bluuebunny/crossref_metadata_2025_split huggingface dataset:
Two different mental disc forms in the Tashan caveGarra:different species or ecotypes?
Authors: Segherloo Iraj Hashemzadeh , Chaloshtory Sajad Najafi , Naser Murtada D. , Yasser Amaal G. , Tabatabaei Seyedeh Narjes , Piette-Lauziere Gabriel , Mashtizadeh Amirhossein , Elmi Amirmohammad , Sedighi Omid , Changizi Alieh , Hallerman Eric , Bernatchez Louis 
Published: May 2022

AbstractIn the Tashan Cave barbGarra tashanensis, inhabiting a small cave in south west Iran, two mental disc forms were observed. To assess their phylogenetic relationships, disc-less and disc-bearing individuals were analyzed using mitochondrial cytochrome oxidase subunit I (COI) partial DNA sequences. Both mental disc forms nested within one clade with absolute bootstrap support (BS= 100), and the genetic distances between the disc-bearing and disc-less individuals (0.3-0.7%) was considerably lower than inter-species mtDNA sequence distances reported among members of the genusGarra. Hence, the observed mental disc variation was not inferred to be a taxonomic feature or a consequence of character displacement. Instead, it was inferred as a case of character release to diversify among ecological niches in the limited subterranean habitat, which should be clarified in follow-up ecological and population genetic studies in more detail.
Extensive mosaicism by somatic L1 retrotransposition in normal human cells
Authors: Nam Chang Hyun , Youk Jeonghwan , Kim Jeong Yeon , Lim Joonoh , Park Jung Woo , Oh Soo A , Lee Hyun Jung , Park Ji Won , Jeong Seung-Yong , Lee Dong-Sung , Oh Ji Won , Han Jinju , Lee Junehawk , Kwon Hyun Woo , Kim Min Jung , Ju Young Seok 
Published: May 2022

SummaryOver the course of an individual’s lifetime, genomic alterations accumulate in somatic cells. However, the mutational landscape by retrotranspositions of long interspersed nuclear element-1 (L1), a widespread mobile element in the human genome, is poorly understood in normal cells. Here, we explored the whole-genome sequences of 892 single-cell clones established from various tissues collected from 28 individuals. Remarkably, 88% of colorectal epithelial cells acquired somatic L1 retrotranspositions (soL1Rs), carrying ∼3 events per cell on average with substantial intra- and inter-individual variances, which was accelerated at least 10-fold during tumourigenesis. Breakpoints of soL1Rs suggested that a few variant mechanisms can be involved in the L1 retrotransposition processes. Fingerprinting of donor L1s using source-specific unique sequences revealed 34 hot L1s, 44% of which were newly discovered in this study, and many ultra-rare hot L1s in the human population showed higher retrotransposition potential in somatic lineages than common sources. Multi-dimensional analysis of soL1Rs with early embryonic developmental relationships, genome-wide methylation, and gene expression profiles of the clones demonstrated that (1) soL1Rs occur from early embryogenesis at a substantial rate, (2) epigenetic activation of hot L1s is stochastically acquired during the wave of early global epigenomic reprogramming, rather than by the sporadic loss-of-methylation at the late stage, and (3) most L1 transcripts in the cytoplasm do not generate soL1Rs in somatic lineages. In summary, this study provides insights into the retrotransposition dynamics of L1s in the human genome and the resultant somatic mosaicism in normal human cells.
Lack of evidence for increased transcriptional noise in aged tissues
Authors: Ibáñez-Solé Olga , Ascensión Alex M. , Araúzo-Bravo Marcos J. , Izeta Ander 
Published: May 2022

