bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Single Trophoblast Layer Acts as the Gatekeeper at the Endothelial-Hematopoietic Crossroad in the Placenta
Authors: Home Pratik , Ghosh Ananya , Kumar Ram Parikshan , Ray Soma , Gunewardena Sumedha , Kumar Rajnish , Dasgupta Purbasa , Roy Namrata , Saha Abhik , Ouseph Madhu M. , Leone Gustavo W. , Paul Soumen 
Published: July 2024

AbstractDuring embryonic development the placental vasculature acts as a major hematopoietic niche, where endothelial to hematopoietic transition ensures emergence of hematopoietic stem cells (HSCs). However, the molecular mechanisms that regulate the placental hematoendothelial niche are poorly understood. Using a parietal trophoblast giant cell (TGC)-specific knockout mouse model and single-cell RNA-sequencing, we show that the paracrine factors secreted by the TGCs are critical in the development of this niche. Disruptions in the TGC-specific paracrine signaling leads to the loss of HSC population and the concomitant expansion of a KDR+/DLL4+/PROM1+ hematoendothelial cell-population in the placenta. Combining single- cell transcriptomics and receptor-ligand pair analyses, we also define the parietal TGC- dependent paracrine signaling network and identify Integrin signaling as a fundamental regulator of this process. Our study elucidates novel mechanisms by which non-autonomous signaling from the primary parietal TGCs maintain the delicate placental hematopoietic- angiogenic balance and ensures embryonic and extraembryonic development.
Langerhans cells regulate immunity in adulthood by regulating postnatal dermal lymphatic development
Authors: Sim Ji Hyun , Bell Richard , Feng Zhonghui , Chyou Susan , Shipman William D , Kataru Raghu P. , Ivashkiv Lionel , Mehrara Babak , Lu Theresa T. 
Published: July 2024

ABSTRACTThe communication between skin and draining lymph nodes is crucial for well-regulated immune responses to skin insults. The skin sends antigen and other signals via lymphatic vessels to regulate lymph node activity, and regulating dermal lymphatic function is another means to control immunity. Here, we show that Langerhans cells (LCs), epidermis-derived antigen-presenting cells, mediate dermal lymphatic expansion and phenotype acquisition postnatally, a function is independent of LC entry into lymphatic vessels. This postnatal LC-lymphatic axis serves in part to control inflammatory systemic T cell responses in adulthood. Our data provide a tissue-based mechanism by which LCs regulate T cells remotely across time and space and raise the possibility that immune diseases in adulthood could reflect compromise of the LC-lymphatic axis in childhood.
Local keratinocyte-nociceptor interactions enhance obesity-mediated small fiber neuropathy via NGF-TrkA-PI3K signaling axis
Authors: Koui Yuta , Song Shuxuan , Dong Xinzhong , Mukouyama Yoh-suke 
Published: July 2024

AbstractThe pathology of diabetic small fiber neuropathy, characterized by neuropathic pain and axon degeneration, develops locally within the skin during the stages of obesity and pre-diabetes. However, the initiation and progression of morphological and functional abnormalities in skin sensory nerves remains elusive. To address this, we utilized ear skin from mice with diet-induced obesity (DIO), the mouse models for obesity and pre-type 2 diabetes. We evaluated pain-associated wiping behavior and conductedex vivolive Ca2+imaging of the DIO ear skin to detect sensory hypersensitivity. Our findings reveal sensory hypersensitivity in skin nociceptive axons followed by axon degeneration. Further mechanistic analysis identified keratinocytes as a major source of nerve growth factor (NGF) in DIO skin, which locally sensitizes nociceptors through NGF-mediated signaling. Indeed, the local inactivation of NGF and its receptor TrkA-mediated downstream signaling, including the phosphoinositide 3-kinases (PI3K) pathway, suppresses sensory hypersensitivity in DIO skin. Thus, targeting these local interactions between keratinocytes and nociceptors offers a therapeutic strategy for managing neuropathic pain, avoiding the adverse effects associated with systemic interventions.
Elp1 function in placode-derived neurons is critical for proper trigeminal ganglion development
Authors: Hines Margaret A. , Taneyhill Lisa A. 
Published: July 2024

