bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of Tokenization on Transformers for Biological Sequences
Authors: Dotan Edo , Jaschek Gal , Pupko Tal , Belinkov Yonatan 
Published: August 2023

AbstractDeep learning models are transforming biological research. Many bioinformatics and comparative genomics algorithms analyze genomic data, either DNA or protein sequences. Examples include sequence alignments, phylogenetic tree inference and automatic classification of protein functions. Among these deep learning algorithms, models for processing natural languages, developed in the natural language processing (NLP) community, were recently applied to biological sequences. However, biological sequences are different than natural languages, such as English, and French, in which segmentation of the text to separate words is relatively straightforward. Moreover, biological sequences are characterized by extremely long sentences, which hamper their processing by current machine-learning models, notably the transformer architecture. In NLP, one of the first processing steps is to transform the raw text to a list of tokens. Deep-learning applications to biological sequence data mostly segment proteins and DNA to single characters. In this work, we study the effect of alternative tokenization algorithms on eight different tasks in biology, from predicting the function of proteins and their stability, through nucleotide sequence alignment, to classifying proteins to specific families. We demonstrate that applying alternative tokenization algorithms can increase accuracy and at the same time, substantially reduce the input length compared to the trivial tokenizer in which each character is a token. Furthermore, applying these tokenization algorithms allows interpreting trained models, taking into account dependencies among positions. Finally, we trained these tokenizers on a large dataset of protein sequences containing more than 400 billion amino acids, which resulted in over a three-fold decrease in the number of tokens. We then tested these tokenizers trained on large-scale data on the above specific tasks and showed that for some tasks it is highly beneficial to train database-specific tokenizers. Our study suggests that tokenizers are likely to be a critical component in future deep-network analysis of biological sequence data.
Dopamine Release Plateau and Outcome Signals in Dorsal Striatum Contrast with Classic Reinforcement Learning Formulations
Authors: Kim Min Jung , Gibson Daniel J. , Hu Dan , Mahar Ara , Schofield Cynthia J. , Sompolpong Patlapa , Yoshida Tomoko , Tran Kathy T. , Graybiel Ann M. 
Published: August 2023

AbstractWe recorded dopamine release signals in medial and lateral sectors of the striatum as mice learned consecutive visual cue-outcome conditioning tasks including cue association, cue discrimination, reversal, and probabilistic discrimination task versions. Dopamine release responses in medial and lateral sites exhibited learning-related changes within and across phases of acquisition. These were different for the medial and lateral sites. In neither sector could these be accounted for by classic reinforcement learning as applied to dopamine-containing neuron activity. Cue responses ranged from initial sharp peaks to modulated plateau responses. In the medial sector, outcome (reward) responses during cue conditioning were minimal or, initially, negative. By contrast, in lateral sites, strong, transient dopamine release responses occurred at both cue and outcome. Prolonged, plateau release responses to cues emerged in both regions when discriminative behavioral responses became required. In most sites, we found no evidence for a transition from outcome to cue signaling, a hallmark of temporal difference reinforcement learning as applied to midbrain dopamine activity. These findings delineate reshaping of dopamine release activity during learning and suggest that current views of reward prediction error encoding need review to accommodate distinct learning-related spatial and temporal patterns of striatal dopamine release in the dorsal striatum.
Estrogen regulates myogenic tone in hippocampal arterioles by enhanced basal release of nitric oxide and endothelial SKCachannel activity
Authors: Jeffrey Danielle A. , Russell Abigail , Guerrero Mayra Bueno , Fontaine Jackson T. , Romero Phinea , Rosehart Amanda C. , Dabertrand Fabrice 
Published: August 2023

