bluuebunny/crossref_metadata_2025_split huggingface dataset:
Decoding DNA sequence-driven evolution of the human brain epigenome at cellular resolution
Authors: Caglayan Emre , Konopka Genevieve 
Published: September 2023

AbstractDNA-based evolutionary comparisons of regulatory genomic elements enable insight into functional changes, overcoming tissue inaccessibility. Here, we harnessed adult and fetal cortex single-cell ATAC-seq datasets to uncover DNA substitutions specific to the human and human-ancestral lineages within apes. We found that fetal microglia identity is evolutionarily divergent in all lineages, whereas other cell types are conserved. Using multiomic datasets, we further identified genes linked to multiple lineage-divergent gene regulatory elements and implicated biological pathways associated with these divergent features. We also uncovered patterns of transcription factor binding site evolution across lineages and identified expansion of bHLH-PAS factor targets in human-hominin lineages, and MEF2 factor targets in the ape lineage. Finally, conserved features were more enriched in brain disease variants, whereas there was no distinct enrichment on the human lineage compared to its ancestral lineages. Our study identifies major evolutionary patterns in the human brain epigenome at cellular resolution.
Multiple parallel expansions of bilaterian-like phototransduction gene families in the eyeless Anthozoa
Authors: Hansen Stacey , Payne Meghan , McCulloch Kyle J 
Published: September 2023

AbstractOpsin-mediated phototransduction cascades in photoreceptor cells are primarily responsible for light-mediated behaviors in animals. Although some visual cascades are well-studied, phototransduction mediated by non-visual opsins and in non-model animal lineages are poorly characterized. In the Cnidaria (jellyfish, corals, sea anemones etc.), the sister group to Bilateria (vertebrates, arthropods, mollusks etc.), limited evidence suggests some overlap with bilaterian phototransduction. This raises the question of whether phototransduction pathways arose a single time early in animal evolution or if light signaling cascades have evolved multiple times. These evolutionary patterns remain obscured because almost nothing is known about phototransduction in a major group within Cnidaria, the eyeless Anthozoa (corals, sea anemones, sea pens etc.). To better understand whether bilaterian-like phototransduction could be present in Anthozoa, we phylogenetically characterized 63 genes in 12 protein families known to be crucial in two types of bilaterian phototransduction in the sea anemoneNematostella vectensis. Using high quality genomic data fromN. vectensis,we took a candidate gene approach to find phototransduction genes and characterize their expression in development and regeneration. We found thatN. vectensispossesses the core suite of proteins for both r-opsin and c-opsin mediated phototransduction. In addition, several new gene subfamilies were identified, particularly in the G protein subunits and TRP channels, and many were anthozoan-specific. We identified a novel G protein α subunit family, which we call GαVI, and characterized its expression inN. vectensiswithin situhybridization. This expansion of phototransduction genes correlates with a large anthozoan-specific radiation in opsin number, suggesting possible coevolution of receptor and signaling diversity in Anthozoa. While further functional experiments on these genes are needed, our findings are in line with the hypothesis that the common ancestor of Eumetazoa had at least two related phototransduction cascades which then further diversified in each animal lineage.
Diverse signatures of convergent evolution in cacti-associated yeasts
Authors: Gonçalves Carla , Harrison Marie-Claire , Steenwyk Jacob L. , Opulente Dana A. , LaBella Abigail L. , Wolters John F. , Zhou Xiaofan , Shen Xing-Xing , Groenewald Marizeth , Hittinger Chris Todd , Rokas Antonis 
Published: September 2023

