bluuebunny/crossref_metadata_2025_split huggingface dataset:
Large Scale Foundation Model on Single-cell Transcriptomics
Authors: Hao Minsheng , Gong Jing , Zeng Xin , Liu Chiming , Guo Yucheng , Cheng Xingyi , Wang Taifeng , Ma Jianzhu , Song Le , Zhang Xuegong 
Published: May 2023

AbstractLarge-scale pretrained models have become foundation models leading to breakthroughs in natural language processing and related fields. Developing foundation models in life science for deciphering the “languages” of cells and facilitating biomedical research is promising yet challenging. We developed a large-scale pretrained model scFoundation with 100M parameters for this purpose. scFoundation was trained on over 50 million human single-cell transcriptomics data, which contain high-throughput observations on the complex molecular features in all known types of cells. scFoundation is currently the largest model in terms of the size of trainable parameters, dimensionality of genes and the number of cells used in the pre-training. Experiments showed that scFoundation can serve as a foundation model for single-cell transcriptomics and achieve state-of-the-art performances in a diverse array of downstream tasks, such as gene expression enhancement, tissue drug response prediction, single-cell drug response classification, and single-cell perturbation prediction.
Common evolutionary origins of the bacterial glycyl tRNA synthetase and alanyl tRNA synthetase
Authors: Alvarez-Carreño Claudia , Arciniega Marcelino , Ribas de Pouplana Lluis , Petrov Anton S. , Hernández-González Adriana , Valencia-Sánchez Marco Igor , Williams Loren Dean , Torres-Larios Alfredo 
Published: May 2023

AbstractAminoacyl-tRNA synthetases (aaRSs) establish the genetic code. Each aaRS covalently links a given canonical amino acid to a cognate set of tRNA isoacceptors. Glycyl tRNA aminoacylation is unusual in that it is catalyzed by different aaRSs in different lineages of the Tree of Life. We have investigated the phylogenetic distribution and evolutionary history of bacterial glycyl tRNA synthetase (bacGlyRS). This enzyme is found in early diverging bacterial phyla such as Firmicutes, Acidobacteria, and Proteobacteria, but not in archaea or eukarya. We observe relationships between each of six domains of bacGlyRS and six domains of four different RNA-modifying proteins. Component domains of bacGlyRS show common ancestry with i) the catalytic domain of class II tRNA synthetases; ii) the HD domain of the bacterial RNase Y; iii) the body and tail domains of the archaeal CCA-adding enzyme; iv) the anti-codon binding domain of the arginyl tRNA synthetase; and v) a previously unrecognized domain that we call ATL (Ancient tRNA latch). The ATL domain is found only in bacGlyRS and in the universal alanyl tRNA synthetase (uniAlaRS). Further, the catalytic domain of bacGlyRS is more closely related to the catalytic domain of uniAlaRS than to any other aminoacyl tRNA synthetase. The combined data suggest that the ATL and catalytic domains of these two enzymes are ancestral to bacGlyRS and uniAlaRS, which emerged from common protein ancestors by bricolage, stepwise accumulation of protein domains, before the last universal common ancestor of life.
Arpin deficiency increases actomyosin contractility and vascular permeability
Authors: Montoya-García Armando , Guerrero-Fonseca Idaira M. , Chánez-Paredes Sandra D. , Hernández-Almaraz Karina B. , León-Vega Iliana I. , Silva-Olivares Angélica , Bentazos Abigail , Mondragón-Castelán Mónica , Mondragón-Flores Ricardo , Salinas-Lara Citlaltepetl , Vargas-Robles Hilda , Schnoor Michael 
Published: May 2023

