bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genome divergence across the Indo-Burman arc: a tale of two peacocks
Authors: Patil Ajinkya Bharatraj , Vijay Nagarjun 
Published: May 2022

AbstractExaggerated traits of the peacock are attributed to sexual selection. Yet, the two species of Asian peacock are conspicuously different in their plumage colouration and level of sexual dichromatism. Our integrative comparative study of bird calls, morphological differences and genomic divergence between the Indian blue peafowl and the green peafowl suggests a strong role of habitat differences in shaping species-specific changes. We estimate a recent (1-3 MYA) split of these species in the Pliocene or early Pleistocene, followed by intermittent periods of gene flow. Despite the relatively recent split, the high levels of genomic differentiation (FST ∼ 0.6) mirror the divergence in morphological traits. Several genes involved in body patterning and colouration have accumulated protein-coding differences between the peacock species. Our estimates suggest genetic diversity in the widespread Indian peafowl (θw ∼ 0.0015) is comparable but slightly higher than in the endangered green peafowl (θw ∼ 0.0012). The ratio of genetic diversity on the Z chromosome to the autosomes (Z/A) is consistent with a polygynous mating system in the Indian peafowl compared to monogamy in the green peafowl. The Asian peacock species continue to provide exciting new insights into speciation and mating system evolution in the post-genomic era.
LUBAC assembles a signaling platform at mitochondria for signal amplification and shuttling of NF-ĸB to the nucleus
Authors: Wu Zhixiao , Berlemann Lena A. , Bader Verian , Sehr Dominik , Eilers Eva , Covallero Alberto , Meschede Jens , Angersbach Lena , Showkat Cathrin , Michaelis Jonas B. , Münch Christian , Rieger Bettina , Namgaladze Dmitry , Herrera Maria Georgina , Fiesel Fabienne C. , Springer Wolfdieter , Mendes Marta , Stepien Jennifer , Barkovits Katalin , Marcus Katrin , Sickmann Albert , Dittmar Gunnar , Busch Karin B. , Riedel Dietmar , Brini Marisa , Tatzelt Jörg , Cali Tito , Winklhofer Konstanze F. 
Published: May 2022

SUMMARYMitochondria are increasingly recognized as cellular hubs to orchestrate signaling pathways that regulate metabolism, redox homeostasis, and cell fate decisions. Recent research revealed a role of mitochondria also in innate immune signaling, however, the mechanisms of how mitochondria affect signal transduction are poorly understood. Here we show that the NF-ĸB pathway activated by TNF employs mitochondria as a platform for signal amplification and shuttling of activated NF-ĸB to the nucleus. TNF induces the recruitment of HOIP, the catalytic component of the linear ubiquitin chain assembly complex (LUBAC), and its substrate NEMO to the outer mitochondrial membrane, where M1- and K63-linked ubiquitin chains are generated. NF-ĸB is locally activated and transported to the nucleus by mitochondria, resulting in an increase in mitochondria-nucleus contact sites in a HOIP-dependent manner. Notably, TNF-induced stabilization of the mitochondrial kinase PINK1 contributes to signal amplification by antagonizing the M1-ubiquitin-specific deubiquitinase OTULIN.
inClust: a general framework for clustering that integrates data from multiple sources
Authors: Wang Lifei , Nie Rui , Zhang Zhang , Gu Weiwei , Wang Shuo , Wang Anqi , Zhang Jiang , Cai Jun 
Published: May 2022

AbstractClustering is one of the most commonly used methods in single-cell RNA sequencing (scRNA-seq) data analysis and other fields of biology. Traditional clustering methods usually use data from a single source as the input (e.g. scRNA-seq data). However, as the data become more and more complex and contain information from multiple sources, a clustering method that could integrate multiple data is required. Here, we present inClust (integrated clustering), a clustering method that integrates information from multiple sources based on variational autoencoder and vector arithmetic in latent space. inClust perform information integration and clustering jointly, meanwhile it could utilize the labeling information from data as regulation information. It is a flexible framework that can accomplish different tasks under different modes, ranging from supervised to unsupervised. We demonstrate the capability of inClust in the tasks of conditional out-of-distribution generation under supervised mode; label transfer under semi-supervised mode and guided clustering mode; spatial domain identification under unsupervised mode. inClust performs well in all tasks, indicating that it is an excellent general framework for clustering and task-related clustering in the era of multi-omics.
Improved prediction of bacterial CRISPRi guide efficiency from depletion screens through mixed-effect modeling and data integration
Authors: Yu Yanying , Gawlitt Sandra , Barros de Andrade e Sousa Lisa , Merdivan Erinc , Piraud Marie , Beisel Chase L. , Barquist Lars 
Published: May 2022

