bluuebunny/crossref_metadata_2025 huggingface dataset:
Nanoneedles for targeted siRNA silencing of p16 in the Human Corneal Endothelium
Authors: Maurizi Eleonora , Martella Davide Alessandro , Schiroli Davide , Merra Alessia , Mustfa Salman Ahmad , Pellegrini Graziella , Macaluso Claudio , Chiappini Ciro
Published: May 2022

Nanoneedles can target nucleic acid transfection to primary cells at tissue interfaces with high efficiency and minimal perturbation. The corneal endothelium is an ideal target for nanoneedle-mediated RNAi aimed at enhancing its proliferative capacity, necessary for tissue regeneration. Here we develop a strategy for siRNA nanoninjection of the human corneal endothelium. We show that nanoneedles can deliver p16-targeting siRNA to primary human corneal endothelial cells in vitro without toxicity. The nanoinjection of siRNA induces p16 silencing and increases cell proliferation, as monitored by ki67 expression. Furthermore, siRNA nanoinjection targeting the human corneal endothelium is non-toxic ex vivo and silences p16 in transfected cells. These data indicate that nanoinjection can support targeted RNAi therapy for the treatment of endothelial corneal dysfunction.
G1-Cyclin2 (Cln2) promotes chromosome hypercondensation in eco1/ctf7 rad61 null cells during hyperthermic stress in Saccharomyces cerevisiae
Authors: Buskirk Sean , Skibbens Robert V.
Published: May 2022

Eco1/Ctf7 is a highly conserved acetyltransferase that activates cohesin complexes and is critical for sister chromatid cohesion, chromosome condensation, DNA damage repair, nucleolar integrity, and gene transcription. Mutations in the human homolog of ECO1 (ESCO2/EFO2), or in genes that encode cohesin subunits, result in severe developmental abnormalities and intellectual disabilities referred to as Roberts Syndrome (RBS) and Cornelia de Lange Syndrome (CdLS), respectively. In yeast, deletion of ECO1 results in cell inviability. Co-deletion of RAD61 (WAPL in humans), however, produces viable yeast cells. These eco1 rad61 double mutants, however, exhibit a severe temperature-sensitive growth defect, suggesting that Eco1 or cohesins respond to hyperthermic stress through a mechanism that occurs independent of Rad61. Here, we report that deletion of the G1 cyclin CLN2 rescues the temperature sensitive lethality otherwise exhibited by eco1 rad61 mutant cells, such that the triple mutant cells exhibit robust growth over a broad range of temperatures. While Cln1, Cln2 and Cln3 are functionally redundant G1 cyclins, neither CLN1 nor CLN3 deletions rescue the temperature-sensitive growth defects otherwise exhibited by eco1 rad61 double mutants. We further provide evidence that CLN2 deletion rescues hyperthermic growth defects independent of START and impacts the state of chromosome condensation. These findings reveal novel roles for Cln2 that are unique among the G1 cyclin family and appear critical for cohesin regulation during hyperthermic stress.
An Empirical Bayes Method for Differential Expression Analysis of Single Cells with Deep Generative Models
Authors: Boyeau Pierre , Regier Jeffrey , Gayoso Adam , Jordan Michael I. , Lopez Romain , Yosef Nir
Published: May 2022

Abstract

Detecting differentially expressed genes is important for characterizing subpopulations of cells. In scRNA-seq data, however, nuisance variation due to technical factors like sequencing depth and RNA capture efficiency obscures the underlying biological signal. Deep generative models have been extensively applied to scRNA-seq data, with a special focus on embedding cells into a low-dimensional latent space and correcting for batch effects. However, little attention has been given to the problem of utilizing the uncertainty from the deep generative model for differential expression. Furthermore, the existing approaches do not allow controlling for the effect size or the false discovery rate. Here, we present lvm-DE, a generic Bayesian approach for performing differential expression from using a fitted deep generative model, while controlling the false discovery rate. We apply the lvm-DE framework to scVI and scSphere, two deep generative models. The resulting approaches outperform the state-of-the-art methods at estimating the log fold change in gene expression levels, as well as detecting differentially expressed genes between subpopulations of cells.
Centris pallida(Hymenoptera: Apidae) male body size decreases across five decades
Authors: Barrett Meghan , Johnson Meredith G.
Published: May 2022