AbstractMany distantly related organisms have convergently evolved traits and lifestyles that enable them to live in similar ecological environments. However, the extent of phenotypic convergence evolving through the same or distinct genetic trajectories remains an open question. Here, we leverage a comprehensive dataset of genomic and phenotypic data from 1,049 yeast species in the subphylum Saccharomycotina (Kingdom Fungi, Phylum Ascomycota) to explore signatures of convergent evolution in cactophilic yeasts, ecological specialists associated with cacti. We inferred that the ecological association of yeasts with cacti arose independently ∼17 times. Using machine-learning, we further found that cactophily can be predicted with 76% accuracy from functional genomic and phenotypic data. The most informative feature for predicting cactophily was thermotolerance, which is likely associated with duplication and altered evolutionary rates of genes impacting the cell envelope in several cactophilic lineages. We also identified horizontal gene transfer and duplication events of plant cell wall-degrading enzymes in distantly related cactophilic clades, suggesting that putatively adaptive traits evolved through disparate molecular mechanisms. Remarkably, multiple cactophilic lineages and their close relatives are emerging human opportunistic pathogens, suggesting that the cactophilic lifestyle—and perhaps more generally lifestyles favoring thermotolerance—may preadapt yeasts to cause human disease. This work underscores the potential of a multifaceted approach involving high throughput genomic and phenotypic data to shed light onto ecological adaptation and highlights how convergent evolution to wild environments could facilitate the transition to human pathogenicity.
3D-intrusions transport active surface microbial assemblages to the dark ocean
Authors: Freilich Mara A. , Poirier Camille , Dever Mathieu , Alou-Font Eva , Allen John , Cabornero Andrea , Sudek Lisa , Choi Chang Jae , Ruiz Simón , Pascual Ananda , Farrar J. Thomas , Johnston T.M. Shaun , D’Asaro Eric , Worden Alexandra Z. , Mahadevan Amala 
Published: September 2023

AbstractSubtropical oceans contribute significantly to global primary production, but the fate of the picophytoplankton that dominate in these low nutrient regions is poorly understood. Working in the subtropical Mediterranean, we demonstrate that subduction of water at ocean fronts generates 3D intrusions with uncharacteristically high carbon, chlorophyll, and oxygen that extend below the sunlit photic-zone into the dark ocean. These contain “fresh” picophytoplankton assemblages that resemble the photic-zone regions where the water originated. Intrusions propagate depth-dependent seasonal variations in microbial assemblages into the ocean interior. Strikingly, the intrusions included dominant biomass contributions from non-photosynthetic bacteria and enrichment of enigmatic heterotrophic bacterial lineages. Thus, the intrusions not only deliver material that differs in composition and nutritional character from sinking detrital particles, but also drive shifts in bacterial community composition, organic matter processing, and interactions between surface and deep communities. Modeling efforts paired with global observations demonstrate that subduction can flux similar magnitudes of particulate organic carbon as sinking export, but is not accounted for in current export estimates and carbon cycle models. Intrusions formed by subduction are a particularly important mechanism for enhancing connectivity between surface and upper mesopelagic ecosystems in stratified subtropical ocean environments that are expanding due to the warming climate.
Range expansion is both slower and more variable with rapid evolution across a spatial gradient in temperature
Authors: Usui Takuji , Angert Amy L. 
Published: September 2023

ABSTRACTRapid evolution in colonizing populations can alter our ability to predict future range expansions. Recent theory suggests that the dynamics of replicate range expansions are less variable, and hence more predictable, with increased selection at the expanding range front. Here, we test whether selection from environmental gradients across space produces more consistent range expansion speeds, using the experimental evolution of replicate duckweed populations colonizing landscapes with and without a temperature gradient. We found that range expansion across a temperature gradient was slower on average, with range-front populations displaying higher population densities, and genetic signatures and trait changes consistent with directional selection. Despite this, we found that with a spatial gradient range expansion speed became more variable and less consistent among replicates over time. Our results therefore challenge current theory, highlighting that chance can still shape the genetic response to selection to influence our ability to predict range expansion speeds.
Partitioning heritability using single-cell multi-omics identifies a novel macrophage subpopulation conveying genetic risks of coronary artery disease
Authors: Jiang Jiahao , Hiron Thomas K. , Agbaedeng Thomas , Malhotra Yashaswat , Drydale Edward , Bancroft James , Ng Esther , Reschen Michael E. , Davison Lucy J. , O’Callaghan Chris A. 
Published: September 2023