AbstractCRISPR interference (CRISPRi), the targeting of a catalytically dead Cas protein to block transcription, is the leading technique to silence gene expression in bacteria. However, design rules for CRISPRi remain poorly defined, limiting predictable design for gene interrogation, pathway manipulation, and high-throughput screens. Here we develop a best-in-class prediction algorithm for guide silencing efficiency by systematically investigating factors influencing guide depletion in multiple genome-wide essentiality screens, with the surprising discovery that gene-specific features such as transcriptional activity substantially impact prediction of guide activity. Accounting for these features as part of algorithm development allowed us to develop a mixed-effect random forest regression model that provides better estimates of guide efficiency than existing methods, as demonstrated in an independent saturating screen. We further applied methods from explainable AI to extract interpretable design rules from the model, such as sequence preferences in the vicinity of the PAM distinct from those previously described for genome engineering applications. Our approach provides a blueprint for the development of predictive models for CRISPR technologies where only indirect measurements of guide activity are available.
New Perspective on GWAS: East Asian Populations from the Viewpoint of Selection Pressure and Linear Algebra with AI
Authors: Kanazawa Masayuki 
Published: May 2022

AbstractGenome Wide Association Studies (GWAS) are useful for comparing the characteristics of different human population groups. However, genomes can change rapidly over time when there is a strong selection pressure, such as a pandemic. The genetic information related to the immune system is thought to be very sensitive to such diseases. Therefore, it may be necessary to conduct not only the standard whole-genome GWAS but also a more detailed, chromosome-focused GWAS.In this study, we compared chromosomes of immune system genes to those that are not thought to be related to the immune system, and analyzed GWAS results for SNPs in each chromosome to examine the differences. In order to keep the sample conditions as identical as possible, we limited the comparisons and the analyses to a few groups for which population movements were easy to interpret, and we also made sure the sample sizes were as close as possible. We selected a population of 403 East Asian people, consisting of 104 Japanese people in Tokyo (JPT), 103 Han Chinese people in Beijing (CHB) and 105 in southern China (CHS), and 91 Korean people (KOR). PCA and Manhattan plot were used to analyze and compare the results.Japanese, Chinese, and Korean populations formed distinctly different groups, with major differences observed. Validity of PCA and Manhattan plot was also discussed using Mahalanobis distance and AI.
Structural dynamics underlying gating and regulation in IP3R channel
Authors: Fan Guizhen , Baker Mariah R. , Terry Lara E. , Arige Vikas , Chen Muyuan , Seryshev Alexander B. , Baker Matthew L. , Ludtke Steven J. , Yule David I. , Serysheva Irina I. 
Published: May 2022

ABSTRACTInositol-1,4,5-trisphosphate receptors (IP3Rs) are activated by IP3 and Ca2+ and their gating is regulated by various intracellular messengers that finely tune the channel activity. Here, using single particle cryo-EM analysis we determined 3D structures of the nanodisc-reconstituted IP3R1 channel in two ligand-bound states. These structures provide unprecedented details governing binding of IP3, Ca2+ and ATP in IP3R1, revealing conformational changes that couple ligand-binding to channel opening. Using a GMM based deep learning approach and 3D variability analysis, we extracted dynamic properties of the key protein domains. From this, we find that IP3 binding relies upon intrinsic flexibility of the cytoplasmic ARM2 domain. Our results highlight a key role of dynamic side chains surrounding the ion conduction path in regulating gating behavior of IP3R channels. Altogether, this work defines a structural platform for mechanistic understanding of the molecular dynamics underlying ligand-binding, activation and regulation of the IP3R activity.
A developmental pathway for epithelial-to-motoneuron transformation in C. elegans
Authors: Rashid Alina , Tevlin Maya , Lu Yun , Shaham Shai 
Published: May 2022