Historical data suggest that many bee species have declined in body size. Larger-bodied bees with narrow phenological and dietary breadth are most prone to declines in body size over time. This may be especially true in solitary, desert-adapted species that are vulnerable to climate change – such asCentris pallida(Hymenoptera: Apidae). In addition, body size changes in species with size-linked behaviors could threaten the prevalence of certain behavioral phenotypes long-term.C. pallidasolitary bees are found in the Sonoran Desert. Males use alternative reproductive tactics (ARTs) and are dimorphic in both morphology and behavior.C. pallidamale body size has been studied since the 1970s in the same population. We collected body size data in 2022 and combined it with published records from 1974-2022. We find a persistent decline in the mean head width of patrolling males, and shifts towards smaller body sizes in the populations of males found foraging and hovering. Both morphs declined in average body size, and the proportion of large-morph males in the population decreased by 8%. Mating males did not decline in mean body size over the last five decades. We discuss hypotheses related to the decline inC. pallidamale head width. Finally, we advocate forC. pallidaas an excellent study system for understanding the stability of ARTs with size-linked behavioral phenotypes.
Affinity-optimizing variants within cardiac enhancers disrupt heart development and contribute to cardiac traits
Authors: Jindal Granton A , Bantle Alexis T , Solvason Joe J , Grudzien Jessica L , D’Antonio-Chronowska Agnieszka , Lim Fabian , Le Sophia H , Larsen Reid O , Klie Adam , Frazer Kelly A , Farley Emma K
Published: May 2022

Enhancers direct precise gene expression patterns during development and harbor the majority of variants associated with disease. We find that suboptimal affinity ETS transcription factor binding sites are prevalent within Ciona and human developmental heart enhancers. Here we demonstrate in two diverse systems, Ciona intestinalis and human iPSC-derived cardiomyocytes (iPSC-CMs), that single nucleotide changes can optimize the affinity of ETS binding sites, leading to gain-of-function gene expression associated with heart phenotypes. In Ciona, ETS affinity-optimizing SNVs lead to ectopic expression and phenotypic changes including two beating hearts. In human iPSC-CMs, an affinity-optimizing SNV associated with QRS duration occurs within an SCN5A enhancer and leads to increased enhancer activity. Our mechanistic approach provides a much-needed systematic framework that works across different enhancers, cell types and species to pinpoint causal enhancer variants contributing to enhanceropathies, phenotypic diversity and evolutionary changes.

In Brief

The prevalent use of low-affinity ETS sites within developmental heart enhancers creates vulnerability within genomes whereby single nucleotide changes can dramatically increase binding affinity, causing gain-of-function enhancer activity that impacts heart development.

Highlights

ETS affinity-optimizing SNVs can lead to migration defects and a multi-chambered heart.

An ETS affinity-optimizing human SNV within an SCN5A enhancer increases expression and is associated with QRS duration.

Searching for ETS affinity-optimizing variants is a systematic and generalizable approach to pinpoint causal enhancer variants.
Lingyuanfructus: The First Gymno-angiosperm
Authors: Wang Xin
Published: May 2022

Distinct from gymnosperms with naked ovules, angiosperms are defined and characterized by their enclosed ovules. According to Darwinism, angiosperms should be derived from their ancestors that have exposed ovules. Theoretically and precisely, such a plant is expected to have started but not yet completed enclosing its ovules. This expectation is hitherto never met by fossil evidence. Here I report a fossil plant,Lingyuanfructus hibridagen. et sp. nov, from the Yixian Formation (Lower Cretaceous) of Liaoning, China meeting this expectation. With ovules naked and enclosed in a single specimen,Lingyuanfructusblurs the former distinct boundary between angiosperms and gymnosperms.
Genomic analyses of theLinumdistyly supergene reveal convergent evolution at the molecular level
Authors: Gutiérrez-Valencia Juanita , Fracassetti Marco , Berdan Emma L. , Bunikis Ignas , Soler Lucile , Dainat Jacques , Kutschera Verena E. , Losvik Aleksandra , Désamoré Aurélie , Hughes P. William , Foroozani Alireza , Laenen Benjamin , Pesquet Edouard , Abdelaziz Mohamed , Pettersson Olga Vinnere , Nystedt Björn , Brennan Adrian , Arroyo Juan , Slotte Tanja
Published: May 2022