AbstractArteries and arterioles exhibit myogenic tone, a partially constricted state that allows further constriction or dilation in response to moment-to-moment fluctuations in blood pressure. The vascular endothelium that lines the internal surface of all blood vessels controls a wide variety of essential functions, including the contractility of the adjacent smooth muscle cells by providing a tonic vasodilatory influence. Studies conducted on large (pial) arteries on the surface of the brain have shown that estrogen lowers myogenic tone in female mice by enhancing nitric oxide (NO) release from the endothelium, however, whether this difference extends to the intracerebral microcirculation remains ambiguous. The existing incomplete picture of sex differences in cerebrovascular physiology combined with a deficiency in treatments that fully restore cognitive function after cerebrovascular accidents places heavy emphasis on the necessity to investigate myogenic tone regulation in the microcirculation from both male and female mice. We hypothesized that sex-linked hormone regulation of myogenic tone extends its influence on the microcirculation level, and sought to characterize it in isolated arterioles from the hippocampus, a major cognitive brain area. Using diameter measurements bothin vivo(acute cranial window vascular diameter) andex vivo(pressure myography experiments), we measured lower myogenic tone responses in hippocampal arterioles from female than male mice. By using a combined surgical and pharmacological approach, we found myogenic tone in ovariectomized (OVX) female mice matches that of males, as well as in endothelium-denuded arterioles. Interestingly, eNOS inhibition induced a larger constriction in female arterioles but only partially abolished the difference in tone. We identified that the remnant difference was mediated by a higher activity and expression of the small-conductance Ca2+-sensitive K+(SK) channels. Collectively, these data indicate that eNOS and SK channels exert greater vasodilatory influence over myogenic tone in female mice at physiological pressures.
Engineered 3D Immuno-Glial-Neurovascular Human miBrain Model
Authors: Stanton Alice E. , Bubnys Adele , Agbas Emre , James Benjamin , Park Dong Shin , Jiang Alan , Pinals Rebecca L. , Liu Liwang , Truong Nhat , Loon Anjanet , Staab Colin , Cerit Oyku , Wen Hsin-Lan , Kellis Manolis , Blanchard Joel W. , Langer Robert , Tsai Li-Huei 
Published: August 2023

AbstractPatient-specific, human-based cellular models integrating a biomimetic blood-brain barrier (BBB), immune, and myelinated neuron components are critically needed to enable accelerated, translationally relevant discovery of neurological disease mechanisms and interventions. By engineering a novel brain-mimicking 3D hydrogel and co-culturing all six major brain cell types derived from patient iPSCs, we have constructed, characterized, and utilized a multicellular integrated brain (miBrain) immuno-glial-neurovascular model within vivo-like hallmarks inclusive of neuronal activity, functional connectivity, barrier function, myelin-producing oligodendrocyte engagement with neurons, multicellular interactions, and transcriptomic profiles. We implemented the model to study Alzheimer’s Disease pathologies associated withAPOE4genetic risk.APOE4miBrains differentially exhibit amyloid aggregation, tau phosphorylation, and astrocytic GFAP. Unlike the co-emergent fate specification of glia and neurons in organoids, miBrains integrate independently differentiated cell types, a feature we harnessed to identify thatAPOE4in astrocytes promotes neuronal tau pathogenesis and dysregulation through crosstalk with microglia.
The apparent loss of PRC2 chromatin occupancy as an artefact of RNA depletion
Authors: Healy Evan , Zhang Qi , Gail Emma H. , Agius Samuel C. , Sun Guizhi , Bullen Michael , Pandey Varun , Das Partha Pratim , Polo Jose M. , Davidovich Chen 
Published: August 2023

AbstractRNA has been implicated in the recruitment of chromatin modifiers, and previous studies have provided evidence in favour and against this idea. RNase treatment of chromatin is a prevalent tool for the study of RNA-mediated regulation of chromatin modifiers, but the limitations of this approach remain unclear. RNase A treatment during chromatin immunoprecipitation (RNase-ChIP or rChIP) reduces chromatin occupancy of the H3K27me3 methyltransferase PRC2. This led to suggestions of an “RNA bridge” between PRC2 and chromatin. Here we show that RNase A treatment during chromatin immunoprecipitation leads to the apparent loss of all facultative heterochromatin, including both PRC2 and H3K27me3 genome wide. This phenomenon persists in mouse embryonic stem cells, human cancer cells and human-induced pluripotent stem cells. We track this observation to a gain of DNA from non-targeted chromatin, sequenced at the expense of DNA from facultative heterochromatin, which reduces ChIP signals. Our results point to substantial limitations in using RNase A treatment for mapping RNA-dependent chromatin occupancy and invalidate conclusions that were previously established for PRC2 based on this assay.HighlightsRNA degradation during ChIP-seq is insufficient to displace PRC2 from chromatin.RNA degradation led to the artificial depletion of ChIP-seq signals in multiple cell lines.Artificially reduced ChIP-seq signals are explained by a gain of non-targeted DNA.RNA is critical in maintaining the solubility of chromatin during experimentation.
Distinct clades of TELOMERE REPEAT BINDING transcriptional regulators interplay to regulate plant development
Authors: Amiard Simon , Feit Léa , Simon Lauriane , Goff Samuel Le , Loizeau Loriane , Wolff Léa , Butter Falk , Bourbousse Clara , Barneche Fredy , Tatout Christophe , Probst Aline. V. 
Published: August 2023

