bluuebunny/crossref_metadata_2025 huggingface dataset:
The angiotensin antagonist Losartan modulates social reward motivation and punishment sensitivity via modulating midbrain-striato-frontal circuits
Authors: Zhou Xinqi , Xu Ting , Zeng Yixu , Zhang Ran , Qi Ziyu , Zhao Weihua , Kendrick Keith M , Becker Benjamin
Published: July 2021

Social deficits and dysregulations in dopaminergic midbrain-striato-frontal circuits represent transdiagnostic symptoms across psychiatric disorders. Animal models suggest that interactions between the dopamine and renin-angiotensin system may modulate learning and reward-related processes. The present study therefore examined the behavioral and neural effects of the angiotensin II type 1 receptor (AT1R) antagonist Losartan on social reward and punishment processing in humans. A pre-registered randomized double-blind placebo-controlled between-subject pharmacological design was combined with a social incentive delay fMRI paradigm during which subjects could avoid social punishment or gain social reward. Healthy volunteers received a single-dose of Losartan (50mg, n=43) or placebo (n=44). Reaction times and emotional ratings served as behavioral outcomes, on the neural level activation and connectivity were modelled. Relative to placebo, Losartan modulated the reaction time and arousal differences between social punishment and social reward. On the neural level the Losartan-enhanced motivational salience of social rewards was accompanied by stronger ventral striatum-prefrontal connectivity during reward anticipation. Losartan increased the reward-neutral difference in the ventral tegmental area (VTA) and attenuated VTA associated connectivity with the bilateral insula in response to punishment during the outcome phase. Losartan modulated approach-avoidance motivation and emotional salience during social punishment versus social reward via modulating distinct core nodes of the midbrain-striato-frontal circuits. The findings document a modulatory role of the renin-angiotensin system in these circuits and associated social processes, suggesting a promising treatment target to alleviate social dysregulations.

Significance Statement

Social deficits and anhedonia characterize several mental disoders and have been linked to the midbrain-striato-frontal circuits of the brain. Based on initial findings from animal models we here combine the pharmacological blockade of the angiotensin II type 1 receptor (AT1R) via Losartan with functional MRI to demonstrate that AT1R blockade enhances the motivational salience of social rewards and attenuates the negative impact of social punishment via modulating the communication in the midbrain-striato-frontal circuits in humans. The findings demonstrate for the first time an important role of the AT1R in social reward processing in humans and render the AT1R as promising novel treatment target for social and motivational deficits in mental disoders.
CulebrONT: a streamlined long reads multi-assembler pipeline for prokaryotic and eukaryotic genomes
Authors: Orjuela Julie , Comte Aurore , Ravel Sébastien , Charriat Florian , Vi Tram , Sabot François , Cunnac Sébastien
Published: July 2021

Using long reads provides higher contiguity and better genome assemblies. However, producing such high quality sequences from raw reads requires to chain a growing set of tools, and determining the best workflow is a complex task.

To tackle this challenge, we developed CulebrONT, an open-source, scalable, modular and traceable Snakemake pipeline for assembling long reads data. CulebrONT enables to perform tests on multiple samples and multiple long reads assemblers in parallel, and can optionally perform, downstream circularization and polishing. It further provides a range of assembly quality metrics summarized in a final user-friendly report.

CulebrONT alleviates the difficulties of assembly pipelines development, and allow users to identify the best assembly options.
Mitochondrial Respiratory Chain Protein Co-Regulation in the Human Brain
Authors: Trumpff Caroline , Owusu-Ansah Edward , Klein Hans-Ulrich , Lee Annie , Petyuk Vladislav , Wingo Thomas S. , Wingo Aliza P. , Thambisetty Madhav , Ferrucci Luigi , Seyfried Nicholas T. , Bennett David A. , De Jager Philip L. , Picard Martin
Published: July 2021

Mitochondrial respiratory chain (RC) function requires the stoichiometric interaction among dozens of proteins but their co-regulation has not been defined in the human brain. Here, using quantitative proteomics across three independent cohorts we systematically characterized the co-regulation patterns of mitochondrial RC proteins in the human dorsolateral prefrontal cortex (DLPFC). Whereas the abundance of RC protein subunits that physically assemble into stable complexes were correlated, indicating their co-regulation, RC assembly factors exhibited modest co-regulation. Within complex I, nuclear DNA-encoded subunits exhibited >2.5-times higher co-regulation than mitochondrial (mt)DNA-encoded subunits. Moreover, mtDNA copy number was unrelated to mtDNA-encoded subunits abundance, suggesting that mtDNA content is not limiting. Alzheimer’s disease (AD) brains exhibited reduced abundance of complex I RC subunits, an effect largely driven by a 2-4% overall lower mitochondrial protein content. These findings provide foundational knowledge to identify molecular mechanisms contributing to age- and disease-related erosion of mitochondrial function in the human brain.
Network expansion of genetic associations defines a pleiotropy map of human cell biology
Authors: Barrio-Hernandez Inigo , Schwartzentruber Jeremy , Shrivastava Anjali , del-Toro Noemi , Zhang Qian , Bradley Glyn , Hermjakob Henning , Orchard Sandra , Dunham Ian , Anderson Carl A. , Porras Pablo , Beltrao Pedro
Published: July 2021

