bluuebunny/crossref_metadata_2025_split huggingface dataset:
Improved functional mapping with GSA-MiXeR implicates biologically specific gene-sets and estimates enrichment magnitude
Authors: Frei Oleksandr , Hindley Guy , Shadrin Alexey A. , van der Meer Dennis , Akdeniz Bayram C. , Cheng Weiqiu , O’Connell Kevin S. , Bahrami Shahram , Parker Nadine , Smeland Olav B. , Holland Dominic ,   Schizophrenia Working Group of the Psychiatric Genomics Consortium, de Leeuw Christiaan , Posthuma Danielle , Andreassen Ole A. , Dale Anders M. 
Published: December 2022

AbstractWhile genome-wide association studies (GWAS) are increasingly successful in discovering genomic loci associated with complex human traits and disorders, the biological interpretation of these findings remains challenging. We developed the GSA-MiXeR analytical tool for gene-set analysis (GSA), which fits a model for gene-set heritability enrichments for complex traits, accounting for linkage disequilibrium across variants, and allowing the quantification of partitioned heritability and fold enrichment for small gene-sets. We validate the method using extensive simulations and sensitivity analyses. When applied to height and schizophrenia, GSA-MiXeR implicates gene-sets with greater biological specificity compared to standard GSA approaches, including insulin-like growth factor for height, as well as calcium channel function, GABAergic and dopaminergic signaling for schizophrenia. Such biologically relevant gene-sets, often with less than ten genes, are more likely to provide new insights into the pathobiology of complex diseases and highlight potential drug targets.
The effect of minimum unit pricing for alcohol on prescriptions for treatment of alcohol dependence: a controlled Interrupted Time Series analysis
Authors: Manca Francesco , Zhang Lisong , Fitzgerald Niamh , Mackay Daniel , McAuley Andrew , Sharp Clare , Lewsey Jim 
Published: December 2022

AbstractIn 2018, Scotland introduced a minimum unit price (MUP) for alcohol to reduce alcohol-related harms. We aimed to study the association between MUP introduction and the volume of prescriptions to treat alcohol dependence, and volume of new patients receiving such prescriptions. We also examined whether effects varied across different socioeconomic groups. A controlled interrupted time series was used to examine variations of our two outcomes. The same prescriptions in England and prescriptions for methadone in Scotland were used as controls. There was no evidence of an association between MUP implementation and the volume of prescriptions for alcohol dependence (immediate change: 2.74%, 95% CI: -0.068 0.014; slope change: 0% 95%CI: -0.001 0.000). A small, significant increase in slope in number of new patients receiving prescriptions was observed (0.2% 95%CI: 0.001 0.003). However, no significant results were confirmed after robustness checks. We found also no variation across different socioeconomic groups.
SpLitteR: Diploid genome assembly using TELL-Seq linked-reads and assembly graphs
Authors: Tolstoganov Ivan , Chen Zhoutao , Pevzner Pavel A. , Korobeynikov Anton 
Published: December 2022

AbstractBackgroundRecent advances in long-read sequencing technologies enabled accurate and contiguousde novoassemblies of large genomes and metagenomes. However, even long and accurate high-fidelity (HiFi) reads do not resolve repeats that are longer than the read lengths. This limitation negatively affects the contiguity of diploid genome assemblies since two haplomes share many long identical regions. To generate the telomere-to-telomere assemblies of diploid genomes, biologists now construct their HiFi-based phased assemblies and use additional experimental technologies to transform them into more contiguous diploid assemblies. The barcoded linked-reads, generated using an inexpensive TELL-Seq technology, provide an attractive way to bridge unresolved repeats in phased assemblies of diploid genomes.ResultsWe developed SpLitteR tool for diploid genome assembly using linked-reads and assembly graphs and benchmarked it against state-of-the-art linked-read scaffolders ARKS and SLR-superscaffolder using human HG002 genome and sheep gut microbiome datasets. The benchmark showed that SpLitteR scaffolding results in 1.5-fold increase in NGA50 compared to baseline LJA assembly and other scaffolders while introducing no additional misassemblies on the human dataset.ConclusionWe developed the SpLitteR tool for haplotype phasing and scaffolding in an assembly graph using barcoded linked-reads. We benchmarked SpLitteR on assembly graphs produced by various long-read assemblers and have shown how TELL-Seq reads facilitate phasing and scaffolding in these graphs. This benchmarking demonstrates that SpLitteR improves upon the state-of-the-art linked-read scaffolders in the accuracy and contiguity metrics. SpLitteR is implemented in C++ as a part of the freely available SPAdes package and is available athttps://github.com/ablab/spades/releases/tag/splitter-preprint.
Rejuvenation of Senescent Cells, in vitro and in vivo, by Low-frequency Ultrasound without Senolysis
Authors: Kureel Sanjay , Maroto Rosario , Powell Simon , Aniqua Maisha , Margadant Felix , Blair Brandon , Rasmussen Blake B. , Sheetz Michael 
Published: December 2022

