CNS. Drug candidates targeting PLCγ2 will need to precisely mimic the effects of the PLCγ2 P522R variant on microglial function, but not those of the PLCγ2 S707Y variant.HighlightsThe impact of strongly hypermorphic variants of PLCγ2 have not been studied in brain and yet PLCγ2 is implicated in modifying risk of CNS disorders including Alzheimer’s diseaseTo address this, we explored the role of the strongly hypermorphic PLCγ2 S707Y variant in hiPSC-derived microgliaS707Y increases PLCγ2 enzymatic activity and intracellular calcium fluxPhagocytosis and cytokine production are diminished in PLCγ2 S707Y microgliaPLCγ2 S707Y downregulates expression of genes related to innate immunity and responseModulation of PLCγ2 for therapy must recapitulate the positive effects of moderate hypermorphic variants on microglial functions whilst avoiding detrimental effects of strongly hypermorphic variants like PLCγ2 S707YGraphical abstract