Supergenes govern balanced polymorphisms in a wide range of systems. The reciprocal placement of stigmas and anthers in pin and thrum floral morphs of distylous species constitutes an iconic example of a balanced polymorphism governed by a supergene, the distylyS-locus. Recent studies have shown that thePrimulaandTurneradistyly supergenes are both hemizygous in thrums, but it remains unknown if hemizygosity is pervasive among distylyS-loci. Here we have characterized the genetic architecture and evolution of the distyly supergene inLinumby generating a chromosome-level genome assembly ofLinum tenue, followed by the identification of theS-locus using population genomic data. We show that hemizygosity and thrum-specific expression ofS-linked genes, including a pistil-expressed candidate gene for style length, are major features of theLinum S-locus. Structural variation is likely instrumental for recombination suppression, and although the non-recombining dominant haplotype has accumulated transposable elements,S-linked genes are not under relaxed purifying selection. Our findings reveal remarkable convergence in the genetic architecture and evolution of independently derived distyly supergenes. The chromosome-level genome assembly and detailed characterization of the distylyS-locus inL. tenuewill facilitate elucidation of molecular mechanisms underlying the different forms of flowers described by Darwin.
Orchestration of alternative splicing regulates bone marrow mesenchymal stem cells fate during aging
Authors: Xiao Ye , Cai Guang-Ping , Feng Xu , Guo Qi , Huang Yan , Su Tian , Li Chang-Jun , Luo Xiang-Hang , Zheng Yong-Jun , Yang Mi
Published: May 2022

Senescence and change of differentiation direction in bone marrow stromal cells (BMSCs) are two of the most important causes of age-related bone loss. As an important post-transcriptional regulatory pathway, alternative splicing (AS) regulates diversity of gene expression. However, the role of AS in BMSCs during aging remains poorly defined. Here we identify AS in specific genes disrupt gene expression pattern and result in age-related debility of BMSCs. We demonstrate the deficiency of splicing factor Y-box protein 1 (YBX1) result in mis-splicing in genes such as Fn1, Taz, Sirt2 and Sp7, further contributing to senescence and shift in differentiation direction of BMSCs during aging. Deletion or over-expression of YBX1 in BMSCs accelerate bone loss or stimulate bone formation in mice. Notably, we identify a small compound sciadopitysin which attenuate the degradation of YBX1 and attenuate bone loss in old mice. Our study demonstrates elaborately controlled RNA splicing governs cell fate of BMSCs and provides a potential therapeutic target for age-related osteoporosis.

This study demonstrates that YBX1 deficiency induces pre-mRNA mis-splicing and causes senescence and shift in differentiation direction of BMSCs and further accelerates aging-related bone loss. This study identifies Sciadopitysin could reverse this process by targeting YBX1.
Deciphering Hierarchical Chromatin Domains and Preference of Genomic Position Forming Boundaries in Single Mouse Embryonic Stem Cells
Authors: Ye Yusen , Zhang Shihua , Gao Lin , Zhu Yuqing , Zhang Jin
Published: May 2022

The exploration of single-cell 3D genome maps reveals that chromatin domains are indeed physical structures presenting in single cells and domain boundaries vary from cell to cell. However, exhaustive analysis of regulatory factor binding or elements for preference of the formation of chromatin domains in single cells has not yet emerged. To this end, we first develop a hierarchical chromatin domain structure identification algorithm (named as HiCS) from individual single-cell Hi-C maps, with superior performance in both accuracy and efficiency. The results suggest that in addition to the known CTCF-cohesin complex, Polycomb, TrxG, pluripotent protein families and other multiple factors also contribute to shaping chromatin domain boundaries in single embryonic stem cells. Different cooperation patterns of regulatory factors decipher the preference of genomic position categories forming boundaries. And the most extensive six types of retrotransposons differentially distributed in these genomic position categories with preferential localization.
Skeletal muscle Nox4 knockout prevents and Nox2 knockout blunts loss of maximal diaphragm force in mice with heart failure with reduced ejection fraction
Authors: Kumar Ravi A. , Hahn Dongwoo , Kelley Rachel C. , Muscato Derek R. , Shamoun Alex , Curbelo-Bermudez Nuria , Butler W. Greyson , Yegorova Svetlana , Ryan Terence E. , Ferreira Leonardo F.
Published: May 2022