SUMMARYMotoneurons and motoneuron-like pancreatic beta cells arise from radial glia and ductal cells, both tube-lining progenitors that share molecular regulators. To uncover programs underlying motoneuron formation, we studied a similar, cell-division-independent transformation of the C. elegans tube-lining Y cell into the PDA motoneuron. We find that lin-12/Notch acts through ngn-1/Ngn and its regulator hlh-16/Olig to control transformation timing. lin-12 loss blocks transformation, while lin-12(gf) promotes precocious PDA formation. Early basal expression of both ngn-1/Ngn and hlh-16/Olig depends on sem-4/Sall and egl-5/Hox. Later, coincident with Y-cell morphological changes, ngn-1/Ngn expression is upregulated in a sem-4/Sall and egl-5/Hox-dependent but hlh-16/Olig-independent manner. Subsequently, Y-cell retrograde extension forms an anchored process priming PDA axon extension. Extension requires ngn-1-dependent expression of the cytoskeleton organizers UNC-119, UNC-44/ANK, and UNC-33/CRMP, which also, unexpectedly, activate PDA terminal-gene expression. Our findings reveal key cell-division-independent regulatory events leading to motoneuron generation, suggesting a conserved pathway for epithelial-to-motoneuron/motoneuron-like differentiation.
Taste cues elicit prolonged modulation of feeding behavior in Drosophila
Authors: Deere Julia U. , Devineni Anita V. 
Published: May 2022

SUMMARYTaste cues regulate immediate feeding behavior, but their ability to modulate future behavior has been less well-studied. Pairing one taste with another can modulate subsequent feeding responses through associative learning, but this requires simultaneous exposure to both stimuli. We investigated whether exposure to one taste modulates future responses to other tastes even when they do not overlap in time. Using Drosophila, we found that brief exposure to sugar enhanced future feeding responses, whereas bitter exposure suppressed them. This modulation relies on neural pathways distinct from those that acutely regulate feeding or mediate learning-dependent changes. Sensory neuron activity was required not only during initial taste exposure but also afterward, suggesting that ongoing sensory activity may maintain experience-dependent changes in downstream circuits. Thus, the brain stores a memory of each taste stimulus after it disappears, enabling animals to integrate information as they sequentially sample different taste cues that signal local food quality.
Androgen Receptor is a Determinant of Melanoma targeted drug resistance
Authors: Samarkina Anastasia , Youssef Markus Kirolos , Ostano Paola , Ghosh Soumitra , Ma Min , Tassone Beatrice , Proust Tatiana , Chiorino Giovanna , Levesque Mitchell P. , Dotto Gian Paolo 
Published: May 2022

AbstractMelanoma provides a primary benchmark for targeted drug therapy. Most melanomas with BRAFV600 mutations regress in response to BRAF/MEK inhibitors (BRAFi/MEKi). However, nearly all relapse within the first two years, and there is a connection between pathways involved in BRAFi/MEKi-resistance and poor response to immune checkpoint therapy. We recently showed that androgen receptor (AR) activity is required for melanoma cell proliferation and tumorigenesis. Here we find that AR expression is markedly increased in BRAFi resistant melanoma cells as well as in sensitive cells soon after BRAFi exposure. Increased AR expression is by itself sufficient to render melanoma cells BRAFi-resistant, eliciting transcriptional changes of BRAFi resistant subpopulations and elevated EGFR and SERPINE1 expression of likely clinical significance. Inhibition of AR expression and activity blunts changes in gene expression and suppresses proliferation and tumorigenesis of BRAFi-resistant melanoma cells, enhances MHC I expression and CD8+ T cells infiltration. Our findings point to targeting AR as a possible co-adjuvant approach for the prevention and management of the disease.
Constructing founder sets under allelic and non-allelic homologous recombination
Authors: Bonnet Konstantinn , Marschall Tobias , Doerr Daniel 
Published: May 2022