AbstractBackgroundCoronary artery disease (CAD), the leading cause of death worldwide, is influenced by both environmental and genetic factors. While over 250 genetic risk loci have been identified through genome-wide association studies, the specific causal variants and their regulatory mechanisms are still largely unknown, particularly in disease-relevant cell types like macrophages.MethodsWe utilized single-cell RNA-seq (scRNA-seq) and single-cell multi-omics approaches in primary human monocyte-derived macrophages to explore the transcriptional regulatory network involved in a critical pathogenic event of coronary atherosclerosis—the formation of lipid-laden foam cells. Meta-analysis of scRNA-seq datasets from 26 human plaque samples was undertaken to provide a comprehensive atlas of lesional macrophages and to correlate subpopulationsin vivoandex vivo. The genetic risk levels of CAD were assessed by partitioning disease heritability across different macrophage subpopulations.ResultsWe identified a novel macrophage subpopulation, termed lipid-handling macrophages, bothex vivoandin vivo, and identified associated marker genes, transcription regulators, and functional pathways. 18,782 cis-regulatory elements were identified by jointly profiling the gene expression and chromatin accessibility of >5000 macrophages. Integration with CAD GWAS data prioritized 121 CAD-related genetic variants and 56 candidate causal genes. We showed that CAD heritability was not uniformly distributed and was particularly enriched in the gene programs of lipid-handling macrophages. We investigated the cis-regulatory effect of a risk variant rs10488763 onFDX1,implicating the recruitment of AP-1 and C/EBP-beta in the causal mechanisms at this locus.ConclusionsOur results provide genetic evidence of the divergent roles of macrophage subsets in atherogenesis and highlight lipid-handling macrophages as a key sub-population through which genetic variants actively influence disease. These findings provide an unbiased framework for functional fine-mapping of GWAS results using single-cell multi-omics and offer new insights into the genotype-environment interactions underlying atherosclerotic disease.
Identification of Genetic and Genomic Influences on Progressive Ethanol Consumption in Diversity Outbred Mice
Authors: Smith ML , Sergi Z , Mignogna KM , Rodriguez NE , Tatom Z , MacLeod L , Choi KB , Philip V , Miles MF 
Published: September 2023

AbstractGenetic factors play a significant role in the risk for development of alcohol use disorder (AUD). Using 3-bottle choice intermittent access ethanol (IEA), we have employed the Diversity Outbred (DO) mouse panel as a model of alcohol use disorder in a genetically diverse population. Through use of gene expression network analysis techniques, in combination with expression quantitative trait loci (eQTL) mapping, we have completed an extensive analysis of the influence of genetic background on gene expression changes in the prefrontal cortex (PFC). This approach revealed that, in DO mice, genes whose expression was significantly disrupted by intermittent ethanol in the PFC also tended to be those whose expression correlated to intake. This finding is in contrast to previous studies of both mice and nonhuman primates. Importantly, these analyses identified genes involved in myelination in the PFC as significantly disrupted by IEA, correlated to ethanol intake, and having significant eQTLs. Genes that code for canonical components of the myelin sheath, such asMbp, also emerged as key drivers of the gene expression response to intermittent ethanol drinking. Several regulators of myelination were also key drivers of gene expression, and had significant QTLs, indicating that genetic background may play an important role in regulation of brain myelination. These findings underscore the importance of disruption of normal myelination in the PFC in response to prolonged ethanol exposure, that genetic variation plays an important role in this response, and that this interaction between genetics and myelin disruption in the presence of ethanol may underlie previously observed behavioral changes under intermittent access ethanol drinking such as escalation of consumption.
Small molecule correctors divert CFTR-F508del from ERAD by stabilizing sequential folding states
Authors: Riepe Celeste , Wąchalska Magda , Deol Kirandeep K. , Amaya Anais K. , Porteus Matthew H. , Olzmann James A. , Kopito Ron R. 
Published: September 2023

