bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reticulate evolution in a neutral model: speciation, extinctions, and hybridizations
Authors: Botelho Larissa Lubiana , Darcie Marquitti Flavia Maria , de Aguiar Marcus Aloizio Martinez 
Published: July 2021

AbstractEvolution is usually pictured as a tree where ancient species branch into new ones and eventually disappear. In this simplified view, the balance between speciation and extinction fully determines the diversity of life. Hybridization, how-ever, introduces another level of complexity, allowing neighboring branches of the tree to interact, mixing their genetic content. This generates further diversity leading to reticulated phylogenetic trees. In this paper we study processes of speciation, extinction and hybridization using a genetically and spatially explicit neutral model of diversification. Speciation, extinction and hybridization events are tracked throughout the evolutionary process leading to complete and exact phylogenetic trees. We found that genome size played a key role in these processes, increasing the extinction rate and decreasing the hybridization rate. In our simulations, hybridization after one speciation event occurred throughout the evolutionary process but hybridization after two speciation events was only observed during the initial radiation. Most hybridization occurred between relatively abundant species, discarding lack of sexual partners or small population sizes as potential causes. We found that hybridization occurred mostly because of opportunity (genetic similarity and spatial proximity) between recently branched species, when the number of accumulated mutations is not yet too large.
CUT&Tag-BS: an efficient and low-cost method for simultaneous profiling of histone modification and DNA methylation
Authors: Li Ruifang , Grimm Sara A , Wade Paul A 
Published: July 2021

SummaryIt remains a challenge to decipher the complex relationship between DNA methylation, histone modification, and the underlying DNA sequence with limited input material. Here, we developed an efficient, low-input, and low-cost method for simultaneous profiling of genomic localization of histone modification and methylation status of the underlying DNA at single-base resolution from the same cells in a single experiment by integrating CUT&Tag with tagmentation-based bisulfite sequencing (CUT&Tag-BS). We demonstrated the validity of our method for both active and repressive histone modifications using 250,000 mouse ESCs. CUT&Tag-BS shows similar enrichment patterns of histone modification to those observed in non-bisulfite-treated control; it further reveals that H3K4me1-marked regions are mostly CpG-poor, lack methylation concordance, and exhibit prevalent DNA methylation heterogeneity among the cells. We anticipate that CUT&Tag-BS will be widely applied to directly address the genomic relationship between DNA methylation and histone modification, especially in low-input scenarios with precious biological samples.
Granulocyte-colony stimulating factor (G-CSF) enhances cocaine effects in the nucleus accumbens via a dopamine release-based mechanism
Authors: Brady Lillian J. , Erickson Kirsty R. , Lucerne Kelsey E. , Osman Aya , Kiraly Drew D. , Calipari Erin S. 
Published: July 2021

AbstractCocaine use disorder is associated with alterations in immune function including altered expression of multiple peripheral cytokines in humans - several of which correlate with drug use. Individuals suffering from cocaine use disorder show altered immune system responses to drug-associated cues, highlighting the interaction between the brain and immune system as a critical factor in the development and expression of cocaine use disorder. We have previously demonstrated in animal models that cocaine use upregulates expression of granulocyte colony stimulating factor (G-CSF) - a pleiotropic cytokine - in the serum and the nucleus accumbens (NAc). G-CSF signaling has been causally linked to behavioral responses to cocaine across multiple behavioral domains. The goal of this study was to define whether increases in G-CSF alter the pharmacodynamic effects of cocaine on the dopamine system and whether this occurs via direct mechanisms within local NAc microcircuits. We find that systemic G-CSF injection increases cocaine effects on dopamine terminals. The enhanced dopamine levels in the presence of cocaine occur through a release-based mechanism, rather than through effects on the dopamine transporter - as uptake rates were unchanged following G-CSF treatment. Critically, this effect could be recapitulated by acute bath application of G-CSF to dopamine terminals, an effect that was occluded by prior G-CSF treatment, suggesting a similar mechanistic basis for direct and systemic exposures. This work highlights the critical interaction between the immune system and psychostimulant effects that can alter drug responses and may play a role in vulnerability to cocaine use disorder.
A Bayesian model selection approach to mediation analysis
Authors: Crouse Wesley L , Keele Gregory R , Gastonguay Madeleine S , Churchill Gary A , Valdar William 
Published: July 2021