Patients with heart failure with reduced ejection fraction (HFrEF) experience diaphragm weakness that contributes to the primary disease symptoms of fatigue, dyspnea, and exercise intolerance. Weakness in the diaphragm is related to excessive production of reactive oxygen species (ROS), but the exact source of ROS remains unknown. NAD(P)H Oxidases (Nox), particularly the Nox2 and 4 isoforms, are important sources of ROS within skeletal muscle that contribute to optimal cell function. There are reports of increased Nox activity in the diaphragm of patients and animal models of HFrEF, implicating these complexes as possible sources of diaphragm dysfunction in HFrEF. To investigate the role of these proteins on diaphragm weakness in HFrEF, we generated inducible skeletal muscle specific knockouts of Nox2 or Nox4 using the Cre-Lox system and assessed diaphragm function in a mouse model of HFrEF induced by myocardial infarction. Diaphragm maximal specific force measuredin vitrowas depressed by ~20% with HFrEF. Knockout of Nox4 provided full protection against the loss of maximal force (p< 0.01), while the knockout of Nox2 provided partial protection (7% depression,p< 0.01). Mitochondrial respiration measured in permeabilized diaphragm muscle bundles increased with HFrEF or the knockout of Nox4 from skeletal muscle fibers (p< 0.05). Knockout of Nox2 from skeletal myofibers improved survival from 50 to 80% following myocardial infarction (p= 0.026). Our findings show an important role for skeletal muscle NAD(P)H Oxidases contributing to loss of diaphragm maximal force in HFrEF, along with systemic pathophysiological responses following myocardial infarction.
Spatial differentiation of background matching strategies along a Late Pleistocene range expansion route
Authors: Spadavecchia Giada , Chiocchio Andrea , Costantini David , Liparoto Anita , Bisconti Roberta , Canestrelli Daniele
Published: May 2022

Late Pleistocene climate changes have deeply impacted the range dynamics of temperate species. While the genetic legacy of these dynamics has been widely investigated, little is known about their phenotypic consequences. Anti-predatory strategies offer intriguing opportunities to study phenotypic evolution in response to dispersal dynamics since the ability to avoid predation can be pivotal for populations colonizing new environments. Here we investigated the spatial differentiation of background colour matching strategies along a Late Pleistocene range expansion route of a temperate species, the Tyrrhenian tree frogHyla sarda. Using common-garden experiments, we investigated whether individuals sampled in the source area (Sardinia) and individuals sampled in the newly founded area (Corsica) differ in two components of the camouflage strategy: colour change abilities and background choice behaviour. We found a remarkable spatial structure in both colour change abilities and background choice behaviour, across the expansion range. Tree frogs from the source area displayed higher colour change abilities and a more pronounced preference for a greener background, with respect to tree frogs from the newly colonized area. We discuss these results in the context of the spatial and demographic components of the expansion dynamics. Our results support the intriguing hypothesis that Late Pleistocene biogeographic history might be an overlooked major player in shaping current spatial patterns of phenotypic traits variation across animal populations.
Mapping the epitopes of the Human Leukocyte Antigen E antibodies 3D12 and 4D12
Authors: Brackenridge Simon , Borrow Persephone , McMichael Andrew J.
Published: May 2022

The commonly used commercially available antibodies 3D12 and 4D12 recognise the human leukocyte antigen E (HLA-E) protein. 3D12 is known to exhibit minimal cross-reactivity with classical HLA-Ia allotypes and we confirm that this is also the case for 4D12. These antibodies bind different epitopes on HLA-E, and differ in their ability to recognise alleles of the major histocompatibility complex E (MHC-E) proteins of rhesus and cynomolgus macaques. Using hybrids of different MHC-E alleles, we have mapped the regions that are critical for the binding of these two antibodies. 3D12 recognises a region on the alpha 3 domain that is unique to HLA-E, on the opposite side to that bound by β2-microglobulin, while 4D12 recognises the start of the alpha 2 domain, adjacent to the C terminus of the presented peptide. Knowledge of the binding sites of these two antibodies will facilitate selection of the best antibody for a given application, and inform interpretation of the resulting data.
OntoContext, a new python package for gene contextualization based on the annotation of biomedical texts
Authors: Bedhiafi Walid , Thomas-Vaslin Véronique , Benammar Elgaaied Amel , Six Adrien
Published: May 2022

Motivation

The automatic mining for bibliography exploitation in given contexts is a challenge according to the increasing number of scientific publications and new concepts. Several indexing systems were developed for biomedical literature. However, such systems have failed to produce contextualised research of genes and proteins and automatically group texts according to shared concepts. In this paper, we present OntoContext, a contextualization system crossing the use of biomedical ontologies to annotate texts containing terms related to cell populations, anatomical locations and diseases and to extract gene, RNA or protein names in these contexts.