ABSTRACTArpin was discovered as an inhibitor of the Arp2/3 complex localized at the lamellipodial tip of fibroblasts, where it regulated migration steering. Recently, we showed that arpin stabilizes the epithelial barrier in an Arp2/3-dependent manner. However, expression and functions of arpin in endothelial cells (EC) have not yet been described. Arpin mRNA and protein are expressed in EC and downregulated by pro-inflammatory cytokines. Arpin depletion in HUVEC causes the formation of actomyosin stress fibers leading to increased permeability in an Arp2/3-independent manner. Instead, inhibitors of ROCK1 and ZIPK, kinases involved in the generation of stress fibers, normalize the loss-of-arpin effects on actin filaments and permeability. Arpin-deficient mice are viable but show a characteristic vascular phenotype in the lung including edema, microhemorrhage and vascular congestion, increased F-actin levels and vascular permeability. Our data show that, apart from being an Arp2/3 inhibitor, arpin is also a regulator of actomyosin contractility and endothelial barrier integrity.SUMMARYThe expression and functions of arpin in endothelial cells are unknown. We show that arpin controls actomyosin contractility and endothelial barrier integrity in an Arp2/3-independent manner via ROCK1/ZIPK. Arpin-deficient mice are viable, but also show increased basal and induced vascular permeability.
A dual hit of α-synuclein internalization and immune challenge leads to the formation and maintenance of Lewy body-like inclusions in human dopaminergic neurons
Authors: Bayati Armin , Ayoubi Riham , Aguila Adriana , Zorca Cornelia E. , Han Chanshuai , Banks Emily , Nguyen-Renou Emmanuelle , Luo Wen , Shlaifer Irina , Del Cid-Pellitero Esther , Yaqubi Moein , Fon Edward A. , Stratton Jo Anne , Durcan Thomas M. , Nahirney Patrick C. , McPherson Peter S. 
Published: May 2023

SUMMARYLewy bodies (LBs), rich in α-synuclein, are a hallmark of Parkinson’s disease (PD). Understanding their biogenesis is likely to provide insight into the pathophysiology of PD, yet a cellular model for LB formation remains elusive. The realization that the immune challenge is a trigger for neurodegenerative diseases has been a breakthrough in the understanding of PD. Here, iPSC-derived human dopaminergic (DA) neurons from multiple healthy donors were found to form LB-like inclusions following treatment with α- synuclein preformed fibrils, but only when coupled to an immune challenge (interferon-gamma or interleukin-1 beta) or when co-cultured with activated microglia. Human cortical neurons derived from the same iPSC lines did not form LB-like inclusions. Exposure to interferon-gamma impairs autophagy in a lysosomal-specific mannerin vitro,similar to the disruption of proteostasis pathways that contribute to PD. We find that lysosomal membrane proteins LAMP1 and LAMP2 and transcription factors regulating lysosomal biogenesis and function are downregulated in DA but not cortical neurons. Finally, due to the excellent sample preservation afforded by cells compared to post-mortem PD brain tissue, we conclude that the LB-like inclusions in DA neurons are membrane-bound, suggesting they are not limited to the cytoplasmic compartment.In BriefBayati et al. identify that iPSC-derived dopaminergic neurons undergoing a dual hit treatment of exogenous α-synuclein fibrils and proinflammatory cytokines form Lewy body-like inclusions. The dual hit treatment also led to the downregulation of lysosomal proteins. Characterization of inclusions revealed that inclusions were membrane-bound and LC3B-positive, suggesting they are dysfunctional autophagosomes.Highlightsα-synuclein preformed fibril administration coupled with Interferon-gamma exposure leads dopaminergic neurons to form Lewy body-like inclusionsInclusions are filamentous, membranous, and filled with aberrant organellesImpaired autophagic flux and downregulation of TFEB, NRF2, LAMP1, and LAMP2 correlated with inclusion formationActivation of NRF2 through the treatment of neurons with the antioxidant perillaldehyde, prevents inclusion formation
A comprehensive workflow for target adaptive sampling long-read sequencing applied to hereditary cancer patient genomes
Authors: Nakamura Wataru , Hirata Makoto , Oda Satoyo , Chiba Kenichi , Okada Ai , Mateos Raúl Nicolás , Sugawa Masahiro , Iida Naoko , Ushiama Mineko , Tanabe Noriko , Sakamoto Hiromi , Kawai Yosuke , Tokunaga Katsushi ,   NCBN Controls WGS Consortium, Tsujimoto Shinichi , Shiba Norio , Ito Shuichi , Yoshida Teruhiko , Shiraishi Yuichi 
Published: June 2023