AbstractHomologous recombination between the maternal and paternal copies of a chromosome is a key mechanism for human inheritance and shapes population genetic properties of our species. However, a similar mechanism can also act between different copies of the same sequence, then called non-allelic homologous recombination (NAHR). This process can result in genomic rearrangements—including deletion, duplication, and inversion—and is underlying many genomic disorders. Despite its importance for genome evolution and disease, there is a lack of computational models to study genomic loci prone to NAHR.In this work, we propose such a computational model, providing a unified framework for both (allelic) homologous recombination and NAHR. Our model represents a set of genomes as a graph, where human haplotypes correspond to walks through this graph. We formulate two founder set problems under our recombination model, provide flow-based algorithms for their solution, and demonstrate scalability to problem instances arising in practice.
Systemic interindividual epigenetic variation in humans is associated with transposable elements and under strong genetic control
Authors: Gunasekara Chathura J. , MacKay Harry , Scott C. Anthony , Li Shaobo , Laritsky Eleonora , Baker Maria S. , Grimm Sandra L. , Jun Goo , Li Yumei , Chen Rui , Wiemels Joseph L. , Coarfa Cristian , Waterland Robert A. 
Published: May 2022

AbstractGenetic variants can modulate phenotypic outcomes via epigenetic intermediates, for example by affecting DNA methylation at CpG dinucleotides (methylation quantitative trait loci – mQTL). Here, we present the first large-scale assessment of mQTL at human genomic regions selected for interindividual variation in CpG methylation (correlated regions of systemic interindividual variation – CoRSIVs). We used target-capture bisulfite sequencing to assess DNA methylation at 4,086 CoRSIVs in multiple tissues from 188 donors in the NIH Genotype-Tissue Expression (GTEx) program (807 samples total). At CoRSIVs, as expected, DNA methylation in peripheral blood correlates with methylation and gene expression in internal organs. We also discovered unprecedented mQTL at these regions. Genetic influences on CoRSIV methylation are extremely strong (median R2=0.76), cumulatively comprising over 70-fold more human mQTL than detected in the most powerful previous study. Moreover, mQTL beta coefficients at CoRSIVs are highly skewed (i.e., the major allele predicts higher methylation). Both surprising findings were independently validated in a cohort of 47 non-GTEx individuals. Genomic regions flanking CoRSIVs show long-range enrichments for LINE-1 and LTR transposable elements; the skewed beta coefficients may therefore reflect evolutionary selection of genetic variants that promote their methylation and silencing. Analyses of GWAS summary statistics show that mQTL polymorphisms at CoRSIVs are associated with metabolic and other classes of disease. A focus on systemic interindividual epigenetic variants, clearly enhanced in mQTL content, should likewise benefit studies attempting to link human epigenetic variation to risk of disease. Our CoRSIV-capture reagents are commercially available from Agilent Technologies, Inc.Significance StatementPopulation epigeneticists have relied almost exclusively on CpG methylation arrays manufactured by Illumina. At most of the >400,000 CpG sites covered by those arrays, however, methylation does not vary appreciably between individuals. We previously identified genomic loci that exhibit systemic (i.e. not tissue-specific) interindividual variation in DNA methylation (CoRSIVs). These can be assayed in blood DNA and, unlike tissue-specific epigenetic variants, do not reflect interindividual variation in cellular composition. Here, studying just 4,086 CoRSIVs in multiple tissues of 188 individuals, we detect much stronger genetic influences on DNA methylation (mQTL) than ever before reported. Because interindividual epigenetic variation is essential for not only mQTL detection, but also for epigenetic epidemiology, our results indicate a major opportunity to advance this field.
Global statistical models of protein coevolution reveal higher-order sectors beyond those obtained from structure alone
Authors: Shiau Carina , Wang Haobo , Lee Young , Ovchinnikov Sergey 
Published: May 2022

1AbstractRecent methods have shown promise in using pairwise sequence coevolution predictions to illuminate physical interactions and functional relationships between pairs of protein residues. As a result, there has been an increased interest in identifying higher-order correlations between sequence positions in an effort to further understand how the multiple sequence alignment (MSA) encodes the conserved biological properties of a protein family. To this end, we propose a robust and generalizable spectral clustering model that can extract interconnected networks of coevolving residues – termed “protein sectors” – using pairwise sequence coevolution predicted by a global statistical model. We assess the statistical and evolutionary origins for protein sectors extracted from the MSA for 120 protein families. We show that protein sectors are extracted from a subset of densely connected components in the sequence coevolution matrix, many of which are not present in the pairwise residue contact graph that is constructed from the protein crystal structure, revealing the existence of networks of paired residues that are not necessarily in direct physical contact but are nonetheless evolutionarily coupled. We found that protein sectors form structurally connected entities in three-dimensional space, despite sector identification being independent of protein crystal structure. Interestingly, protein families with high structural similarity do not share similar protein sectors, suggesting that nuances in the sequence coevolution matrix can differentiate between the evolutionary histories of structurally-related protein families.
Transcriptome sequencing suggests that pre-mRNA splicing counteracts widespread intronic cleavage and polyadenylation
Authors: Vlasenok Mariia , Margasyuk Sergey , Pervouchine Dmitri D. 
Published: May 2022