AbstractTELOMERE REPEAT BINDING proteins (TRBs) are plant-specific transcriptional regulators that combine two DNA-binding domains, the GH1 domain shared with H1 histones that binds to linker DNA and the Myb/SANT domain that specifically recognizes the telobox DNA binding site motif. TRB1, TRB2 and TRB3 proteins recruit the Polycomb group complex 2 (PRC2) to deposit H3K27me3 and JMJ14 to remove H3K4me3 at target genes containing telobox motifs in their promoters to repress transcription. Here, we characterize the function of TRB4 and TRB5, which belong to a separate TRB clade conserved in spermatophytes. TRB4 and TRB5 affect the transcriptional control of several hundred genes involved in developmental responses to environmental cues, the majority of which differ from differentially regulated genes intrb1 trb2 trb3,suggesting distinct modes of action at the chromatin level. Indeed, TRB4 binds to several thousand sites in the genome, mainly at TSS and promoter regions of transcriptionally active and H3K4me3-marked genes but is not enriched at H3K27me3-marked gene bodies. TRB4 physically interacts with the PRC2 component CURLY LEAF (CLF), but, unexpectedly, loss of TRB4 and TRB5 partially suppresses the developmental defects ofclfmutant plants, by acting as transcriptional activators of the key flowering genesSOC1andFT.We further show that TRB4 and TRB1 share multiple target genes and reveal physical and genetic interactions between TRBs of the two distinct clades, collectively unveiling that TRB proteins engage in both positive and negative interactions with other members of the family to regulate plant development through PRC2-dependent and independent mechanisms.
Highly multiplexed mRNA quantitation with CRISPR-Cas13
Authors: Kang Brian , Zhang Jiayu , Schwoerer Michael P. , Nelson Amy N. , Schoeman Emily , Guo Andrew , Ploss Alexander , Myhrvold Cameron 
Published: August 2023

AbstractRNA quantitation tools are often either high-throughput or cost-effective, but rarely are they both. Existing methods can profile the transcriptome at great expense or are limited to quantifying a handful of genes by labor constraints. A technique that permits more throughput at a reduced cost could enable multi-gene kinetic studies, gene regulatory network analysis, and combinatorial genetic screens. Here, we introducequantitativeCombinatorialArrayedReactions forMultiplexedEvaluation ofNucleic acids (qCARMEN): an RNA quantitation technique which leverages the programmable RNA-targeting capabilities of CRISPR-Cas13 to address this challenge by quantifying over 4,500 gene-sample pairs in a single experiment. Using qCARMEN, we studied the response profiles of interferon-stimulated genes (ISGs) during interferon (IFN) stimulation and flavivirus infection. Additionally, we observed isoform switching kinetics during epithelial-mesenchymal transition. qCARMEN is a simple and inexpensive technique that greatly enhances the scalability of RNA quantitation for novel applications with performance similar to gold-standard methods.
Detecting altered hepatic lipid oxidation by MRI in an animal model of NAFLD
Authors: McLeod Marc , Ragavan Mukundan , Chang Mario , Mahar Rohit , Giacalone Anthony , Rushin Anna , Glanz Max , Malut Vinay , Graham Dalton , Sunny Nishanth E. , Merritt Matthew E. 
Published: August 2023

