bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bridging Transcriptome Regulation and Cellular Operational Efficiency with the Locality and Caching System Optimization Principles
Authors: Jiang Wen , Feliers Denis , Zheng W. Jim , Zhang Fangyuan , Wang Degeng 
Published: January 2022

AbstractGene expression is time-consuming and sequentially more so from bacteria to yeast to human, rendering human cells vulnerable to proteomic-response and operational latency. Computers once suffered such latency, imposed by much-slower information retrieval (hard-drive (HD) to memory to central-processing-unit (CPU)) than CPU execution. Optimization principles, namely, spatiotemporal-locality-principles that control specialized user-programs and caching that controls operating system (OS) kernel (the HD-CPU information flow channel), successfully mitigated the latency by gearing the memory towards near-future or high-priority CPU needs. We report evidence that the principles similarly act in cellular latency-mitigation via analogizing genome-mRNA-protein gene-expression to HD-memory-CPU information-retrieval, and transcriptome to memory. First, temporal-locality-principle is equivalent to mRNA stabilization-by-translation regulation and controls specialized cellular functions. Second, caching is equivalent to cytoplasmic mRNA sequestration. Highly sequestered mRNAs defy the locality-principle. In both cells and computers, caching controls the information channels; gene expression machinery and their regulators,i.e., the cellular channel (OS-kernel equivalent) that regulates arguably all cellular processes, are top sequestered mRNAs. Third, mRNA-caching contributes to the mRNA-protein expression discrepancy. Thus, locality and caching principles control specialized and core cellular functions, respectively, orchestrating transcriptome regulation and bridging it to cellular operational efficiency.
Deep Learning Based Long Term Mortality Prediction in the National Lung Screening Trial
Authors: Lu Yaozhi , Aslani Shahab , Emberton Mark , Alexander Daniel C. , Jacob Joseph 
Published: January 2022

AbstractIn this study, the long-term mortality in the National Lung Screening Trial (NLST) was investigated using a deep learning-based method. Binary classification of the non-lung-cancer mortality (i.e. cardiovascular and respiratory mortality) was performed using neural network models centered around a 3D-ResNet. The models were trained on a participant age, gender, and smoking history matched cohort. Utilising both the 3D CT scan and clinical information, the models can achieve an AUC of 0.73 which outperforms humans at cardiovascular mortality prediction. By interpreting the trained models with 3D saliency maps, we examined the features on the CT scans that correspond to the mortality signal. The saliency maps can potentially assist the clinicians’ and radiologists’ to identify regions of concern on the image that may indicate the need to adopt preventative healthcare management strategies to prolong the patients’ life expectancy.
Mosaic deletions in X-linked dystonia-parkinsonism influence repeat stability and disease onset
Authors: Trinh Joanne , Lüth Theresa , Schaake Susen , Laβ Joshua , Laabs Björn-Hergen , Schlüter Kathleen , Pozojevic Jelena , Tse Ronnie , Köenig Inke , Jamora Roland Dominic , Rosales Raymond L. , Brüggemann Norbert , Saranza Gerard , Diesta Cid Czarina E. , Kaiser Frank J. , Depienne Christel , Westenberger Ana , Klein Christine 
Published: January 2022