AbstractAging is often associated with a loss of cell type identity that results in an increase in transcriptional noise in aged tissues. If this phenomenon reflects a fundamental property of aging remains an open question. Transcriptional changes at the cellular level are best detected by single-cell RNA sequencing (scRNAseq). However, the diverse computational methods used for the quantification of age-related loss of cellular identity have prevented reaching meaningful conclusions by direct comparison of existing scRNAseq datasets. To address these issues we created Decibel, a Python toolkit that implements side-to-side four commonly used methods for the quantification of age-related transcriptional noise in scRNAseq data. Additionally, we developed Scallop, a novel computational method for the quantification of membership of single cells to their assigned cell type cluster. Cells with a greater Scallop membership score are transcriptionally more stable. Application of these computational tools to seven aging datasets showed large variability between tissues and datasets, suggesting that increased transcriptional noise is not a universal hallmark of aging. To understand the source of apparent loss of cell type identity associated with aging, we analyzed cell type-specific changes in transcriptional noise and the changes in cell type composition of the mammalian lung. No robust pattern of cell type-specific transcriptional noise alteration was found across aging lung datasets. In contrast, age-associated changes in cell type composition of the lung were consistently found, particularly of immune cells. These results suggest that claims of increased transcriptional noise of aged tissues should be reformulated.
Fibroblasts-derived from Pluripotent Cells Harboring a Single Allele Knockout in Two Pluripotency Genes Exhibit DNA Methylation Abnormalities and pluripotency induction Defects
Authors: Lasry Rachel , Maoz Noam , Cheng Albert W. , Tov Nataly Yom , Kulenkampff Elisabeth , Azagury Meir , Yang Hui , Ople Cora , Markoulaki Styliani , Faddah Dina A. , Makedonski Kirill , Sabbag Ofra , Jaenisch Rudolf , Buganim Yosef 
Published: May 2022

ABSTRACTA complete knockout (KO) of a single key pluripotency gene has been shown to drastically affect embryonic stem cell (ESC) function and epigenetic reprogramming. However, knockin (KI)/KO of a reporter gene only in one of two alleles in a single pluripotency gene is considered harmless and is largely used in the stem cell field. Here, we sought to understand the impact of simultaneous elimination of a single allele in two ESC key genes on pluripotency potential and acquisition. We established multiple pluripotency systems harboring KI/KO in a single allele of two different pluripotency genes (i.e. Nanog+/-; Sall4+/-, Nanog+/-; Utf1+/-, Nanog+/-; Esrrb+/- and Sox2+/-; Sall4+/-). Interestingly, although these double heterozygous mutant lines maintain their stemness and contribute to chimeras equally to their parental control cells, fibroblasts derived from these systems show a significant reduction in their capability to induce pluripotency either by Oct4, Sox2, Klf4 and Myc (OSKM) or by nuclear transfer (NT). Tracing the expression of Sall4 and Nanog, as representative key pluripotency targeted genes, at early phases of reprogramming could not explain the seen delay/blockage. Further exploration identifies abnormal methylation landscape around pluripotent and developmental genes in the double heterozygous mutant fibroblasts. Accordingly, treatment with 5-azacytidine two days prior to transgene induction rescues the reprogramming defects. This study emphasizes the importance of maintaining two intact alleles for pluripotency induction and suggests that insufficient levels of key pluripotency genes leads to DNA methylation abnormalities in the derived-somatic cells later on in development.
wrmXpress: A modular package for high-throughput image analysis of parasitic and free-living worms
Authors: Wheeler Nicolas J. , Gallo Kendra J. , Garncarz Elena J. , Ryan Kaetlyn T. , Chan John D. , Zamanian Mostafa 
Published: May 2022

AbstractAdvances in high-throughput and high-content imaging technologies require concomitant development of analytical software capable of handling large datasets and generating relevant phenotypic measurements. Several tools have been developed to analyze drug response phenotypes in parasitic and free-living worms, but these are siloed and often limited to specific instrumentation, worm species, and single phenotypes. No effort has been made to unify tools for analyzing high-content phenotypic imaging data of worms and provide a platform for future extensibility. We have developed wrmXpress, a unified framework for analyzing a variety of phenotypes matched to high-content experimental assays of free-living and parasitic nematodes and flatworms. We demonstrate its utility for analyzing a suite of phenotypes, including motility, development/size, and feeding, and establish the package as a platform upon which to build future custom phenotypic modules, including those that incorporate deep learning techniques. We show that wrmXpress can serve as an analytical workhorse for anthelmintic screening efforts across schistosomes, filarial nematodes, and free-living model nematodes, and holds promise for enabling collaboration among investigators with diverse interests.
A neural theory for counting memories
Authors: Dasgupta Sanjoy , Hattori Daisuke , Navlakha Saket 
Published: May 2022