AbstractNonalcoholic fatty liver disease (NAFLD) prevalence is increasing annually and affects over a third of U.S. adults. NAFLD can progress to nonalcoholic steatohepatitis (NASH), characterized by severe inflammation and fibrosis. NASH is predicted to become the primary cause of liver transplant by 2030. Although the etiology of NAFLD/NASH is incompletely understood, dysregulated fatty acid oxidation is implicated in disease pathogenesis. Here, we developed a method for estimating hepatic β-oxidation from the metabolism of [D15]octanoate to deuterated water and detection with deuterium magnetic resonance methods. Application of this method to perfused liver from a mouse model of NAFLD revealed dysregulated hepatic β-oxidation, findings that we confirmed within vivoimaging. The high-fat diet–induced NAFLD mouse studies indicated that decreased β-oxidative efficiency in the fatty liver could serve as a prognostic indicator of NAFLD progression. Furthermore, our method provides a clinically translatable imaging approach for determining hepatic β-oxidation efficiency.
CDK activity at the centrosome regulates the cell cycle
Authors: Roberts Emma L. , Kapadia Nitin , Auchynnikava Tania , Basu Souradeep , Nurse Paul 
Published: August 2023

AbstractCyclin-dependent kinases (CDKs) complexed with cyclins drive progression through the eukaryotic cell cycle. From yeast to human cells, cyclin-CDK localises to the centrosome, but the importance of this localisation is unclear. The conserved ‘hydrophobic patch’ substrate docking site on human Cyclin B1 and on the equivalent fission yeast Cdc13 mediates their localisation to the centrosome and the spindle-pole body (SPB, yeast centrosome equivalent). A hydrophobic patch mutant (HPM) of Cdc13 cannot enter mitosis, but whether this mitotic defect is due to defective SPB localisation or defective cyclin-substrate docking is unknown. Here we show that artificially restoring Cdc13HPMSPB localisation in fission yeast partially rescues both mitosis and defective CDK substrate phosphorylation at both the SPB and within the cytoplasm. In addition, we found that an HPM of the S-phase cyclin Cig2 has defective SPB localisation but is still able to perform bulk DNA synthesis. Our results demonstrate that the hydrophobic patch mediates the SPB localisation of both S- and M-phase cyclins, and that Cdc13 SPB localisation is essential for mitotic entry and for full phosphorylation of CDK substrates, supporting the view that the centrosome plays a role as a signalling hub regulating CDK cell cycle control.
Long-term combination therapy with Metformin and Oxymetholone in a Fanconi Anemia mouse model
Authors: Dorrell Craig , Peters Alexander M , Zhang Qingshuo , Balaji Niveditha , Baradar Kevin , Mochizuki-Kashio Makiko , Major Angela , Finegold Milton , Liu Chih-Wei , Lu Kun , Grompe Markus 
Published: August 2023

AbstractFanconi Anemia (FA) is a disease caused by defective DNA repair which manifests as bone marrow failure, cancer predisposition, and developmental defects. Mice containing inactivating mutations in one or more genes in the FA pathway partially mimic the human disease. We previously reported that monotherapy with either metformin (MET) or oxymetholone (OXM) improved peripheral blood (PB) counts and the number and functionality of bone marrow (BM) hematopoietic stem progenitor cells (HSPCs) number inFancd2-/-mice. To evaluate whether the combination treatment of these drugs has a synergistic effect to prevent bone marrow failure in FA, we treated cohorts ofFancd2-/-mice and wild-type controls with either MET alone, OXM alone, MET+OXM or placebo diet. Both male and female mice were treated from age 3 weeks to 18 months. The OXM treated animals showed modest improvements in blood parameters including platelet count (p=0.01) and hemoglobin levels (p<0.05). In addition, the percentage of quiescent HSC (LSK) was significantly increased (p=0.001) by long-term treatment with MET alone. However, the absolute number of progenitors, measured by LSK frequency or CFU-S, was not significantly altered by MET therapy. The combination of metformin and oxymetholone did not result in a significant synergistic effect on any parameter. Male animals on MET+OXM or MET alone were significantly leaner than controls at 18 months, regardless of genotype. Gene expression analysis of liver tissue from these animals showed that some of the expression changes caused byFancd2deletion were partially normalized by metformin treatment. Importantly, no adverse effects of the individual or combination therapies were observed, despite the long-term administration.Highlights-Long-term coadministration of metformin in combination oxymetholone is well tolerated byFancd2-/-mice.-HSC quiescence in mutant mice was enhanced by treatment with metformin alone.-Metformin treatment caused a partial normalization of gene expression in the livers of mutant mice.
DifferentialRegulation: a Bayesian hierarchical approach to identify differentially regulated genes
Authors: Tiberi Simone , Meili Joël , Cai Peiying , Soneson Charlotte , He Dongze , Sarkar Hirak , Avalos-Pacheco Alejandra , Patro Rob , Robinson Mark D 
Published: August 2023