AbstractBackgroundWhile multiple genetic causes of movement disorders have been identified in the past decade, modifying factors of disease expression are still largely unknown for most conditions. X-linked dystonia-parkinsonism (XDP) is an inherited neurodegenerative disease caused by a SINE-VNTR-Alu (SVA)-type retrotransposon insertion that contains a hexanucleotide repeat within an intron of the TAF1 gene. To date, four putative genetic modifiers explain about 65% of variance in age at onset in XDP. However, additional genetic modifiers are conceivably at play in XDP and may include mismatches of the SVA hexanucleotide repeat motif. We aim to identify additional genetic modifiers of XDP expressivity and age at onset (AAO).MethodsThird-generation sequencing of PCR amplicons from XDP patients (n=202) was performed to assess potential repeat interruption and instability. Repeat-primed PCR and Cas9-mediated targeted enrichment were used to confirm the presence of identified repeat mismatches.ResultsAn increased frequency of deletions at the beginning of the hexanucleotide repeat (CCCTCT)n domain was found. Specifically, three deletions at positions 11, 14, and 17 of the TAF1 SVA repeat motif of somatic mosaic origins were detected in different combinations. The most common one was three deletions (1-2-3) at a median frequency 0.425 (IQR:0.42-0.43) and deletions within positions 11 and 14 (1-2-wt) at a median frequency 0.128 (IQR:0.12-0.13). The frequency of deletions at positions 11 and 14 correlated with repeat number (r=-0.48, p=9.5×10-13) and AAO (r=0.34, p=9.5×10-7). The association with AAO still stands when including other modifier genotypes (MSH3 and PMS2) in a regression model. However, the association dissipates when including repeat numbers.ConclusionWe present a novel mosaic repeat motif deletion within the hexanucleotide repeat (CCCTCT)n domain of TAF1 SVA. Our study illustrates: 1) the importance of somatic mosaic genotypes; 2) the biological plausibility of multiple modifiers (both germline and somatic) that can have additive effects on repeat instability; 3) that these variations may remain undetected without assessment of single molecules.
Patients with Alzheimer’s disease have increased cellular amyloid uptake
Authors: Zaretsky Dmitry V. , Zaretskaia Maria V. , Molkov Yaroslav I. ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: January 2022

ABSTRACTAmyloid plaques are the main signature of Alzheimer’s disease (AD). Beta-amyloid (Aβ) concentration in cerebrospinal fluid (CSF-Aβ) and the density of amyloid depositions have a strong negative correlation. However, AD patients have lower CSF-Aβ levels compared to cognitively normal people even after accounting for this correlation. The goal of this study was to infer variations of parameters in Aβ metabolism of AD patients that underlie this difference using data from the Alzheimer’s Disease Neuroimaging Initiative cohort.We found that AD patients had dramatically increased rates of cellular amyloid uptake compared to individuals with normal cognition (NC). A group with late-onset mild cognitive impairment (LMCI) also exhibited stronger amyloid uptake, however this was less pronounced than in the AD group. Estimated parameters in the early-onset MCI group did not differ significantly from those in the NC group.Aβ cytotoxicity depends on both the amount of peptide internalized by cells and its intracellular degradation into toxic products. Based on our results, we speculate that AD and LMCI are associated with increased cellular amyloid uptake which leads to faster disease progression, whereas the early-onset MCI may be mediated by the increased production of toxic amyloid metabolites.
Glucocorticoid Receptor-Regulated Enhancers Play a Central Role in the Gene Regulatory Networks Underlying Drug Addiction
Authors: Duttke Sascha H. , Montilla-Perez Patricia , Chang Max W. , Li Hairi , Chen Hao , Carrette Lieselot L. G. , de Guglielmo Giordano , George Olivier , Palmer Abraham A. , Benner Christopher , Telese Francesca 
Published: January 2022

AbstractSubstance abuse and addiction represent a significant public health problem that impacts multiple dimensions of society, including healthcare, the economy, and the workforce. In 2021, over 100,000 drug overdose deaths were reported in the US, with an alarming increase in fatalities related to opioids and psychostimulants. Understanding the fundamental gene regulatory mechanisms underlying addiction and related behaviors could facilitate more effective treatments. To explore how repeated drug exposure alters gene regulatory networks in the brain, we combined capped small (cs)RNA-seq, which accurately captures nascent-like initiating transcripts from total RNA, with Hi-C and single nuclei (sn)ATAC-seq. We profiled initiating transcripts in two addiction-related brain regions, the prefrontal cortex (PFC) and the nucleus accumbens (NAc), from rats that were never exposed to drugs or were subjected to prolonged abstinence after oxycodone or cocaine intravenous self-administration (IVSA). Interrogating over 100,000 active transcription start regions (TSRs) revealed that most TSRs had hallmarks of bonafide enhancers and highlighted the KLF/SP1, RFX, and AP1 transcription factors families as central to establishing brain-specific gene regulatory programs. Analysis of rats with addiction-like behaviors versus controls identified addiction-associated repression of transcription at regulatory enhancers recognized by nuclear receptor subfamily 3 group C (NR3C) factors, which include glucocorticoid receptors. Cell-type deconvolution analysis using snATAC-seq uncovered a potential role of glial cells in driving the gene regulatory programs associated with addiction-related phenotypes. These findings highlight the power of advanced transcriptomics methods to provide insight into how addiction perturbs gene regulatory programs in the brain.
Multimodal cues displayed by submissive rats promote prosocial choices by dominants
Authors: Gachomba Michael Joe Munyua , Esteve-Agraz Joan , Caref Kevin , Maroto Aroa Sanz , Bortolozzo-Gleich Helena , Laplagne Diego Andrés , Márquez Cristina 
Published: January 2022