AbstractMediation analysis is a powerful tool for discovery of causal relationships. We describe a Bayesian model selection approach to mediation analysis that is implemented in our bmediatR software. Using simulations, we show that bmediatR performs as well or better than established methods including the Sobel test, while allowing greater flexibility in both model specification and in the types of inference that are possible. We applied bmediatR to genetic data from mice and human cell lines to demonstrate its ability to derive biologically meaningful findings. The Bayesian model selection framework is extensible to support a wide variety of mediation models.
Osteopontin deficiency leads to the resolution of prostatic fibrosis and inflammation
Authors: Popovics Petra , Jain Asha , Skalitzky Kegan O. , Schroeder Elise , Ruetten Hannah M. , Cadena Mark , Uchtmann Kristen S. , Vezina Chad M. , Ricke William A. 
Published: July 2021

ABSTRACTFibrogenic and inflammatory processes in the prostate are linked to the development of lower urinary tract symptoms (LUTS) in men. Our previous studies identified that osteopontin (OPN), a pro-fibrotic cytokine, is abundant in the prostate of men with LUTS and its secretion is stimulated by inflammatory cytokines potentially to drive fibrosis. This study investigates whether the lack of OPN ameliorates inflammation and fibrosis in the mouse prostate.We instilled uropathogenic E. coli (UTI89) or saline (control) transurethrally to C57BL/6J (WT) or Spp1tm1Blh/J (OPN-KO) mice and collected the prostates one or 8 weeks later. We found that OPN mRNA and protein expression were significantly induced by E. coli-instillation in the dorsal prostate (DP) after one week in WT mice. Deficiency in OPN expression led to decreased inflammation and fibrosis and the prevention of urinary dysfunction after 8 weeks. RNAseq analysis identified that E. coli-instilled WT mice expressed increased levels of inflammatory and fibrotic marker RNAs compared to OPN-KO mice including Col3a1, Dpt, Lum and Mmp3 which were confirmed by RNAscope.Our results indicate that OPN is induced by inflammation and prolongs the inflammatory state; genetic blockade of OPN accelerates recovery after inflammation, including a resolution of prostate fibrosis.
Evolutionary Sparse Learning for phylogenomics
Authors: Kumar Sudhir , Sharma Sudip 
Published: July 2021

AbstractWe introduce a supervised machine learning approach with sparsity constraints for phylogenomics, referred to as evolutionary sparse learning (ESL). ESL builds models with genomic loci—such as genes, proteins, genomic segments, and positions—as parameters. Using the Least Absolute Shrinkage and Selection Operator (LASSO), ESL selects only the most important genomic loci to explain a given phylogenetic hypothesis or presence/absence of a trait. ESL does not directly model conventional parameters such as rates of substitutions between nucleotides, rate variation among positions, and phylogeny branch lengths. Instead, ESL directly employs the concordance of variation across sequences in an alignment with the evolutionary hypothesis of interest. ESL provides a natural way to combine different molecular and non-molecular data types and incorporate biological and functional annotations of genomic loci directly in model building. We propose positional, gene, function, and hypothesis sparsity scores, illustrate their use through an example and suggest several applications of ESL. The ESL framework has the potential to drive the development of a new class of computational methods that will complement traditional approaches in evolutionary genomics. ESL’s fast computational times and small memory footprint will also help democratize big data analytics and improve scientific rigor in phylogenomics.
A Quantitative Paradigm for Water Assisted Proton Transport Through Proteins and Other Confined Spaces
Authors: Li Chenghan , Voth Gregory A. 
Published: July 2021