ABSTRACTBackgroundThe trigeminal nerve is the largest cranial nerve and functions in somatosensation. Cell bodies of this nerve are positioned in the trigeminal ganglion, which arises from the coalescence of neural crest and placode cells. While this dual cellular origin has been known for decades, the molecular mechanisms controlling trigeminal ganglion development remain obscure. We performed RNAsequencing on the forming chick trigeminal ganglion and identifiedElongator acetyltransferase complex subunit 1(Elp1) for further study. Mutations inELP1cause familial dysautonomia (FD), a fatal disorder characterized by the presence of smaller trigeminal nerves and sensory deficits. While Elp1 has established roles in neurogenesis, its functions in placode cells during trigeminal gangliogenesis have not been investigated.ResultsTo this end, we used morpholinos to deplete Elp1 from chick trigeminal placode cells. Elp1 knockdown decreased trigeminal ganglion size and led to aberrant innervation of the eye by placode-derived neurons. Trigeminal nerve branches exhibited fewer axons, and abnormal interactions between placode-derived neurons and neural crest cells were observed.ConclusionsThese findings reveal a new role for Elp1 in chick placode-derived neurons during trigeminal ganglion development. These results have potential high significance to provide new insights into trigeminal ganglion development and the etiology of FD.Bullet pointsElp1 is expressed in undifferentiated neural crest cells and placode-derived neurons contributing to the trigeminal ganglion.Elp1 knockdown in trigeminal placode cells reduces trigeminal ganglion size.Elp1 depletion from trigeminal placode cells leads to aberrant target tissue innervation and disrupts proper neural crest-placodal neuron interactions in the trigeminal ganglion.Grant sponsor and numberNIH R01DE024217 and NIH R03HD108480.
Protein-Induced Membrane Strain Drives Supercomplex Formation
Authors: Pöverlein Maximilian C. , Jussupow Alexander , Kim Hyunho , Kaila Ville R. I. 
Published: July 2024

AbstractMitochondrial membranes harbor the electron transport chain (ETC) that powers oxidative phosphorylation (OXPHOS) and drives the synthesis of ATP. Yet, under physiological conditions, the OXPHOS proteins operate as higher-order supercomplex (SC) assemblies, although their functional role remains poorly understood and much debated. By combining large-scale atomistic and coarse-grained molecular simulations with analysis of cryo-electron microscopic data and statistical as well as kinetic models, we show here that the formation of the mammalian I/III2supercomplex reduces the molecular strain of inner mitochondrial membranes by altering the local membrane thickness, and leading to an accumulation of both cardiolipin and quinone around specific regions of the SC. We find that the SC assembly also affects the global motion of the individual ETC proteins with possible functional consequences. On a general level, our findings suggest that molecular crowding and entropic effects provide a thermodynamic driving force for the SC formation, with a possible flux enhancement in crowded biological membranes under constrained respiratory conditions.Significance StatementThe membrane-bound proteins of respiratory chains power oxidative phosphorylation (OXPHOS) and drive the synthesis of ATP. However, recent biochemical and structural data show that the OXPHOS proteins operate as higher-order supercomplex assemblies for reasons that remain elusive and much debated. Here we show that the mammalian respiratory supercomplexes reduce the molecular strain of inner mitochondrial membranes and enhance the allosteric crosstalk by altering the protein dynamics with important biochemical and physiological implications.
Massive experimental quantification of amyloid nucleation allows interpretable deep learning of protein aggregation
Authors: Thompson Mike , Martín Mariano , Olmo Trinidad Sanmartín , Rajesh Chandana , Koo Peter K. , Bolognesi Benedetta , Lehner Ben 
Published: July 2024

AbstractProtein aggregation is a pathological hallmark of more than fifty human diseases and a major problem for biotechnology. Methods have been proposed to predict aggregation from sequence, but these have been trained and evaluated on small and biased experimental datasets. Here we directly address this data shortage by experimentally quantifying the amyloid nucleation of >100,000 protein sequences. This unprecedented dataset reveals the limited performance of existing computational methods and allows us to train CANYA, a convolution-attention hybrid neural network that accurately predicts amyloid nucleation from sequence. We adapt genomic neural network interpretability analyses to reveal CANYA’s decision-making process and learned grammar. Our results illustrate the power of massive experimental analysis of random sequence-spaces and provide an interpretable and robust neural network model to predict amyloid nucleation.
RFMix-reader: Accelerated reading and processing for local ancestry studies
Authors: Benjamin Kynon J.M. 
Published: July 2024