AbstractInnovations in sequencing technology have led to the discovery of novel mutations that cause inherited diseases. However, many patients with suspected genetic diseases remain undiagnosed. Long-read sequencing technologies are expected to significantly improve the diagnostic rate by overcoming the limitations of short-read sequencing. In addition, Oxford Nanopore Technologies (ONT) offers a computationally-driven target enrichment technology, adaptive sampling, which enables intensive analysis of targeted gene regions at low cost. In this study, we developed an efficient computational workflow for target adaptive sampling long-read sequencing (TAS-LRS) and evaluated it through application to 33 genomes collected from suspected hereditary cancer patients. Our workflow can identify single nucleotide variants with nearly the same accuracy as the short-read platform and elucidate complex forms of structural variations. We also newly identified SVAs affecting theAPCgene in two patients with familial adenomatous polyposis, as well as their sites of origin. In addition, we demonstrated that off-target reads from adaptive sampling, which are typically discarded, can be effectively used to accurately genotype common SNPs across the entire genome, enabling the calculation of a polygenic risk score. Furthermore, we identified allele-specificMLH1promoter hypermethylation in a Lynch syndrome patient. In summary, our workflow with TAS-LRS can simultaneously capture monogenic risk variants including complex structural variations, polygenic background as well as epigenetic alterations, and will be an efficient platform for genetic disease research and diagnosis.
Reducing the equity gap in under-5 mortality through an innovative community health program in Ethiopia: An implementation research study
Authors: Drown Laura , Amberbir Alemayehu , Teklu Alula M. , Zelalem Meseret , Tariku Abreham , Tadesse Yared , Gebeyehu Solomon , Semu Yirdachew , Ntawukuriryayo Jovial Thomas , VanderZanden Amelia , Binagwaho Agnes , Hirschhorn Lisa R. 
Published: May 2023

AbstractBackgroundThe Ethiopian government implemented a national community health program, the Health Extension Program (HEP), to provide community-based health services to address persisting access-related barriers to care using health extension workers (HEWs). We used implementation research to understand how Ethiopia leveraged the HEP to widely implement evidence-based interventions (EBIs) known to reduce under-5 mortality (U5M) and address health inequities.MethodsThis study was part of a six-country case study series using implementation research to understand how countries implemented EBIs between 2000-2015. Our mixed-methods research was informed by a hybrid implementation science framework using desk review of published and gray literature, analysis of existing data sources, and 11 key informant interviews. We used implementation of pneumococcal conjugate vaccine (PCV-10) and integrated community case management (iCCM) to illustrate Ethiopia’s ability to rapidly integrate interventions into existing systems at a national level through leveraging the HEP and other implementation strategies and contextual factors which influenced implementation outcomes.ResultsEthiopia implemented numerous EBIs known to address leading causes of U5M, leveraging the HEP as a platform for delivery to successfully introduce and scale new EBIs nationally. By 2014/15, estimated coverage of three doses of PCV-10 was at 76%, with high acceptability (nearly 100%) of vaccines in the community. Between 2000 and 2015, we found evidence of improved care-seeking; coverage of oral rehydration solution for treatment of diarrhea, a service included in iCCM, doubled over this period.HEWs made health services more accessible to rural and pastoralist communities, which account for over 80% of the population, with previously low access, a contextual factor that had been a barrier to high coverage of interventions.ConclusionsLeveraging the HEP as a platform for service delivery allowed Ethiopia to successfully introduce and scale existing and new EBIs nationally, improving feasibility and reach of introduction and scale-up of interventions. Additional efforts are required to reduce the equity gap in coverage of EBIs including PCV-10 and iCCM among pastoralist and rural communities. As other countries continue to work towards reducing U5M, Ethiopia’s experience provides important lessons in effectively delivering key EBIs in the presence of challenging contextual factors.
Analytical validation of HepatoPredict kit to assess hepatocellular carcinoma prognosis prior to a liver transplantation
Authors: Gonçalves-Reis Maria , Proença Daniela , Frazão Laura P. , Neto João L. , Silva Sílvia , Pinto-Marques Hugo , Pereira-Lea José B. , Cardoso Joana 
Published: June 2023