AbstractWater assisted proton transport through confined spaces influences many phenomena in biomolecular and nanomaterial systems. In such cases, the water molecules that fluctuate in the confined pathways provide the environment and the medium for the hydrated excess proton migration via Grotthuss shuttling. However, a definitive collective variable (CV) that accurately couples the hydration and the connectivity of the proton wire with the proton translocation has remained elusive. To address this important challenge – and thus to define a new quantitative paradigm for facile proton transport in confined spaces – a CV is derived in this work from graph theory, which is verified to accurately describe water wire formation and breakage coupled to the proton translocation in carbon nanotubes and the Cl−/H+ antiporter protein, ClC-ec1. Significant alterations in the conformations and thermodynamics of water wires are uncovered after introducing an excess proton into them. Large barriers in the proton translocation free energy profiles are found when water wires are defined to be disconnected according to the new CV, even though the pertinent confined space is still reasonably well hydrated and – by the simple measure of the mere existence of a water structure – the proton transport would have been predicted to be facile via that oversimplified measure. In this new paradigm, however, the simple presence of water is not sufficient for inferring proton translocation since an excess proton itself is able to drive hydration and, additionally, the water molecules themselves must be adequately connected to facilitate any successful proton transport.Significance StatementAs first proposed more than 200 years ago by Grotthuss, proton transport is enabled by a chemical bond-breaking and bond-making proton hopping mechanism through water networks or “wires”, often contained within confined systems such as protein channels or nanotubes. Herein, concepts from graph theory are utilized in order to define a new continuously differentiable collective variable (CV) for water wire connectivity and facile proton transport. As such, the water connectivity can be explicitly quantified via free energy sampling, to both qualitatively and quantitatively describe the thermodynamics and kinetics of water-facilitated proton transport via Grotthuss hopping – something that has been lacking since the first conceptual identification of this key chemical process in Nature.
Specialized neurons in the right habenula mediate response to aversive olfactory cues
Authors: Choi Jung-Hwa , Duboué Erik , Macurak Michelle , Chanchu Jean-Michael , Halpern Marnie E. 
Published: July 2021

AbstractHemispheric specializations are well studied at the functional level but less is known about the underlying neural mechanisms. We identified a small cluster of cholinergic neurons in the right dorsal habenula (dHb) of zebrafish, defined by their expression of the lecithin retinol acyltransferase domain containing 2a (lratd2a) gene and their efferent connections with a subregion of the ventral interpeduncular nucleus (vIPN). The unilateral lratd2a-expressing neurons are innervated by a subset of mitral cells from both the left and right olfactory bulb and are activated upon exposure of adult zebrafish to the aversive odorant cadaverine that provokes avoidance behavior. Using an intersectional strategy to drive expression of the botulinum neurotoxin specifically in these neurons, we find that adults no longer show protracted avoidance to cadaverine. Mutants with left-isomerized dHb that lack these neurons are less repelled by cadaverine and their behavioral response to alarm substance, a potent aversive cue, is diminished. However mutants in which both dHb have right identity appear more reactive to alarm substance. The results implicate an asymmetric dHb-vIPN neural circuit in processing of aversive olfactory cues and modulating resultant behavioral responses.
Synthetic genome rearrangement reveals dynamics of chromosome evolution shaped by hierarchical chromatin organization
Authors: Zhou Sijie , Wu Yi , Zhao Yu , Zhang Zhen , Jiang Limin , Liu Lin , Zhang Yan , Tang Jijun , Yuan Ying-Jin 
Published: July 2021

AbstractSynthetic genome evolution provides a dynamic approach to systematically and straightforwardly explore evolutionary processes. SCRaMbLE is an evolutionary system intrinsic to the synthetic yeast genome that can rapidly drive structural variations. Here, we detect over 260,000 rearrangement events after SCRaMbLEing of a novel yeast strain harboring 6 synthetic yeast chromosomes. Remarkably, we find that the rearrangement events exhibit a specific landscape of rearrangement frequency. We further reveal that the landscape is shaped by combinatorial effects of chromatin accessibility and spatial contact probability. The rearrangements tend to occur in 3D spatially proximal and chromatin-accessible regions. Enormous numbers of rearrangements by SCRaMbLE provide a driving force to potentiate directed genome evolution, and investigation of the rearrangement landscape offers mechanistic insights into the dynamics of genome evolution.
Somatic point mutations are enriched in long non-coding RNAs with possible regulatory function in breast cancer
Authors: Rezaie Narges , Bayati Masroor , Tahaei Maedeh Sadat , Hamidi Mehrab , Khorasani Sadegh , Lovell Nigel H. , Breen James , Rabiee Hamid R. , Alinejad-Rokny Hamid 
Published: July 2021