ABSTRACTOver 80% of people with cystic fibrosis (CF) carry the F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR), a chloride ion channel at the apical plasma membrane (PM) of epithelial cells. F508del impairs CFTR folding causing it to be destroyed by endoplasmic reticulum associated degradation (ERAD). Small molecule correctors, which act as pharmacological chaperones to divert CFTR-F508del from ERAD, are the primary strategy for treating CF, yet corrector development continues with only a rudimentary understanding of how ERAD targets CFTR-F508del. We conducted genome-wide CRISPR/Cas9 knockout screens to systematically identify the molecular machinery that underlies CFTR-F508del ERAD. Although the ER-resident ubiquitin ligase, RNF5 was the top E3 hit, knocking outRNF5only modestly reduced CFTR-F508del degradation. Sublibrary screens in anRNF5knockout background identified RNF185 as a redundant ligase, demonstrating that CFTR-F508del ERAD is highly buffered. Gene-drug interaction experiments demonstrated that correctors tezacaftor (VX-661) and elexacaftor (VX-445) stabilize sequential, RNF5-resistant folding states. We propose that binding of correctors to nascent CFTR-F508del alters its folding landscape by stabilizing folding states that are not substrates for RNF5-mediated ubiquitylation.SIGNIFICANCE STATEMENTClinically effective small molecule cystic fibrosis (CF) correctors divert mutant CFTR molecules from ER-associated degradation (ERAD). However, the mechanisms underlying CFTR ERAD are not well-understood.The authors used CRISPR knockout screens to identify ERAD machinery targeting CFTR-F508del and found that the pathway is highly buffered, with RNF185 serving as a redundant ubiquitin ligase for RNF5. Gene-drug interaction experiments demonstrated that correctors act synergistically by stabilizing sequential RNF5-resistant folding states.Inhibiting proteostasis machinery is a complementary approach for enhancing current CF corrector therapies.
Simultaneous assessment of mechanical and electrical function in Langendorff-perfused ex-vivo mouse heart
Authors: Louradour Julien , Ottersberg Rahel , Segiser Adrian , Olejnik Agnieszka , Martínez-Salazar Berenice , Siegrist Mark , Egle Manuel , Barbieri Miriam , Nimani Saranda , Alerni Nicolò , Döring Yvonne , Odening Katja E. , Longnus Sarah 
Published: September 2023

BackgroundThe Langendorff-perfusedex-vivoisolated heart model has been extensively used to study cardiac function for many years. However, electrical and mechanical function are often studied separately - despite growing proof of a complex electro-mechanical interaction in cardiac physiology and pathology. Therefore, we developed an isolated mouse heart perfusion system that allows simultaneous recording of electrical and mechanical function.MethodsIsolated mouse hearts were mounted on a Langendorff setup and electrical function was assessed via a pseudo-ECG and an octapolar catheter inserted in the right atrium and ventricle. Mechanical function was simultaneously assessed via a balloon inserted into the left ventricle coupled with pressure determination. Hearts were then submitted to an ischemia-reperfusion protocol.ResultsAt baseline, heart rate, PR and QT intervals, intra-atrial and intra-ventricular conduction times, as well as ventricular effective refractory period, could be measured as parameters of cardiac electrical function. Left ventricular developed pressure (DP), left ventricular work (DP-heart rate product) and maximal velocities of contraction and relaxation were used to assess cardiac mechanical function. Cardiac arrhythmias were observed with episodes of bigeminy during which DP was significantly increased compared to that of sinus rhythm episodes. In addition, the extrasystole-triggered contraction was only 50% of that of sinus rhythm, recapitulating the “pulse deficit” phenomenon observed in bigeminy patients. After ischemia, the mechanical function significantly decreased and slowly recovered during reperfusion while most of the electrical parameters remained unchanged. Finally, the same electro-mechanical interaction during episodes of bigeminy at baseline was observed during reperfusion.ConclusionOur modified Langendorff setup allows simultaneous recording of electrical and mechanical function on a beat-to-beat scale and can be used to study electro-mechanical interaction in isolated mouse hearts.
Risk assessments underestimate threat of pesticides to wild bees
Authors: Shahmohamadloo René S. , Tissier Mathilde L. , Guzman Laura Melissa 
Published: September 2023