AbstractMotivationLocal ancestry inference is a powerful technique in genetics, revealing population history and the genetic basis of diseases. It is particularly valuable for improving eQTL discovery and fine-mapping in admixed populations. Despite the widespread use of theRFMixsoftware for local ancestry inference, large-scale genomic studies face challenges of high memory consumption and processing times when handlingRFMixoutput files.ResultsHere, I presentRFMix-reader, a new Python-based parsing software, designed to streamline the analysis of large-scale local ancestry datasets. This software prioritizes computational eiciency and memory optimization, leveraging GPUs when available for additional speed boosts. By overcoming these data processing hurdles,RFMix-readerempowers researchers to unlock the full potential of local ancestry data for understanding human health and health disparities.AvailabilityRFMix-readeris freely available on PyPI athttps://pypi.org/project/rfmix-reader/, implemented in Python 3, and supported on Linux, Windows, and Mac OS.ContactKynonJade.Benjamin@libd.orgSupplementary informationSupplementary data are available athttps://rfmix-reader.readthedocs.io/en/latest/.
Dynamical forces drive organ morphology changes during embryonic development
Authors: Manna Raj Kumar , Retzlaff Emma M. , Hinman Anna Maria , Lan Yiling , Abdel-Razek Osama , Bates Mike , Hehnly Heidi , Amack Jeffrey D. , Manning M. Lisa 
Published: July 2024

AbstractOrgans and tissues must change shape in precise ways during embryonic development to execute their functions. Multiple mechanisms including biochemical signaling pathways and biophysical forces help drive these morphology changes, but it has been difficult to tease apart their contributions, especially from tissue-scale dynamic forces that are typically ignored. We use a combination of mathematical models andin vivoexperiments to study a simple organ in the zebrafish embryo called Kupffer’s vesicle. Modeling indicates that dynamic forces generated by tissue movements in the embryo produce shape changes in Kupffer’s vesicle that are observed during development. Laser ablations in the zebrafish embryo that alter these forces result in altered organ shapes matching model predictions. These results demonstrate that dynamic forces sculpt organ shape during embryo development.
HERV-derived epitopes represent new targets for T-cell based immunotherapies in ovarian cancer
Authors: Bonaventura Paola , Tabone Olivier , Estornes Yann , Page Audrey , Mutez Virginie , Delles Marie , Moran Sarah , Dubois Clarisse , Lacourrege Marjorie , Tawfik Dina , Etchegaray Ema , Valente Adrian , Boulos Rasha E. , Jimenez Dominguez Gabriel , Chuvin Nicolas , Gadot Nicolas , Wang Qing , Valladeau-Guilemond Jenny , Depil Stéphane 
Published: July 2024

AbstractBackgroundOvarian cancer represents the most lethal gynecological cancer with poor results of checkpoint inhibitors. Human endogenous retroviruses (HERVs) are aberrantly expressed by tumor cells and may represent a source of shared T cell epitopes for cancer immunotherapy regardless of the tumor mutational burden.MethodsA transcriptomic analysis based on RNA-sequencing (RNA-seq) was developed to quantify the expression of HERV-K sequences containing the selected epitopes. The presence of HERV-K/HML-2 Gag antigen was then assessed by immunohistochemistry (IHC) on tumor microarrays from ovarian cancer samples and normal ovarian tissues. A specific immunopeptidomics approach was developed to detect epitopes on HLA molecules. Epitope-specific CD8+T cells were quantified by multimer staining andin vitrotarget cell killing was evaluated using xCELLigence technology.In vivoantitumor efficacy of HERV-specific T cells was assessed in an avian embryo model.ResultsEpitope-containing HERV transcripts were significantly higher in ovarian cancers compared to normal tissues. The presence of HERV-K/HML-2 Gag antigen was confirmed by IHC in 20/40 (50%) ovarian cancers while no Gag expression was found in normal ovarian tissue samples. Immunopeptidomics analysis showed the presence of epitopes on HLA molecules on the surface of ovarian tumor cell lines but not on normal primary cells from critical tissues. HERV-specific T cells were detected among tumor infiltrating lymphocytes (TILs) from ovarian cancers, confirming the immunogenicity of these epitopes in patients.In vitro, HERV-specific T cells specifically killed ovarian cancer cells in an HLA class I-restricted manner while sparing normal HLA-A2-positive primary cells derived from critical tissues. Epitope-specific CD8+T cells exhibited a strong anti-tumoral activityin vivo, inducing a highly significant decrease in tumor volume in comparison with control groups.ConclusionThese results provide the preclinical rationale for developing T-cell based approaches against HERV-K-derived epitopes in ovarian cancer.Graphical abstractSome HERVs are specifically overexpressed in ovarian cancer compared to normal tissues.HERV-K/HML-2 Gag antigen is detected by immunohistochemistry in ovarian cancers but not in normal ovarian tissues. Furthermore, HERV-K-derived epitopes are presented on HLA molecules on the surface of ovarian cancer cells but not on normal cells.These epitopes are immunogenic in patients and induce high-avidity CD8+T cells that specifically kill ovarian cancer cellsin vitroandin vivowhile sparing normal cells.
MALAT1expression indicates cell quality in single-cell RNA sequencing data
Authors: Clarke Zoe A. , Bader Gary D. 
Published: July 2024