AbstractDe novo somatic point mutations identified in breast cancer are predominantly non-coding and typically attributed to altered regulatory elements such as enhancers and promoters. However, while the non-coding RNAs (ncRNAs) form a large portion of the mammalian genome, their biological functions are mostly poorly characterized in cancers. In this study, using a newly developed tool, SomaGene, we reanalyze de novo somatic point mutations from the International Cancer Genome Consortium (ICGC) whole-genome sequencing data of 1,855 breast cancers. We identify 929 candidates of ncRNAs that are significantly and explicitly mutated in breast cancer samples. By integrating data from the ENCODE regulatory features and FANTOM5 expression atlas, we show that the candidate ncRNAs in breast cancer samples significantly enrich for active chromatin histone marks (1.9 times), CTCF binding sites (2.45 times), DNase accessibility (1.76 times), HMM predicted enhancers (2.26 times) and eQTL polymorphisms (1.77 times). Importantly, we show that the 929 ncRNAs contain a much higher level (3.64 times) of breast cancer-associated genome-wide association (GWAS) single nucleotide polymorphisms (SNPs) than genome-wide expectation. Such enrichment has not been seen with GWAS SNPs from other diseases. Using breast tissue related Hi-C data we then show that 82% of our candidate ncRNAs (1.9 times) significantly interact with the promoter of protein-coding genes, including previously known cancer-associated genes, suggesting the critical role for candidate ncRNA genes in activation of essential regulators of development and differentiation in breast cancer. We provide an extensive web-based resource (http://ncrna.ictic.sharif.edu), to communicate our results with the research community. Our list of breast cancer-specific ncRNA genes has the potential to provide a better understanding of the underlying genetic causes of breast cancer. Lastly, the tool developed in this study can be used in the analysis of somatic mutations in all cancers.
Phylogenomic analyses of echinoid diversification prompt a re-evaluation of their fossil record
Authors: Koch Nicolás Mongiardino , Thompson Jeffrey R , Hatch Avery S , McCowin Marina F , Armstrong A Frances , Coppard Simon E , Aguilera Felipe , Bronstein Omri , Kroh Andreas , Mooi Rich , Rouse Greg W 
Published: July 2021

AbstractEchinoids are key components of modern marine ecosystems. Despite a remarkable fossil record, the emergence of their crown group is documented by few specimens of unclear affinities, rendering much of their early history uncertain. The origin of sand dollars, one of its most distinctive clades, is also unclear due to an unstable phylogenetic context and discrepancies between molecular divergence times and fossil evidence. We employ seventeen novel genomes and transcriptomes to build a phylogenomic dataset with a near-complete sampling of major lineages. With it, we revise the phylogeny and divergence times of echinoids, and place their history within the broader context of echinoderm evolution. We also introduce the concept of a chronospace—a multidimensional representation of node ages—and use it to explore the effects of using alternative gene samples, models of molecular evolution, and clock priors. We find the choice of clock model to have the strongest impact on divergence times, while the use of site-heterogeneous models shows little effects. The choice of loci shows an intermediate impact, affecting mostly deep Paleozoic nodes, for which clock-like genes recover dates more congruent with fossil evidence. Our results reveal that crown group echinoids originated in the Permian and diversified rapidly in the Triassic, despite the relative lack of fossil evidence for this early diversification. We also clarify the relationships among sand dollars and their close relatives, showing that the genusApatopygusrepresents a relict lineage with a deep Jurassic origin. Surprisingly, the origin of sand dollars is confidently dated to the Cretaceous, implying ghost ranges spanning approximately 50 million years, a remarkable discrepancy with their rich fossil record.
PSINDB: A comprehensive database of postsynaptic protein-protein interactions
Authors: Kalman Zsofia E. , Dudola Dániel , Mészáros Bálint , Gáspári Zoltán , Dobson Laszlo 
Published: July 2021