AbstractThe presence of an appreciable number of senescent cells causes age-related pathologies as their removal by genetic or pharmacological means, as well as possibly by exercise, improves outcome in animal models. An alternative to depleting such cells would be to rejuvenate them to promote their return to a replicative state. Means to do so have not been explored, but here we report that treatment of non-growing senescent cells with low-frequency ultrasound (LFU) rejuvenates the cells. Notably, we find 15 characteristics of senescent cells that are reversed by LFU, including decreased cell and organelle motility. Mechanistically, LFU causes Ca2+entry that precedes dramatic increases in autophagy and an inhibition of mTORC1 signaling and the movement of Sirtuin1 from the nucleus to cytoplasm. Also, there is inhibition of SASP secretion, as well as β-galactosidase expression, telomere length is increased, while nuclear 5mc, H3K9me3, γH2AX, nuclear p53, ROS and mitoROS levels are all restored to normal levels. Repeated LFU treatments enables expansion of primary cells and stem cells beyond normal replicative limits without altering their phenotype. The rejuvenation process is enhanced by co-treatment with rapamycin or Rho kinase inhibition but is inhibited by blocking Sirtuin1 or Piezo1 activity. We further optimized the LFU treatment parameters to increase mouse lifespan and healthspan. These results suggest that mechanically-induced pressure waves alone can reverse senescence and aging effects at the cellular and organismal level, providing a non-pharmacological way to treat the effects of aging.One-Sentence SummaryLow frequency ultrasound is sufficient to rejuvenate senescent cells by activating autophagy in aged mice to improve healthspan.
Herbarium Specimen Sequencing Allows Precise Datation ofXanthomonas citripv.citriDiversification History
Authors: Campos PE , Pruvost O , Boyer K , Chiroleu F , Cao TT , Gaudeul M , Baider C , Utteridge TMA , Dominick S , Becker N , Rieux A , Gagnevin L 
Published: December 2022

AbstractOver the past decade, the field of ancient genomics has triggered considerable progress in the study of various pathogens, including those affecting crops. In this context, herbarium collections have been an important source of dated, identified and preserved DNA, whose use in comparative genomics and phylogeography may shed light into the emergence and evolutionary history of plant pathogens. In this study, we reconstructed 13 historical genomes of the bacterial crop pathogenXanthomonas citripv.citri(Xci) from infected citrus herbarium specimens using a shotgun-based deep sequencing strategy. Following authentication of the historical genomes based on ancient DNA damage patterns, we compared them to a large set of modern genomes to reconstruct their phylogenetic relationships, pathogeny-associated genes content and estimate several evolutionary parameters, using Bayesian tip-dating calibration and phylogeography inferences. Our results reveal thatXcioriginated in Southern Asia ~11,500 years ago and diversified during the beginning of the 13thcentury, afterCitrusdiversification and before spreading to the rest of the world. This updated scenario linksXcispecialization to Neolithic climatic change and the development of agriculture, and its diversification to the human-driven expansion of citriculture through the early East-West trade and later colonization. The analysis of data obtained from such historical specimens is challenging and must undergo adapted treatment before being compared to modern samples. Nevertheless, we confirm here that herbarium collections are a precious tool to improve the knowledge of the evolutionary history of plant pathogens.
Persistent gene flow suggests an absence of reproductive isolation in an African antelope speciation model
Authors: Wang Xi , Pedersen Casper-Emil Tingskov , Athanasiadis Georgios , Garcia-Erill Genis , Hanghøj Kristian , Bertola Laura D. , Rasmussen Malthe Sebro , Schubert Mikkel , Liu Xiaodong , Li Zilong , Lin Long , Jørsboe Emil , Nursyifa Casia , Liu Shanlin , Muwanika Vincent , Masembe Charles , Chen Lei , Wang Wen , Moltke Ida , Siegismund Hans R. , Albrechtsen Anders , Heller Rasmus 
Published: December 2022