AbstractBackgroundThe best curative treatment for hepatocellular carcinoma (HCC) is liver transplant (LT), but the limited number of organs available for LT dictates strict eligibility criteria. Despite this patient selection stringency, current criteria often fail in pinpointing patients at risk of HCC relapse and in identifying good prognosis patients that could benefit from a LT. HepatoPredict kit was developed and clinically validated to forecast the benefit of LT in patients diagnosed with HCC. By combining clinical variables and a gene expression signature in an ensemble of machine learning algorithms, HepatoPredict stratifies HCC patients according to their risk of relapse after LT.MethodsAiming at the characterization of the analytical performance of HepatoPredict kit in terms of sensitivity, specificity and robustness, several variables were tested which included reproducibility between operators and between RNA extractions and RT-qPCR runs, interference of input RNA levels or varying reagent levels. The described methodologies, included in the HepatoPredict kit, were tested according to analytical validation criteria of multi-target genomic assays described in guidelines such as ISO201395-2019, MIQE, CLSI-MM16, CLSI-MM17, and CLSI-EP17-A. Furthermore, a new retrained version of the HepatoPredict algorithms is also presented and tested.ResultsThe results of the analytical performance demonstrated that the HepatoPredict kit performed within the required levels of robustness (p> 0.05), analytical specificity (inclusivity ≥ 95 %), and sensitivity (LoB, LoD, linear range, and amplification efficiency between 90 – 110 %). The introduced operator, equipment, input RNA and reagents into the assay had no significant impact on HepatoPredict classifier results. As demonstrated in a previous clinical validation, a new retrained version of the HepatoPredict algorithm still outperformed current clinical criteria, in the accurate identification of HCC patients that more likely will benefit from a LT.ConclusionsDespite the variations in the molecular and clinical variables, the prognostic information obtained with HepatoPredict kit and does not change and can accurately identify HCC patients more likely to benefit from a LT. HepatoPredict performance robustness also validates its easy integration into standard diagnostic laboratories.
STAREG: an empirical Bayesian approach to detect replicable spatially variable genes in spatial transcriptomic studies
Authors: Li Yan , Zhou Xiang , Chen Rui , Zhang Xianyang , Cao Hongyuan 
Published: May 2023

AbstractIdentifying replicable genes that display spatial expression patterns from different yet related spatially resolved transcriptomic studies provides stronger scientific evidence and more powerful inference. We present an empirical Bayesian method, STAREG, for identifying replicable spatially variable genes in data generated from various spatially resolved transcriptomic techniques. STAREG models the joint distribution ofp-values from different studies with a mixture model and accounts for the heterogeneity of different studies. It provides effective control of the false discovery rate and has higher power by borrowing information across genes and different studies. Moreover, it provides different rankings of important spatially variable genes. With the EM algorithm in combination with pool-adjacent-violator-algorithm (PAVA), STAREG is scalable to datasets with tens of thousands of genes measured on tens of thousands of spatial spots without any tuning parameters. Analyzing three pairs of spatially resolved transcriptomic datasets using STAREG, we show that it makes biological discoveries that otherwise cannot be obtained by using existing methods.
Non-invasive vagus nerve stimulation decreases vagally mediated heart rate variability
Authors: Kaduk Kristin , Petrella Alessandro , Müller Sophie J. , Koenig Julian , Kroemer Nils B. 
Published: May 2023

AbstractThe vagus nerve plays a critical role in balancing the body’s physiological functions, including the cardiovascular system. Measures of heart rate (HR) and its variability (HRV) may provide non-invasive proxies of vagal activity in humans, but transcutaneous auricular vagus nerve stimulation (taVNS) has produced mixed effects so far—limited by a lack of studies stimulating the right branch. Here, we used a randomized cross-over design to study the effects of taVNS on HR and HRV. To estimate how the side of the stimulation (left vs. right ear) affects cardiovascular function, we recorded an electrocardiogram in four sessions per person (factors: Stimulation × Side). To evaluate potential interactions with physiological states, we investigated three phases per session: baseline, during stimulation (taVNS vs. sham), and after consuming a milkshake (∼400 kcal) with concurrent stimulation. First, we found moderate evidence against an effect of taVNS on HR (BF10=0.21). Second, taVNS decreased HRV (multivariatep=.004) independent of physiological state with strong evidence for RMSSD (BF10=15.11) and HF-HRV (BF10=11.80). Third, taVNS-induced changes were comparable across sides and more strongly correlated (vs. sham), indicating similar cardiovascular effects independent of the stimulation side. We conclude that taVNS reduces HRV without altering HR, contradicting the common assumption that increased HRV indexes a heightened vagal tone. Instead, our results support a putative role of vagal afferent activation in arousal. Crucially, modulatory effects on the cardiovascular system can be safely elicited by taVNS on both sides, opening new options for treatment.Graphical AbstractCreated withBioRender.com
New strategy for bioplastic and exopolysaccharides production: Enrichment of field microbiomes with cyanobacteria
Authors: Altamira-Algarra Beatriz , Rueda Estel , Lage Artai , San León David , Martínez-Blanch Juan F. , Nogales Juan , García Joan , Gonzalez-Flo Eva 
Published: May 2023