AbstractAlternative splicing (AS) and alternative polyadenylation (APA) are two crucial steps in the post-transcriptional regulation of eukaryotic gene expression. Protocols capturing and sequencing RNA 3’-ends have uncovered widespread intronic polyadenylation (IPA) in normal and disease conditions, where it is currently attributed to stochastic variations in the pre-mRNA processing. Here, we took advantage of the massive amount of RNA-seq data generated by the Genotype Tissue Expression project (GTEx) to simultaneously identify and match tissue-specific expression of intronic polyadenylation sites with tissue-specific splicing. A combination of computational methods including the analysis of short reads with non-templated adenines revealed that APA events are more abundant in introns than in exons. While the rate of IPA in composite terminal exons and skipped terminal exons expectedly correlates with splicing, we observed a considerable fraction of IPA events that lack AS support and attributed them to spliced polyadenylated introns (SPI). We hypothesize that SPIs represent transient byproducts of a dynamic coupling between APA and AS, in which the spliceosome removes an intron after cleavage and polyadenylation have already occurred in it. These findings indicate that cotranscriptional pre-mRNA splicing could serve as a rescue mechanism to suppress premature transcription termination at intronic polyadenylation sites.
The BRD4S-LOXL2-MED1 interaction at the forefront of cell cycle transcriptional control in triple-negative breast cancer
Authors: Pascual-Reguant Laura , Tian Tian V. , Datta Debayan , Cianferoni Damiano , Kourtis Savvas , Gañez-Zapater Antoni , Cannatá Chiara , Serra-Camprubi Queralt , Espinar Lorena , Guirola Maria , Querol Jessica , Miró Canturri Andrea , Arribas Joaquin , Serrano Luis , Peiró Sandra , Sdelci Sara 
Published: May 2022

AbstractTriple-negative breast cancer often develops resistance to single-agent treatments, which can be circumvented with targeted combinatorial approaches. Here, we demonstrate that the simultaneous inhibition of LOXL2 and BRD4 cooperate to reduce triple-negative breast cancer proliferation in vitro and in vivo. Mechanistically, we reveal that LOXL2 interacts in the nucleus with the short isoform of BRD4 and MED1 to control cell cycle progression at the gene expression level via sustaining the formation of BRD4-MED1 nuclear transcriptional foci. Indeed, the pharmacological or transcriptional repression of LOXL2 provokes downregulation of cell cycle gene expression, G1-S cell cycle arrest, and loss of BRD4-MED1 foci. Our results indicate that the BRD4S-LOXL2-MED1 interaction is fundamental for the proliferation of triple-negative breast cancer. Therefore, targeting such interaction holds potential for the development of novel triple-negative breast cancer therapies.
Full-duplex acoustic interaction system for cognitive experiments with cetaceans
Authors: Rychen Jörg , Semoroz Julie , Eckerle Alexander , Hahnloser Richard HR , Kleinberger Rébecca 
Published: May 2022

AbstractCetaceans show high cognitive abilities and strong social bonds. Acoustics is their primary modality to communicate and sense the environment. Research on their echolocation and vocalizations with conspecifics and with humans typically uses visual and tactile systems adapted from research on primates or birds. Such research would benefit from a purely acoustic communication system in which signals flow in both directions simultaneously. We designed and implemented a full duplex system to acoustically interact with cetaceans in the wild, featuring digital echo-suppression. We pilot tested the system in Arctic Norway and achieved an echo suppression of 18 dB leaving room for technical improvements addressed in the discussion. Nevertheless, the system enabled vocal interaction with the underwater acoustic scene by allowing experimenters to listen while producing sounds. We describe our motivations, then present our pilot deployment and give examples of initial explorative attempts to vocally interact with wild orcas and humpback whales.