AbstractThe postsynaptic region is the receiving part of the synapse comprising thousands of proteins forming an elaborate and dynamically changing network indispensable for the molecular mechanisms behind fundamental phenomena such as learning and memory. Despite the growing amount of information about individual protein-protein interactions in this network, these data are mostly scattered in the literature or are stored in generic databases that are not designed to display aspects which are fundamental to understanding postsynaptic functions. To overcome these limitations we collected postsynaptic protein-protein interactions (PPIs) together with a high amount of detailed structural and biological information and launched a freely available resource, the Postsynaptic Interaction Database (PSINDB) to make these data and annotations accessible. PSINDB includes tens of thousands of binding regions together with structural features mediating and regulating the formation of PPIs, annotated with detailed experimental information about each interaction. PSINDB is expected to be useful for numerous aspects of molecular neurobiology research, from experiment design to network and systems biology-based modeling and analysis of changes in the protein network upon various stimuli. PSINDB is available at http://psindb.itk.ppke.hu/.
Tissue-engineered collagenous fibrous cap models to systematically elucidate atherosclerotic plaque rupture
Authors: Wissing T.B. , Van der Heiden K. , Serra S.M. , Smits A.I.P.M. , Bouten C.V.C. , Gijsen F.J.H. 
Published: July 2021

AbstractA significant amount of vascular thrombotic events is associated with rupture of the fibrous cap that overlie atherosclerotic plaques. Cap rupture is however difficult to predict due to the heterogenous composition of the plaque, unknown material properties, and the stochastic nature of the event. Here, we aim to create tissue engineered human fibrous cap models with a variable but controllable collagen composition, suitable for mechanical testing, to scrutinize the reciprocal relationships between composition and mechanical properties.Myofibroblasts were cultured in 1 × 1.5 cm-sized fibrin-based constrained gels for 21 days according to established (dynamic) culture protocols (i.e. static, intermittent or continuous loading) to vary collagen composition (e.g. amount, type and organization). At day 7, a soft 2 mm Ø fibrin inclusion was introduced in the centre of each tissue to mimic the soft lipid core, simulating the heterogeneity of a plaque.Results demonstrate reproducible collagenous tissues, that mimic the bulk mechanical properties of human caps and vary in collagen composition due to the presence of an successfully integrated soft inclusion and the culture protocol applied. The models can be deployed to assess tissue mechanics, evolution and failure of fibrous caps or complex heterogeneous tissues in general.
Fast Grip Force Adaptation To Friction Relies On Localized Fingerpad Strains
Authors: Schiltz Félicien , Delhaye Benoit P. , Crevecoeur Frédéric , Thonnard Jean-Louis , Lefèvre Philippe 
Published: July 2021

AbstractHumans can quickly adjust their grip force to a change in friction at the object-skin interface during dexterous manipulation in a precision grip. To perform this adjustment, they rely on the feedback of the mechanoreceptive afferents innervating the fingertip skin. Because these tactile afferents encode information related to skin deformation, the nature of the feedback signaling a change in friction must somehow originate from a difference in the way the skin deforms when manipulating objects of different frictions. To better characterize the origin of the underlying sensory events, we asked human participants to perform a grip-lifting task with a manipulandum equipped with an optical imaging system. This system enabled to monitor fingertip skin strains through transparent plates of glass that had different levels of friction. We observed that, following an unexpected change in friction, participants adapted their grip force within 370ms after contact with the surface. By comparing the deformation patterns when unexpectedly switching from a high to a low friction condition, we found a significant increase in skin deformation inside the contact area arising over 100ms before the motor response, during the loading phase, suggesting that local and partial deformation patterns prior to lift-off are used in the nervous system to adjust the grip force as a function of the frictional condition.