AbstractSeven photosynthethic microbiomes were collected from field environmental samples to test their potential in polyhydroxybutirate (PHB) and exopolysaccharides (EPS) production, two alternatives to chemical-based polymers. Microscope observations together with microbial sequence analysis revealed the microbiome enrichment in cyanobacteria after culture growth under phosphorus limitation. PHB and EPS production were studied under three culture factors (phototrophy, mixotrophy and heterotrophy) by evaluating and optimizing the effect of three parameters (organic and inorganic carbon and days under light:dark cycles) by Box-Behnken design. Results showed that optimal conditions for both biopolymers synthesis were microbiome-dependent; however, the addition of organic carbon boosted PHB production in all the tested microbiomes, producing up to 14%dcwPHB with the addition of 1.2 g acetate·L-1and seven days under light:dark photoperiods. The highest EPS production was 59 mg·L-1with the addition of 1.2 g acetate·L-1and four days under light:dark photoperiods. The methodology used in this article is suitable for enriching microbiomes in cyanobacteria, and for testing the best conditions for bioproducts synthesis for further scale up.
Multisensory integration enhances audiovisual responses in the Mauthner cell
Authors: Otero-Coronel Santiago , Preuss Thomas , Medan Violeta 
Published: May 2023

ABSTRACTMultisensory integration combines information from multiple sensory modalities to create a coherent perception of the world. In contexts where sensory information is limited or equivocal, it also allows animals to integrate individually ambiguous stimuli into a clearer or more accurate percept and, thus, react with a more adaptive behavioral response. Although responses to multisensory stimuli have been described at the neuronal and behavioral levels, a causal or direct link between these two is still missing. In this study, we studied the integration of audiovisual inputs in the Mauthner cell, a command neuron necessary and sufficient to trigger a stereotypical escape response in fish. We performed intracellular recordings in adult goldfish while presenting a diverse range of stimuli to determine which stimulus properties affect their integration. Our results show that stimulus modality, intensity, temporal structure, and interstimulus delay affect input summation. Mechanistically, we found that the distinct decay dynamics of feedforward inhibition triggered by auditory and visual stimuli can account for certain aspects of input integration. Altogether, this is a rare example of the characterization of multisensory integration in a cell with clear behavioral relevance, providing both phenomenological and mechanistic insights into how multisensory integration depends on stimulus properties.
Melanin found in wheat spike husks
Authors: Bazhenov Mikhail S. , Litvinov Dmitry Y. , Divashuk Mikhail G. 
Published: May 2023

AbstractMelanin is the dark polymer pigment found in all kingdoms of life. Plant melanin, formed through the oxidation and polymerization of phenolic compounds, does not contain nitrogen, however it possesses similar properties with melanin of animal, fungal or bacterial origin. Melanin in plants is usually found in seed coats or fruit pericarp and is ascribed mechanical barrier or some other protective functions. Wild and formerly locally cultivated wheat species, like Persian wheat (Triticum carthlicumNevski) frequently exhibit black color of spike husks and awns. The pigment causing it and the biological purpose of this coloration was not clarified before. In this paper using standard chemical extraction procedures for anthocyanins and melanin, ultraviolet-visible-near-infrared spectroscopy and hyperspectral imaging, we prove that the black color of Persian wheat spikes is caused by melanin but not anthocyanins. Also, we show that the dark pigment in husks and awns is located in epiderma and subepidermal sclerenchyma cells, that implies melanin potentially to have mechanical-enhancing and protection function. Other possible functions of melanin in cereals are discussed.