SummaryMotivationAlthough transcriptomics data is typically used to analyse mature spliced mRNA, recent attention has focused on jointly investigating spliced and unspliced (or precursor-) mRNA, which can be used to study gene regulation and changes in gene expression production. Nonetheless, most methods for spliced/unspliced inference (such as RNA velocity tools) focus on individual samples, and rarely allow comparisons between groups of samples (e.g., healthyvs. diseased). Furthermore, this kind of inference is challenging, because spliced and unspliced mRNA abundance is characterized by a high degree of quantification uncertainty, due to the prevalence of multi-mapping reads, i.e., reads compatible with multiple transcripts (or genes), and/or with both their spliced and unspliced versions.ResultsHere, we presentDifferentialRegulation, a Bayesian hierarchical method to discover changes between experimental conditions with respect to the relative abundance of unspliced mRNA (over the total mRNA). We model the quantification uncertainty via a latent variable approach, where reads are allocated to their gene/transcript of origin, and to the respective splice version. We designed several benchmarks where our approach shows good performance, in terms of sensitivity and error control, versus state-of-the-art competitors. Importantly, our tool is flexible, and works with both bulk and single-cell RNA-sequencing data.Availability and implementationDifferentialRegulationis distributed as a Bioconductor R package.
Childhood experience of being forced to eat: focussing on its association with vegetable consumption among young adults
Authors: Kim So-young 
Published: August 2023

PurposeThis study aimed to explore the association of childhood experience of being forced to eat – where a particular person forced a child to eat a specific food item against one's will – on food consumption, especially vegetables later in young adulthood.Design/methodology/approachAn online questionnaire survey was conducted from 19 to 24 February 2020 with 1,277 young Korean adults in their 20s. A total of 1,226 eligible responses were obtained, wherein 410 (33.4%) responses with forced-eating experiences in childhood were collected. To answer the survey questionnaire, the respondents were asked to recall one of the most memorable forced-eating episodes.FindingsThe results showed that forced-eating occurred mostly among lower grades or pre-schoolers, at home or in schools/childcare facilities, and by parents or homeroom teachers. Vegetables were the most common target food for forced-eating. The Forced-Eating-Experienced group with vegetables as the target food tended to have significantly lower preference for and acceptance of vegetables. Furthermore, among this group, those who had displayed unpleasant post-ingestion physical symptoms after forced-eating or refused to eat the target vegetables at all despite forced-eating, showed significantly lower acceptance of vegetables. Additionally, they were also less likely to eat the target vegetable at present, but more likely to agree that their current dietary habits were affected by their childhood experiences of forced-eating.Originality/valueThe study attempted to fill the knowledge gap on the association of negative childhood experiences of forced-eating with food consumption, especially vegetables, later in young adulthood.
Identifying factors determining the quality of mango: a design of experiments assessment
Authors: J. Krishna Manasvi , Matai Rajesh , Murthy Nagesh N. 
Published: August 2023

PurposeDue to the recent disruptions caused by COVID-19, global supply chains are stress tested. The affected supply chains have interfered with market tonnage prices for the yield of perishable products like mangoes that are highly dependent on their quality. This research, through empirical findings, thus determines and comprehends the factors influencing mango quality (size).Design/methodology/approachA framework is developed for finding the potential factors of quality building on the previous literature and studies on the available topic. The data collection included face-to-face interviews comprising 240 farmers, hired managers and preharvest contractors in India's Jangaon, Rangareddy and Yadadri Bhuvanagiri districts of Telangana state. The data analysis is done using multiple regression, and the outcomes form the basis of the design of the experiments model.FindingsThe empirical insights support that the quality of mango is affected by factors such as the number of picking cycles, the cost of fertilizer, the variety of fertilizers used, the variety of pesticides used and pesticide application frequency. The direct implications are the benefit to farmers in improving mango quality and maximizing profit per yield cycle.Research limitations/implicationsTo the best of the authors’ knowledge, the first research that has specifically focused on holistically improving the quality(size) of mangoes.Originality/valueThe findings contribute to the perishable supply chain literature, specifically to the mango study, to comprehensively showcase the factors impacting the quality of mangoes and provide guidance to farmers regarding orchard practices.