SUMMARYAnimals often display prosocial behaviours, performing actions that benefit others. Although prosociality is essential for social bonding and cooperation, we still know little about how animals integrate behavioural cues from those in need to make decisions that increase their wellbeing. To address this question, we used a two-choice task where rats can provide rewards to a conspecific in the absence of self-benefit, and interrogated which conditions promote prosociality by manipulating the social context of the interacting animals. While sex or degree of familiarity did not affect prosocial choices in rats, social hierarchy revealed to be a potent modulator, with dominant decision-makers showing faster emergence and higher levels of prosocial choices towards their submissive cage-mates. Leveraging quantitative analysis of multimodal social dynamics prior to choice, we identified that pairs with dominant decision-makers exhibited more proximal interactions. Interestingly, these closer interactions were driven by submissive animals that modulated their position and movement following their dominants and whose 50kHz vocalisation rate correlated with dominants’ prosociality. Moreover, Granger causality revealed stronger bidirectional influences in pairs with dominant focals and submissive recipients, indicating increased behavioural coordination. Finally, multivariate analysis highlighted body language as the main information dominants use on a trial-by-trial basis to learn that their actions have effects on others. Our results provide a refined understanding of the behavioural dynamics that rats use for action-selection upon perception of socially relevant cues and navigate social decision-making.
Improved biodiversity detection using a large-volume environmental DNA sampler with in situ filtration and implications for marine eDNA sampling strategies
Authors: Govindarajan Annette F. , McCartin Luke , Adams Allan , Allan Elizabeth , Belani Abhimanyu , Francolini Rene , Fujii Justin , Gomez-Ibañez Daniel , Kukulya Amy , Marin Fredrick , Tradd Kaitlyn , Yoerger Dana R. , McDermott Jill M. , Herrera Santiago 
Published: January 2022

ABSTRACTMetabarcoding analysis of environmental DNA samples is a promising new tool for marine biodiversity and conservation. Typically, seawater samples are obtained using Niskin bottles and filtered to collect eDNA. However, standard sample volumes are small relative to the scale of the environment, conventional collection strategies are limited, and the filtration process is time consuming. To overcome these limitations, we developed a new large – volume eDNA sampler with in situ filtration, capable of taking up to 12 samples per deployment. We conducted three deployments of our sampler on the robotic vehicle Mesobot in the Flower Garden Banks National Marine Sanctuary in the northwestern Gulf of Mexico and collected samples from 20 to 400 m depth. We compared the large volume (∼40 – 60 liters) samples collected by Mesobot with small volume (∼2 liters) samples collected using the conventional CTD – mounted Niskin bottle approach. We sequenced the V9 region of 18S rRNA, which detects a broad range of invertebrate taxa, and found that while both methods detected biodiversity changes associated with depth, our large volume samples detected approximately 66% more taxa than the CTD small volume samples. We found that the fraction of the eDNA signal originating from metazoans relative to the total eDNA signal decreased with sampling depth, indicating that larger volume samples may be especially important for detecting metazoans in mesopelagic and deep ocean environments. We also noted substantial variability in biological replicates from both the large volume Mesobot and small volume CTD sample sets. Both of the sample sets also identified taxa that the other did not – although the number of unique taxa associated with the Mesobot samples was almost four times larger than those from the CTD samples. Large volume eDNA sampling with in situ filtration, particularly when coupled with robotic platforms, has great potential for marine biodiversity surveys, and we discuss practical methodological and sampling considerations for future applications.
Ancestral acetylcholine receptor β-subunit forms homopentamers that prime before opening spontaneously
Authors: Tessier Christian J. G. , Sturgeon R. Michel , Emlaw Johnathon R. , McCluskey Gregory D. , Pérez-Areales F. Javier , daCosta Corrie J. B. 
Published: January 2022