AbstractSingle-cell RNA sequencing (scRNA-seq) has revolutionized our understanding of cell types and tissues. However, empty droplets and poor quality cells are often captured in single cell genomics experiments and need to be removed to avoid cell type interpretation errors. Many automated and manual methods exist to identify poor quality cells or empty droplets, such as minimum RNA count thresholds and comparing the gene expression profile of an individual cell to the overall background RNA expression of the experiment. A versatile approach is to use unbalanced overall RNA splice ratios of cells to identify poor quality cells or empty droplets. However, this approach is computationally intensive, requiring a detailed search through all sequence reads in the experiment to quantify spliced and unspliced reads. We found that the expression level ofMALAT1,a non-coding RNA retained in the nucleus and ubiquitously expressed across cell types, is strongly correlated with this splice ratio measure and thus can be used to similarly identify low quality cells in scRNA-seq data. Since it is easy to visualize the expression of a single gene in single-cell maps,MALAT1expression is a simple cell quality measure that can be quickly used during the cell annotation process to improve the interpretation of cells in tissues of human, mouse and other species with a conservedMALAT1function.
Parallelized Droplet Vitrification Enables Single-Run Vitrification of the Whole Rat Liver Hepatocyte Yield
Authors: Taggart M. S. , Tchir A. , Van Dieren L. , Chen H. , Hassan M. , Taveras C. , Lellouch AG. , Toner M. , Sandlin R. D. , Uygun K. 
Published: July 2024

AbstractDrug discovery pipelines rely on the availability of isolated primary hepatocytes for investigating potential hepatotoxicity prior to clinical application. These hepatocytes are typically isolated from livers rejected for transplantation and subsequently cryopreserved for later usage. The gold-standard cryopreservation technique, slow-freezing, is a labor-intensive process, with significant post-storage viability loss. In this work, we introduce parallelized droplet vitrification, a technique for high-volumetric, rapid vitrification of suspended cells. We show the utility of this technique through the single-run vitrification of the whole-rate liver hepatocyte yield, resulting in a 1600% increase in single-batch vitrification and a 500% increase in droplet generation rate compared to previous droplet vitrification approaches. Additionally, we showed that these implementations maintained improved post-preservation outcomes in primary rat hepatocytes.
Spatial and temporal transmission dynamics of respiratory syncytial virus in New Zealand before and after the COVID-19 pandemic
Authors: Jelley Lauren , Douglas Jordan , O’Neill Meaghan , Berquist Klarysse , Claasen Ana , Wang Jing , Utekar Srushti , Johnston Helen , Judy Bocacao , Allais Margot , de Ligt Joep , Tan Chor Ee , Seeds Ruth , Wood Tim , Aminisani Nayyereh , Jennings Tineke , Welch David , Turner Nikki , McIntyre Peter , Dowell Tony , Trenholme Adrian , Byrnes Cass ,   The SHIVERS investigation team, Webby Richard , French Nigel , Winter David , Huang Q. Sue , Geoghegan Jemma L 
Published: July 2024