Results

OntoContext, a new python package contains two modules. The “annot” module for “annotation” function, is based on combination of morphosyntactic labelling and exact matching and on dictionaries derived from the Cell Ontology, the UBERON Ontology (anatomical context), the Human Disease Ontology and geniatagger, (which contains particular tags for gene-related names). The “annot” output is used as input for the second module “crisscross” generating lists of gene-related names obtained by crossing annotations from the three mentioned ontologies. OntoContext showed better performances than NCBO Annotator after evaluation on two text corpuses. OntoContext is freely available in the pypi.

Availability

https://pypi.python.org/pypi/OntoContext and https://github.com/walidbedhiafi/OntoContext1.

Contact

adrien.six@sorbonne-universite.fr
Neurologically healthy humans’ ability to make saccades toward unseen targets
Authors: Olkoniemi Henri , Hurme Mikko , Railo Henry
Published: May 2022

Some patients with a visual field loss due to a lesion in the primary visual cortex (V1) can shift their gaze to stimuli presented in their blind visual field. The extent to which a similar “blindsight” capacity is present in neurologically healthy individuals remains unknown. Using retinotopically navigated transcranial magnetic stimulation (TMS) of V1 (Experiment 1) and metacontrast masking (Experiment 2) to suppress conscious vision, we examined neurologically healthy humans’ ability to make saccadic eye movements toward visual targets that they reported not seeing. In the TMS experiment, the participants were more likely to initiate a saccade when a stimulus was presented, and they reported not seeing it, than in trials which no stimulus was presented. However, this happened only in a very small proportion (~8%) of unseen trials, suggesting that saccadic reactions were largely based on conscious perception. In both experiments, saccade landing location was influenced by unconscious information: When the participants denied seeing the target but made a saccade, the saccade was made toward the correct location (TMS: 68%, metacontrast: 63%) more often than predicted by chance. Signal detection theoretic measures suggested that in the TMS experiment, saccades toward unseen targets may have been based on weak conscious experiences. In both experiments, reduced visibility of the target stimulus was associated with slower and less precise gaze shifts. These results suggest that saccades made by neurologically healthy humans may be influenced by unconscious information, although the initiation of saccades is largely based on conscious vision.
Genome divergence across the Indo-Burman arc: a tale of two peacocks
Authors: Patil Ajinkya Bharatraj , Vijay Nagarjun
Published: May 2022

Exaggerated 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

Mitochondria 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

Clustering 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

CRISPR 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

Genome 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

Inositol-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

Motoneurons 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

Taste 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

Melanoma 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

Homologous 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

Genetic 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 Statement

Population 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

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Recent 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

Alternative 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

Triple-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.
Evolutionary rescue is promoted in compact cellular populations
Authors: Aif Serhii , Appold Nico , Kampman Lucas , Hallatschek Oskar , Kayser Jona
Published: May 2022

Mutation-mediated drug resistance is one of the primary causes for the failure of modern antibiotic or chemotherapeutic treatment. Yet, in the absence of treatment many drug resistance mutations are associated with a fitness cost and therefore subject to purifying selection. While, in principle, resistant subclones can escape purifying selection via subsequent compensatory mutations, current models predict such evolutionary rescue events to be exceedingly unlikely. Here, we show that the probability of evolutionary rescue, and the resulting long-term persistence of drug resistant subclones, is dramatically increased in dense microbial populations via an inflation-selection balance that stabilizes the less-fit intermediate state. Tracking the entire evolutionary trajectory of fluorescence-augmented “synthetic mutations” in expanding yeast colonies, we trace the origin of this balance to the opposing forces of radial population growth and a clone-width-dependent weakening of selection pressures, inherent to crowded populations. Additionally conducting agent-based simulations of tumor growth, we corroborate the fundamental nature of the observed effects and demonstrate the potential impact on drug resistance evolution in cancer. The described phenomena should be considered when predicting the evolutionary dynamics of any sufficiently dense cellular populations, including pathogenic microbial biofilms and solid tumors, and their response to therapeutic interventions. Our experimental approach could be extended to systematically study rates of specific evolutionary trajectories, giving quantitative access to the evolution of complex adaptations.
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

Cetaceans 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.