AbstractHuman adult muscle-type acetylcholine receptors are heteropentameric ion channels formed from two α-subunits, and one each of the β-, δ-, and ε-subunits. To form functional channels, the subunits must assemble with one another in a precise stoichiometry and arrangement. Despite being different, the four subunits share a common ancestor that is presumed to have formed homopentamers. The extent to which the properties of the modern-day receptor result from its subunit complexity is unknown. Here we show that a reconstructed ancestral muscle-type β-subunit can form homopentameric ion channels. These homopentamers open spontaneously and display single-channel hallmarks of muscle-type acetylcholine receptor activity. Our findings demonstrate that signature features of muscle-type acetylcholine receptor function are independent of agonist, and do not necessitate the complex heteropentameric architecture of the modern-day receptor.
Estimating alpha, beta, and gamma diversity through deep learning
Authors: Andermann Tobias , Antonelli Alexandre , Barrett Russell L. , Silvestro Daniele 
Published: January 2022

AbstractThe reliable mapping of species richness is a crucial step for the identification of areas of high conservation priority, alongside other value considerations. This is commonly done by overlapping range maps of individual species, which requires dense availability of occurrence data or relies on assumptions about the presence of species in unsampled areas deemed suitable by environmental niche models. Here we present a deep learning approach that directly estimates species richness, skipping the step of estimating individual species ranges. We train a neural network model based on species lists from inventory plots, which provide ground truthing for supervised machine learning. The model learns to predict species richness based on spatially associated variables, including climatic and geographic predictors, as well as counts of available species records from online databases. We assess the empirical utility of our approach by producing independently verifiable maps of alpha, beta and gamma plant diversity at high spatial resolutions for Australia, a continent with highly contrasting diversity patterns. Our deep learning framework provides a powerful and flexible new approach for estimating biodiversity patterns.
Factor VII activating protease (FSAP) inhibits the outcome of ischemic stroke in mouse models
Authors: Kim Jeong Yeon , Manna Dipankar , Leergaard Trygve B. , Kanse Sandip M. 
Published: January 2022

AbstractFactor VII activating protease (FSAP) is a circulating serine protease, and individuals with the Marburg I (MI) single nucleotide polymorphism (SNP), which results in an inactive enzyme, have an increased risk of stroke. The outcome of ischemic stroke is more marked in FSAP-deficient mice compared to their wild-type (WT) counterparts. Plasma FSAP levels are raised in patients as well as mice after stroke. In vitro, FSAP promotes fibrinolysis by cleavage of fibrinogen, activates protease-activated receptors and decreases the cellular cytotoxicity of histones. Since these are desirable properties in stroke treatment, we tested the effect of recombinant serine protease domain of FSAP (FSAP-SPD) on ischemic stroke in mice. A combination of tissue plasminogen activator (tPA) and FSAP-SPD enhanced clot lysis, improved microvascular perfusion and neurological outcome and reduced infarct volumes in a mouse model of thromboembolic stroke. In the tail bleeding model FSAP-SPD treatment provoked a faster clotting time indicating that it has a pro-coagulant effect that is described before. FSAP-SPD improved stroke outcome and diminished the negative effects of co-treatment with tPA in the transient middle cerebral artery occlusion model. The inactive MI-isoform of FSAP did not have any effects in either model. In mice with FSAP deficiency there were minor differences in the outcomes of stroke but the treatment with FSAP-SPD was equally effective. Thus, FSAP represents a promising novel therapeutic strategy in the treatment of ischemic stroke that requires further evaluation.
Multiple horizontal acquisitions of plant genes in the whitefly Bemisia tabaci
Authors: Gilbert Clément , Maumus Florian 
Published: January 2022