Abstract“I’ve never smelled anything like this.” “I’ve seen you once before.” “I’ve heard this song many times.” Keeping track of the number of times different stimuli have been experienced is a critical computation for behavior. This computation occurs ubiquitously across sensory modalities, and naturally without reward or punishment. However, the neural circuitry that mediates this computation remains unknown. Here, we propose a theoretical two-layer neural circuit that can store counts of stimulus occurrence frequencies. This circuit implements a data structure, called a count sketch, that is commonly used in computer science to maintain item frequencies in streaming data. Our first model implements the count sketch data structure using Hebbian synapses and outputs stimulus-specific frequencies. Our second model uses anti-Hebbian plasticity and only tracks frequencies within four count categories (“1-2-3-many”), which we suggest makes a better trade-off between the number of categories that need to be distinguished and the potential ethological value of those categories. Using real-world datasets, we show how both models can closely track the frequencies of different stimuli experienced, while being robust to noise, thus expanding the traditional novelty-familiarity memory axis from binary to continuous. Finally, we show that an implementation of the “1-2-3-many” count sketch — including network architecture, synaptic plasticity rule, and output neuron that encodes count categories — exists in a novelty detection circuit in the insect mushroom body, and we argue that similar circuit motifs also appear in mammals, suggesting that basic memory counting machinery may be broadly conserved.
Analysis of Cyp51 protein sequences shows 4 major Cyp51 gene family groups across Fungi
Authors: Celia-Sanchez Brandi N , Mangum Brandon , Brewer Marin , Momany Michelle 
Published: May 2022

AbstractAzole drugs target fungal sterol biosynthesis and are used to treat millions of human fungal infections each year. Resistance to azole drugs has emerged in multiple fungal pathogens including Candida albicans, Cryptococcus neoformans, Histoplasma capsulatum, and Aspergillus fumigatus. The most well-studied resistance mechanism in A. fumigatus arises from missense mutations in the coding sequence combined with a tandem repeat in the promoter of cyp51A, which encodes a cytochrome P450 enzyme in the fungal sterol biosynthesis pathway. Filamentous members of Ascomycota such as A. fumigatus have either one or two of three Cyp51 paralogs (Cyp51A, Cyp51B, and Cyp51C). Most previous research in A. fumigatus has focused on Cyp51A due to its role in azole resistance. We used the A. fumigatus Cyp51A protein sequence as the query in database searches to identify Cyp51 proteins across Fungi. We found 435 Cyp51 proteins in 301 species spanning from early-diverging fungi (Blastocladiomycota, Chytridiomycota, Zoopagomycota and Mucormycota) to late-diverging fungi (Ascomycota and Basidiomycota). We found these sequences formed 4 major Cyp51 groups: Cyp51, Cyp51A, Cyp51B, and Cyp51C. Surprisingly, we found all filamentous Ascomycota had a Cyp51B paralog, while only 50% had a Cyp51A paralog. We created maximum likelihood trees to investigate the evolution of Cyp51 in Fungi. Our results suggest Cyp51 is present in all fungi with three paralogs emerging in Pezizomycotina, including Cyp51C which appears to have diverged from the progenitor of the Cyp51A and Cyp51B groups.Author SummaryEach year millions of people are infected by a fungal pathogen and receive antifungal treatment with azole drugs. Resistance to azole drugs is becoming increasingly prevalent and is mostly caused by mutations in the azole drug target, Cyp51. Aspergillus fumigatus is an airborne fungal pathogen that causes more than 600,000 deaths every year. Azole resistance in A. fumigatus is primarily driven by a promoter repeat coupled with mutations in cyp51A. In our study, we found 435 Cyp51 proteins in 4 major groups across Fungi, with some species having multiple Cyp51 proteins (Cyp51, Cyp51A, Cyp51B, and Cyp51C). Although most research in A. fumigatus has focused on Cyp51A, we found Cyp51B in all filamentous Ascomycota fungi showing it is more conserved than Cyp51A and likely plays a vital role in these fungi.Author Summary (Shortened)Resistance to azole drugs is becoming increasingly prevalent and is mostly caused by mutations in the azole drug target, Cyp51. Azole resistance in Aspergillus fumigatus is primarily driven by a promoter repeat coupled with mutations in cyp51A. We found 435 Cyp51 proteins in 4 major groups across Fungi, with some species having multiple Cyp51 proteins (Cyp51, Cyp51A, Cyp51B, and Cyp51C). Although most research focuses on Cyp51A, we found Cyp51B in all filamentous Ascomycota fungi showing it’s more conserved than Cyp51A.
Structural analysis of cholesterol binding and sterol selectivity by ABCG5/G8
Authors: Farhat Danny , Rezaei Fatemeh , Ristovski Milica , Yang Yidai , Stancescu Albert , Dzimkova Lucia , Samnani Sabrina , Couture Jean-François , Lee Jyh-Yeuan 
Published: May 2022