AbstractAfrican antelope diversity is a globally unique vestige of a much richer world-wide Pleistocene megafauna. Despite this, the evolutionary processes leading to the prolific radiation of African antelopes are not well understood. Here, we sequenced 145 whole genomes from both subspecies of the waterbuck, an African antelope believed to be in the process of speciation. We investigated genetic structure and population divergence and found evidence of a mid-Pleistocene separation on either side of the eastern Great Rift Valley, consistent with vicariance caused by a rain shadow along the so-called ‘Kingdon’s Line’. However, we also found pervasive evidence of not only isolated and recent, but also widespread historical gene flow across the Rift Valley barrier. By inferring the genome-wide landscape of variation among subspecies, we found 14 genomic regions of elevated differentiation, including a locus that may be related to each subspecies’ distinctive coat pigmentation pattern. We investigated these regions as candidate speciation islands.However, we observed no significant reduction in gene flow in these regions, nor any indications of selection against hybrids. Altogether, these results suggest a pattern whereby climatically driven vicariance is the most important process driving the African antelope radiation, and suggest that reproductive isolation may not set in until very late in the divergence process.
Assessing timing of fledging in a cavity-nesting passerine using temperature data loggers
Authors: Dubiec Anna , Mazgajski Tomasz D. 
Published: December 2022

AbstractIn altricial birds, the length of the nestling period, i.e. time from hatching until fledging (young leaving the nest) varies within and between species. In general, however, variation in the time of fledging and factors mediating such variation remain largely unexplored. To assess the time of nestlings leaving the nest, daily observer visits to the nest are usually done in the predicted fledging period. However, this might initiate premature fledging of young and/or increase the predation risk. The application of iButtons – coin-sized temperature data loggers, which are increasingly used in ornithological studies – may help to overcome these obstacles. We tested whether nest temperatures recorded with iButtons might be used to identify the date and hour of young fledging, i.e. when the last nestling in the brood left the nest, in a small cavity-nesting passerine – the Great Tit (Parus major). We installed iButtons in 38 nests when nestlings were 14-15 days old (hatching day = day 0) and verified the presence of nestlings during daily inspections starting on day 17 post-hatching or later. We found that the day of fledging could be accurately determined based on the difference between the temperature of the nest cup and the outside. The age of nestlings ranged between 17 and 22 days at fledging, with nearly 58% of broods fledging at the age of 20 and 21 days. The majority (81.6%) of broods fledged within 6 h after sunrise. We discuss the advantages and disadvantages of using iButtons to identify fledging time in altricial birds.
A Deep Learning Approach for Histology-Based Nuclei Segmentation and Tumor Microenvironment Characterization
Authors: Rong Ruichen , Sheng Hudanyun , Jin Kevin W. , Wu Fangjiang , Luo Danni , Wen Zhuoyu , Tang Chen , Yang Donghan M. , Jia Liwei , Amgad Mohamed , Cooper Lee A.D. , Xie Yang , Zhan Xiaowei , Wang Shidan , Xiao Guanghua 
Published: December 2022

AbstractMicroscopic examination of pathology slides is essential to disease diagnosis and biomedical research; however, traditional manual examination of tissue slides is laborious and subjective. Tumor whole-slide image (WSI) scanning is becoming part of routine clinical procedure and produces massive data that capture tumor histological details at high resolution. Furthermore, the rapid development of deep learning algorithms has significantly increased the efficiency and accuracy of pathology image analysis. In light of this progress, digital pathology is fast becoming a powerful tool to assist pathologists.Studying tumor tissue and its surrounding microenvironment provides critical insight into tumor initiation, progression, metastasis, and potential therapeutic targets. Nuclei segmentation and classification are critical to pathology image analysis, especially in characterizing and quantifying the tumor microenvironment (TME). Computational algorithms have been developed for nuclei segmentation and TME quantification within image patches; however, existing algorithms are computationally intensive and time-consuming for WSI analysis.In this study, we present Histology-based Detection using Yolo (HD-Yolo), a new method that significantly accelerates nuclei segmentation and TME quantification. We demonstrate that HD-Yolo outperforms existing methods for WSI analysis in nuclei detection and classification accuracy, as well as computation time.
Gross anatomy of the Pacific hagfish,Eptatretus burgeri, with special reference to the coelomic viscera
Authors: Muramatsu Banri , Suzuki Daichi G. , Suzuki Masakazu , Higashiyama Hiroki 
Published: December 2022