AbstractThe extent to which horizontal gene transfer (HGT) has shaped eukaryote evolution remains an open question. Two recent studies reported four plant-like genes acquired through two HGT events by the whitefly Bemisia tabaci, a major agricultural pest (Lapadula et al. 2020; Xia et al. 2021). Here, we uncovered a total of 49 plant-like genes deriving from at least 24 independent HGT events in the genome of the MEAM1 whitefly. Orthologs of these genes are present in three cryptic B. tabaci species, they are phylogenetically nested within plant sequences, and expressed and under purifying selection. The predicted functions of these genes suggest that most of them are involved in plant-insect interactions. Thus, substantial plant-to-insect HGT may have facilitated the evolution of B. tabaci towards adaptation to a large host spectrum. Our study shows that eukaryote-to-eukaryote HGT may be relatively common in some lineages and it provides new candidate genes that may be targeted to improve current control strategies against whiteflies.
Rare Genetic Variants Correlate with Better Processing Speed
Authors: Song Zeyuan , Gurinovich Anastasia , Nygaard Marianne , Mengel-From Jonas , Andersen Stacy , Cosentino Stephanie , Schupfs Nicole , Lee Joseph , Zmuda Joseph , Ukraintseva Svetlana , Arbeev Konstantin , Christensen Kaare , Perls Thomas , Sebastiani Paola 
Published: January 2022

AbstractWe conducted a genome-wide association study (GWAS) of Digit Symbol Substitution Test (DSST) scores administered in 4207 family members of the Long Life Family Study (LLFS). Genotype data were imputed to the HRC panel of 64,940 haplotypes resulting in ~15M genetic variants with quality score > 0.7. The results were replicated using genetic data imputed to the 1000 Genomes phase 3 reference panel from two Danish twin cohorts: the study of Middle Aged Danish Twins and the Longitudinal Study of Aging Danish Twins. The GWAS in LLFS discovered 20 rare genetic variants (minor allele frequency (MAF) < 1.0%) that reached genome-wide significance (p-value < 5×10−8). Among these, 18 variants had large protective effects on the processing speed, including rs7623455, rs9821776, rs9821587, rs78704059 on chromosome 3, which were replicated in the combined Danish twin cohort. These SNPs are located in/near two genes, THRB and RARB, that belonged to thyroid hormone receptors family that may influence speed of metabolism and cognitive aging. The gene-level tests in LLFS confirmed that these two genes are associated with processing speed.
SNP-level FST outperforms window statistics for detecting soft sweeps in local adaptation
Authors: da Silva Ribeiro Tiago , Galván José A. , Pool John E. 
Published: January 2022

AbstractLocal adaptation can lead to elevated genetic differentiation at the targeted genetic variant and nearby sites. Selective sweeps come in different forms, and depending on the initial and final frequencies of a favored variant, very different patterns of genetic variation may be produced. If local selection favors an existing variant that had already recombined onto multiple genetic backgrounds, then the width of elevated genetic differentiation (high FST) may be too narrow to detect using a typical windowed genome scan, even if the targeted variant becomes highly differentiated. We therefore used a simulation approach to investigate the power of SNP-level FST (specifically, the maximum SNP FST value within a window) to detect diverse scenarios of local adaptation, and compared it against whole-window FST and the Comparative Haplotype Identity statistic. We found that SNP FST had superior power to detect complete or mostly complete soft sweeps, but lesser power than window-wide statistics to detect partial hard sweeps. To investigate the relative enrichment and nature of SNP FST outliers from real data, we applied the two FST statistics to a panel of Drosophila melanogaster populations. We found that SNP FST had a genome-wide enrichment of outliers compared to demographic expectations, and though it yielded a lesser enrichment than window FST, it detected mostly unique outlier genes and functional categories. Our results suggest that SNP FST is highly complementary to typical window-based approaches for detecting local adaptation, and merits inclusion in future genome scans and methodologies.Significance statementStudies that use genetic variation to search for genes evolving under population-specific natural selection tend to analyze data at the level of genomic windows that may each contain hundreds of variable sites. However, some models of natural selection (e.g. favoring an existing genetic variant) may result in genetic signals of local adaptation that are too narrow to be detected by such approaches. Here we use both simulations and empirical data analysis to show that searching for a site-specific signal of elevated genetic differentiation can find instances of local adaptation that other approaches miss, and therefore the integration of this signal into future studies may significantly improve our understanding of adaptive evolution and its genetic targets.