AbstractHuman respiratory syncytial virus (RSV) is a major cause of acute respiratory infection. In 2020, RSV was effectively eliminated from the community in New Zealand due to non-pharmaceutical interventions (NPI) used to control the spread of COVID-19. However, in April 2021, following a brief quarantine-free travel agreement with Australia, there was a large-scale nationwide outbreak of RSV that led to reported cases more than five times higher, and hospitalisations more than three times higher, than the typical seasonal pattern. In this study, we generated 1,471 viral genomes of both RSV-A and RSV-B sampled between 2015 and 2022 from across New Zealand. Using a phylodynamics approach, we used these data to better understand RSV transmission patterns in New Zealand prior to 2020, and how RSV became re-established in the community following the relaxation of COVID-19 restrictions. We found that in 2021, there was a large epidemic of RSV in New Zealand that affected a broader age group range compared to the usual pattern of RSV infections. This epidemic was due to an increase in RSV importations, leading to several large genomic clusters of both RSV-A ON1 and RSV-B BA9 genotypes in New Zealand. However, while a number of importations were detected, there was also a major reduction in RSV genetic diversity compared to pre-pandemic seasonal outbreaks. These genomic clusters were temporally associated with the increase of migration in 2021 due to quarantine-free travel from Australia at the time. The closest genetic relatives to the New Zealand RSV genomes, when sampled, were viral genomes sampled in Australia during a large, off-season summer outbreak several months prior, rather than cryptic lineages that were sustained but not detected in New Zealand. These data reveal the impact of NPI used during the COVID-19 pandemic on other respiratory infections and highlight the important insights that can be gained from viral genomes.
Genomic epidemiology demonstrates spatially clustered, local transmission ofPlasmodium falciparumin forest-going populations in southern Lao PDR
Authors: Chen Ying-An , Vickers Eric Neubauer , Aranda-Diaz Andres , Murphy Maxwell , Gerlovina Inna , Rerolle Francois , Dantzer Emily , Hongvanthong Bouasy , Chang Hsiao-Han , Lover Andrew A. , Hathaway Nicholas J. , Bennett Adam , Greenhouse Bryan 
Published: July 2024

AbstractWhile there has been significant progress in controlling falciparum malaria in the Lao People’s Democratic Republic (PDR), sporadic cases persist in southern provinces where the extent and patterns of transmission remain largely unknown. To assess parasite transmission in this area, 53Plasmodium falciparum(Pf) positive cases detected through active test and treat campaigns from December 2017 to November 2018 were sequenced, targeting 204 highly polymorphic amplicons. Two R packages,MOIREandDcifer, were applied to assess the multiplicity of infections (MOI), effective MOI (eMOI), within-host parasite relatedness, and between-host parasite relatedness (). Genomic data were integrated with survey data to characterize the temporal and spatial structures of identified clusters. The positive cases were mainly captured during the focal test and treat campaign conducted in 2018, and in the Pathoomphone area, which had the highest test positivity and forest activity. About 30% of the cases were polyclonal infections, with over half of theses (63%) showing within-host relatedness greater than 0.6, suggesting that cotransmission rather than superinfection was primarily responsible for maintaining polyclonality. A large majority of cases (81%) were infected by parasites genetically linked to one or more other cases. We identified five genetically distinct clusters in forest fringe villages within the Pathoomphone district, characterized by a high degree of genetic relatedness between parasites (mean= 0.8). Four smaller clusters of 2-3 cases linked Moonlapamok and Pathoomphone districts, with an averageof 0.6, suggesting cross-district transmission. Most of the clustered cases occurred within 20 km and 2 months of each other, consistent with focal transmission. Transmission clusters identified in this study confirm the role of ongoing focal parasite transmission occurring within the forest or forest-fringe in the highly mobile population.Author summaryIn low-transmission settings, integrating genomic data could help capture fine-scale dynamics in circulating parasites that may not be easily detected by traditional surveillance. Our work demonstrates that even with very few malaria cases, incorporating active surveillance and genomic analysis can help track residual transmission pockets and routes, including among highly mobile populations whose infection sources are historically difficult to trace. Transmission clusters identified in this study provided clear evidence of ongoing focal transmission ofPlasmodium falciparumin southern Laos. The addition of high-resolution genomic data to active surveillance can aid in targeting and assessing interventions in similar areas approaching elimination.