AbstractHagfish (Myxinoidea) are a deep-sea taxon of cyclostomes, the extant jawless vertebrates. Many researchers have examined the anatomy and embryology of hagfish to shed light on the early evolution of vertebrates; however, the diversity within hagfish is often overlooked. Hagfish have two lineages, Myxininae and Eptatretinae. Usually, textbook illustrations of hagfish anatomy reflect the morphology of the former lineage, especiallyMyxine glutinosa, with its single pair of external branchial pores. Here, we instead report the gross anatomy of an Eptatretinae,Eptatretus burgeri, which has six pairs of branchial pores, especially focusing on the coelomic organs. Dissections were performed on fixed and unfixed specimens to provide a guide for those doing organ- or tissue-specific molecular experiments. Our dissections revealed that the ventral aorta is Y-branched inE. burgeri, which differs from the unbranched morphology ofMyxine. Otherwise, there were no differences in the morphology of the lingual apparatus or heart in the pharyngeal domain. The thyroid follicles were scattered around the ventral aorta, as has been reported for adult lampreys. The hepatobiliary system more closely resembled those of jawed vertebrates than those of adult lampreys, with the liver having two lobes and a bile duct connecting the gallbladder to each lobe. Overall, the visceral morphology ofE. burgeridoes not differ significantly from that of the knownMyxineat the level of gross anatomy, except for the number of branchial pores.
Mathematical modeling of ion homeostasis & cell volume stabilization: impact of ion transporters, impermeant molecules, & Donnan effect
Authors: Aminzare Zahra , Kay Alan R. 
Published: December 2022

AbstractThe pump-leak mechanism (PLM) first, described by Tosteson and Hoffman (1960), demonstrates how the activity of theNa+−K+ATPase (NKA) can counteract the osmotic influx of water stimulated by the presence of impermeant intracellular molecules. We derive analytical solutions for the steady state ion concentrations, voltage, and volume of a cell, by including impermeant extracellular molecules, variable impermeant charge, and Cation-Chloride Co-transporters (CCC). We demonstrate that impermeant extracellular molecules could stabilize a cell without NKA activity but argue that it is unlikely to play a significant rolein vivo. Significantly we have shown that the precise form of the NKA is unimportant for determining the steady state in PLMs. We have derived an analytical expression for the steady state of the PLM with one of the Cation-Chloride Co-transporters, either KCC, NCC, or NKCC, active. Notably, we have demonstrated that NCC at high pump rates can destabilize cells, which could account for the rarity of this co-transporter. In addition, we show that the reversal of any of the CCCs is unlikely. Importantly, we link the thermodynamics of the NKA to the PLM to show that there is a natural limit to the energy utilized by the PLM that prevents futile cycles. We show that the average charge on the intracellular impermeant molecules influences ion distributions but has no impact on energy utilization. Our study shows that analytical mathematical solutions from physically well-grounded models provide insight into ion transport systems that could only be obtained from numerical simulations with great difficulty.Significance StatementThe regulation of cell volume is fundamental to the stability of all tissue. Animal cells regulate their volume by actively pumping sodium and potassium ions, preventing the water’s osmotic influx from blowing up the cell. Based on the physical laws that determine ion and water fluxes, we derive equations that allow one to predict how pump rates and ion conductances combine to stabilize cell volume. The action of the sodium pump consumes about 30% of a cell’s energy budget, and we demonstrate the rate of ion pumping is constrained so that cells do not consume excessive energy. Our work also demonstrates the power of closed-form mathematical equations in characterizing such pump-leak systems.
Social tolerance as strategy to resolve group conflicts: an experimental study on tug-of-war competition of burying beetles
Authors: Ma Long , Wang Wenxia , Roffel Denise , van der Velde Marco , Komdeur Jan 
Published: December 2022