AbstractEcological risk assessments (ERA) are crucial when developing national strategies to manage adverse effects from pesticide exposure to natural populations. Yet, estimating risk with surrogate species in controlled laboratory studies jeopardizes the ERA process because natural populations exhibit intraspecific variation within and across species. Here, we investigate the extent to which the ERA process misestimates risk from pesticides on different species by conducting a meta-analysis of all records in the ECOTOX Knowledgebase for honey bees and wild bees exposed to neonicotinoids. We found the knowledgebase is largely populated by acute lethality data on the Western honey bee and exhibits within and across species variation in LD50 up to six orders of magnitude from neonicotinoid exposure. We challenge the reliability of surrogate species as predictors when extrapolating pesticide toxicity data to wild pollinators and recommend solutions to address the (a)biotic interactions occurring in nature that make such extrapolations unreliable in the ERA process.SynopsisEcological risk assessments misestimate pesticide threats to pollinators sixfold by overextending acute lethality data on surrogate species to natural populations.
Brain Connectivity Changes in Meditators and Novices during Yoga Nidra: A Novel fMRI Study
Authors: Fialoke Suruchi , Tripathi Vaibhav , Thakral Sonika , Dhawan Anju , Majahan Vidur , Garg Rahul 
Published: September 2023

AbstractYoga Nidra practice aims to induce a deeply relaxed state akin to sleep while maintaining heightened awareness. Despite the growing interest in its clinical applications, a comprehensive understanding of the underlying neural correlates of the practice of Yoga Nidra (YN) remains largely unexplored. In this novel fMRI investigation, we aim to discover the differences between wakeful resting states and states attained during YN practice. The study included individuals experienced in meditation and/or yogic practices, referred to as ‘meditators’ (n=30), and novice controls (n=31). The GLM analysis, based on audio instructions, demonstrated activation related to auditory cues without concurrent Default Mode Network (DMN) deactivation. Additionally, meditators exhibited heightened bilateral thalamic activation compared to novices. DMN seed based Functional connectivity (FC) analysis revealed significant reductions in connectivity among meditators during YN as compared to controls. We did not find differences between the two groups during the pre and post resting state scans. Moreover, when DMN-FC was compared between the YN state and resting state, meditators showed distinct decoupling, whereas controls showed increased DMN-FC. Finally, meditators exhibit a remarkable correlation between reduced DMN connectivity during Yoga Nidra and self-reported hours of cumulative meditation and yoga practice. Together, these results suggest a unique neural modulation of the DMN in meditators during Yoga Nidra which results in being restful yet aware, aligned with their subjective experience of the practice. The study deepens our understanding of the neural mechanisms of Yoga Nidra, revealing distinct DMN connectivity decoupling in meditators and its relationship with meditation and yoga experience. These findings have interdisciplinary implications for neuroscience, psychology, and yogic disciplines.
A CRISPR activation screen identifies FBXO22 as an E3 ligase supporting targeted protein degradation
Authors: Basu Ananya A. , Zhang Chenlu , Riha Isabella A. , Magassa Assa , Ko Felicia , Zhang Xiaoyu 
Published: September 2023

AbstractTargeted protein degradation (TPD) represents a potent chemical biology paradigm that leverages the cellular degradation machinery to pharmacologically eliminate specific proteins of interest. Although multiple E3 ligases have been discovered to facilitate TPD, there exists a compelling requirement to diversify the pool of E3 ligases available for such applications. This expansion will broaden the scope of potential protein targets, accommodating those with varying subcellular localizations and expression patterns. In this study, we describe a CRISPR-based transcriptional activation screen focused on human E3 ligases, with the goal of identifying E3 ligases that can facilitate heterobifunctional compound-mediated target degradation. This approach allows us to address the limitations associated with investigating candidate degrader molecules in specific cell lines that either lack or have low levels of the desired E3 ligases. Through this approach, we identified a candidate proteolysis-targeting chimera (PROTAC), 22-SLF, that induces the degradation of FKBP12 when the FBXO22 gene transcription is activated. 22-SLF induced the degradation of endogenous FKBP12 in a FBXO22-dependent manner across multiple cancer cell lines. Subsequent mechanistic investigations revealed that 22-SLF interacts with C227 and/or C228 in FBXO22 to achieve the target degradation. Finally, we demonstrated the versatility of FBXO22-based PROTACs by effectively degrading another endogenous protein BRD4. This study uncovers FBXO22 as an E3 ligase capable of supporting ligand-induced protein degradation through electrophilic PROTACs. The platform we have developed can readily be applied to elucidate protein degradation pathways by identifying E3 ligases that facilitate either small molecule-induced or endogenous protein degradation.