ABSTRACTThe ATP-binding cassette (ABC) sterol transporters are responsible for maintaining cholesterol homeostasis in mammals by participating in reverse cholesterol transport (RCT) or transintestinal cholesterol efflux (TICE). The heterodimeric ABCG5/G8 carries out selective sterol excretion, preventing the abnormal accumulation of plant sterols in human bodies, while homodimeric ABCG1 contributes to the biogenesis and metabolism of high-density lipoproteins. A sterol-binding site on ABCG5/G8 was proposed at the interface of the transmembrane domain and the core of lipid bilayers. In this study, we have determined the crystal structure of ABCG5/G8 in a cholesterol-bound state. The structure combined with amino acid sequence analysis shows that in the proximity of the sterol-binding site, a highly conserved phenylalanine array supports functional implications for ABCG cholesterol/sterol transporters. Lastly, in silico docking analysis of cholesterol and stigmasterol (a plant sterol) suggests sterol-binding selectivity on ABCG5/G8, but not ABCG1. Together, our results provide a structural basis for cholesterol binding on ABCG5/G8 and the sterol selectivity by ABCG transporters.
Mutant huntingtin exon-1 impaired GTPCH and DHFR expression in plants and mice
Authors: Hung Chiu-Yueh , Zhu Chuanshu , Kittur Farooqahmed S. , He Maotao , Arning Erland , Zhang Jianhui , Johnson Asia J. , Jawa Gurpreet S. , Thomas Michelle D. , Ding Tomas T. , Xie Jiahua 
Published: May 2022

AbstractPathophysiology associated with Huntington’s disease (HD) has been studied extensively in various cell and animal models since the 1993 discovery of the mutant huntingtin (mHtt) with abnormally expanded polyglutamine (polyQ) tracts as the causative factor. However, the sequence of early pathophysiological events leading to HD still remains elusive. To gain new insights into the polyQ-induced early pathogenic events, we expressed Htt exon1 (Httex1) with a normal (21), or an extended (42 or 63) number of polyQ in tobacco plants, which lack an Htt ortholog to avoid any associated effects from endogenous Htt. Here, we show that transgenic plants accumulated Httex1 proteins with corresponding polyQ tracts, and that mHttex1 induced protein aggregation and affected plant growth, especially root and root hair development, in a polyQ length-dependent manner. Quantitative proteomic analysis of young roots from severely affected Httex1Q63 and unaffected Httex1Q21 plants showed that the most impaired protein by polyQ63 is a GTP cyclohydrolase I (GTPCH) along with many its related one-carbon (C1) metabolic pathway enzymes. GTPCH is a key enzyme involved in folate biosynthesis in plants and tetrahydrobiopterin (BH4) biosynthesis in mammals. Validating studies in 4-week-old R6/2 HD mice expressing a mHttex1 showed reduced levels of GTPCH and dihydrofolate reductase (DHFR, a key folate utilization/alternate BH4 biosynthesis enzyme), and impaired C1 and BH4 metabolisms. Our findings from mHttex1 plants and mice reveal impaired expressions of GTPCH and DHFR and contribute to a better understanding of mHtt-altered C1 metabolism and C1 interconnected BH4 metabolism leading to the pathogenesis of HD.
Effect of pressure insole sampling frequency on peak force accuracy during running
Authors: Elstub L.J. , Grohowski L.M. , Wolf D.N. , Owen M.K. , Noehren B. , Zelik K.E. 
Published: May 2022

AbstractPressure sensing insoles enable us to estimate forces under the feet during activities such as running, which can provide valuable insight into human movement. Pressure insoles also afford the opportunity to collect more data in more representative environments than can be achieved in laboratory studies. One key challenge with real-world use of pressure insoles is limited battery life which restricts the amount of data that can be collected on a single charge. Reducing sampling frequency is one way to prolong battery life, at the cost of decreased measurement accuracy, but this trade-off has not been quantified, which hinders decision-making by researchers and developers. Therefore, we characterized the effect of decreasing sampling frequency on peak force estimates from pressure insoles (Novel Pedar, 100 Hz) across a range of running speeds and slopes. Data were downsampled to 50, 33, 25, 20, 16 and 10 Hz. Force peaks were extracted due to their importance in biomechanical algorithms trained to estimate musculoskeletal forces and were compared with the reference sampling frequency of 100 Hz to compute relative errors. Peak force errors increased exponentially from 0.7% (50 Hz) to 9% (10 Hz). However, peak force errors were <3% for all sampling frequencies down to 20 Hz. For some pressure insoles, sampling rate is inversely proportional to battery life. Therefore, these findings suggest that battery life could be increased up to 5x at the expense of 3% errors. These results are encouraging for researchers aiming to deploy pressure insoles for remote monitoring or in longitudinal studies.
mRNA-based vaccines against SARS-CoV-2 do not stimulate interferon stimulatory gene expression in individuals affected by Aicardi Goutières Syndrome
Authors: Takanohashi Asako , Alameh Mohamad-Gabriel , Woidill Sarah , Hacker Julia , Davis Benjamin , Helman Guy , Gavazzi Francesco , Adang Laura , D’Aiello Russell , Winters Patrick , Cordova Devon , Khandaker Taibeen , Ni Houping , Tam Ying , Lin Paulo , Weissman Drew , Shults Justine , Vanderver Adeline 
Published: May 2022

AbstractThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses threats to individuals with rare disease, in part because so little is known about the impact of COVID-19 infection and vaccination safety in rare disease populations. Of particular concern, given the overlap in disease manifestations and interferon dysregulation, are a group of heritable autoinflammatory conditions called type I interferonopathies. The most common of these, Aicardi Goutières Syndrome (AGS), is caused by altered nucleic acid metabolism and sensing, resulting in additional concerns surrounding the use of mRNA vaccination approaches. To determine whether mRNA vaccines induce an interferon response in AGS, we applied mRNA SARS-CoV-2 vaccines to whole blood samples and assessed internalization and interferon signaling gene expression responses to the mRNA. In all cases (11 AGS and 11 control samples), interferon signatures did not significantly increase from baseline, regardless of baricitinib treatment status in the AGS subjects, and were even decreased, when using codon optimized SARS-CoV-2 di-proline modified spike sequence (S2P). Internalization of S2P in human dendritic cells was verified by Western Blot, and in control and AGS blood cells was verified by Luciferase activity. Although numbers of tested samples in this rare disease are small, based on these findings, we suggest that COVID vaccination is unlikely to directly stimulate the interferon signaling gene expression in AGS patients via response to mRNA internalization. The in vitro nature of this study cannot exclude an exaggerated interferon response to spike protein production at a systemic level in individuals with a primary heritable interferonopathy. In the context of continued SARS-CoV-2 spread in the community, we do not recommend withholding vaccination in this rare disease group. However, we recommend that vaccinations for AGS patients are provided in a controlled setting with appropriate observation and used with caution in individuals with prior vaccine associated adverse events.
The regulatory landscapes of human ovarian ageing
Authors: Jin Chen , Wang Xizhe , Hudgins Adam D. , Gamliel Amir , Pei Mingzhuo , Kim Seungsoo , Contreras Daniela , Hoeijmakers Jan , Campisi Judith , Lobo Rogerio , Williams Zev , Rosenfeld Michael G. , Suh Yousin 
Published: May 2022

Summary paragraphThe ovary is the first organ to age in the human body, affecting both fertility and overall health in women1-8. However, the biological mechanisms underlying human ovarian ageing remain poorly understood. Here we performed single-nuclei multi-omics analysis of young and reproductively aged human ovaries to understand the molecular and cellular basis of ovarian ageing in humans. Our analysis reveals coordinated changes in transcriptomic output and chromatin accessibility across cell types during ageing, including elevated mTOR and MAPK signaling, decreased activity of the oxidative phosphorylation and DNA damage repair pathways, and an increased signature of cellular senescence. By constructing cell type-specific regulatory networks, we uncover enhanced activity of the transcription factor CEBPD across cell types in the aged ovary, with a corresponding significant loss of activity of most cell identity-associated transcription factors. Moreover, by performing integrative analyses of our single-nuclei multi-omics data with common genetic variants associated with age at natural menopause (ANM) from genome-wide association studies, we demonstrate a global impact of functional variants on changes in gene regulatory networks across ovarian cell types. Finally, we nominate about a dozen of functional non-coding variants, their target genes and cell types and regulatory mechanisms that underlie genetic association with ANM. This work provides a comprehensive multimodal landscape of human ovarian ageing and mechanistic insights into inherited variation of ANM.
Metadata retrieval from sequence databases with ffq
Authors: Gálvez-Merchán Ángel , Min Kyung Hoi (Joseph) , Pachter Lior , Booeshaghi A. Sina 
Published: May 2022

AbstractWe present a command-line tool, called ffq, for querying user-generated data and metadata from sequence databases. The code can be found here: https://github.com/pachterlab/ffq.