AbstractIn animal groups with dominance hierarchies, there often occurs a tug-of-war competition over resources and reproduction between dominants and subordinates, because neither is able to fully control the other. Consequently, individuals may mitigate within-group conflict, either by fighting others or by signalling their willingness to tolerate others. Nevertheless, how such a tolerance interaction evolves remains unclear. Here, we addressed this knowledge gap and tested the tug-of-war competition hypothesis, by investigating whether subordinates pay to stay in the group by helping dominants (pay-to-stay), and whether dominants pay costs by living with subordinates in the group (pay-from-staying). We used the burying beetles,Nicrophorus vespilloides, which compete with intra- and inter-specifics for valuable carcasses that are needed for reproduction. Multiple conspecifics can reproduce together through communal breeding, thereby enhancing benefits in terms of reproduction and resource defence against competitors. In communal associations, larger individuals are often dominant in carcass use and reproduction, whereas subordinates have restricted access to the carcass. Our findings show that cooperative subordinates paid costs by helping dominant breeders in carcass preparation in order to be tolerated (i.e. increased access towards the carcass) by dominant breeders, but subordinates did not increase their reproductive success by helping. Such tolerance was eliminated by a high interspecific competition with blowfly maggots. Our results also show that dominant males, but not dominant females, benefitted more from the presence of subordinates, partly due to a sex difference in the compensation strategy of dominants. Overall, our study demonstrates that a social tolerance occurring in situations with a tug-of-war competition could be a common strategy to resolve conflicts in animal societies.
Birthweight, Childhood Obesity, Adulthood Obesity and Body Compositions, and Gastrointestinal Diseases: A Mendelian Randomization Study
Authors: Yuan Shuai , Ruan Xixian , Sun Yuhao , Fu Tian , Zhao Jianhui , Deng Minzi , Chen Jie , Li Xue , Larsson Susanna C. 
Published: December 2022

AbstractBackgroundObesity has been established as a risk factor for several gastrointestinal diseases, whether the associations are causal is uncertain. In addition, the associations of obesity-related factors with gastrointestinal diseases have been scarcely explored. This Mendelian randomization aimed to investigate the associations of birth weight, childhood body mass index (BMI), adulthood BMI and waist-hip ratio, and body composition with the risk of 24 gastrointestinal diseases.MethodsIndependent genetic instruments associated with the exposures at the genome-wide significance level (P<5×10−8) were selected from corresponding large-scale genome-wide association studies. Summary-level data for gastrointestinal diseases were obtained from the UK Biobank and large consortia.ResultsGenetically predicted higher levels of birth weight was associated with a lower risk of gastroesophageal reflux. Genetically predicted higher childhood BMI was associated with an increased risk of duodenal ulcer, non-alcoholic fatty liver disease, and cholelithiasis. However, the associations did not persist after adjusting for genetically predicted adulthood BMI. Genetically predicted higher adulthood BMI and waist-hip ratio were associated with 19 and 17 gastrointestinal diseases, respectively. Genetically predicted greater visceral adiposity was associated with an increased risk of 18 gastrointestinal diseases. There were no strong associations between genetically predicted whole body fat and fat-free mass indices with gastrointestinal diseases.ConclusionThis study suggests that greater adulthood adiposity, measured as either BMI, waist-hip ratio, or visceral adipose tissue, is causally associated with an increased risk of a broad range of gastrointestinal diseases.
Identification of a protein expression signature distinguishing early from organising diffuse alveolar damage in COVID-19 patients
Authors: Ashwin Helen , Milross Luke , Wilson Julie , Majo Joaquim , Hang Lee Jimmy Tsz , Calder Grant , Hunter Bethany , James Sally , Lagos Dimitris , Signoret Nathalie , Filby Andrew , Bayraktar Omer Ali , Fisher Andrew J. , Kaye Paul M. 
Published: December 2022

ABSTRACTDiffuse alveolar damage (DAD) is a histopathological finding associated with severe viral infections, including SARS-CoV-2. However, the mechanisms mediating progression of DAD are poorly understood. Applying protein digital spatial profiling to lung tissue obtained from a cohort of 27 COVID-19 autopsy cases from the UK, we identified a protein signature (ARG1, CD127, GZMB, IDO1, Ki67, phospho-PRAS40 (T246), and VISTA that distinguishes early / exudative DAD from late / organising DAD with good predictive accuracy. These proteins warrant further investigation as potential immunotherapeutic targets to modulate DAD progression and improve patient outcome.