Proteins that interact within molecular networks tend to have similar functions and when perturbed influence the same organismal traits. Interaction networks can be used to expand the list of likely trait associated genes from genome-wide association studies (GWAS). Here, we used improvements in SNP-to-gene mapping to perform network based expansion of trait associated genes for 1,002 human traits showing that this recovers known disease genes or drug targets. The similarity of network expansion scores identifies groups of traits likely to share a common genetic basis as well as the biological processes underlying this. We identified 73 pleiotropic gene modules linked to multiple traits that are enriched in genes involved in processes such as protein ubiquitination and RNA processing. We show examples of modules linked to human diseases enriched in genes with pathogenic variants found in patients or relevant mouse knock-out phenotypes and can be used to map targets of approved drugs for repurposing opportunities. Finally, we illustrate the use of the network expansion scores to study genes at inflammatory bowel disease (IBD) GWAS loci, and implicate IBD-relevant genes with strong functional and genetic support.
The zebra finch auditory cortex reconstructs occluded syllables in conspecific song
Authors: Le Bao , Bjoring Margot C , Meliza C Daniel
Published: July 2021

In the perceptual illusion known as phonemic (or auditory) restoration, listeners hear sounds occluded by short bursts of noise. The neural mechanisms that create this illusion by generating predictions of the missing information remain poorly understood. Zebra finches (Taeniopygia guttata) use song, a sequence of complex vocal elements, to communicate in noisy social environments. Here, we found that in anesthetized finches, populations of single units in the homolog of auditory cortex respond to occluded songs as if the missing elements were present. This occurs even for songs birds have never heard, but not if the context is masked or lacks species-typical syntax. These results suggest that local neural dynamics pre-attentively instantiate a general model of conspecific song that biases auditory responses to restore missing information.
A high-throughput assay for directly monitoring nucleolar rRNA biogenesis
Authors: Bryant Carson J. , McCool Mason A. , Abriola Laura , Surovtseva Yulia V. , Baserga Susan J.
Published: July 2021

Studies of the regulation of nucleolar function are critical for ascertaining clearer insights into the basic biological underpinnings of ribosome biogenesis, and for future development of therapeutics to treat cancer and ribosomopathies. A number of high-throughput primary assays based on morphological alterations of the nucleolus can indirectly identify hits affecting ribosome biogenesis. However, there is a need for a more direct high-throughput assay for nucleolar function to further evaluate hits. Previous reports have monitored nucleolar RNA biogenesis using 5-ethynyl uridine (5-EU) in low-throughput. We report a miniaturized, high-throughput 5-EU assay for nucleolar function which enables specific calculation of nucleolar rRNA biogenesis inhibition, based on co-staining of the nucleolar protein fibrillarin (FBL). The assay utilizes two siRNA controls, a negative non-targeting siRNA control (siNT) and a positive siRNA control targetingPOLR1A(siPOLR1A), and specifically quantifies median 5-EU signal within nucleoli. Maximum nuclear 5-EU signal can also be used to monitor the effects of putative small molecule inhibitors of RNAP1, like BMH-21, or other treatment conditions that cause FBL dissociation. We validate the 5-EU assay on 68 predominately nucleolar hits from a high-throughput primary screen, showing that 58/68 hits significantly inhibit nucleolar rRNA biogenesis. Our new method establishes direct quantification of nucleolar function in high-throughput, facilitating closer study of ribosome biogenesis in health and disease.
A natural single nucleotide mutation in the small regulatory RNA ArcZ ofDickeya solaniswitches off the antimicrobial activities against yeast and bacteria
Authors: Brual T , Effantin G , Baltenneck J , Attaiech L , Grosbois C , Royer M , Cigna J , Faure D , Hugouvieux-Cotte-Pattat N , Gueguen E
Published: July 2021

The necrotrophic plant pathogenic bacteriumDickeya solaniemerged in the potato agrosystem in Europe. All isolated strains ofD. solanicontain several large polyketide synthase/non-ribosomal peptide synthetase gene clusters. Analogy with genes described in other bacteria suggests that the clustersoocandzmsare involved in the production of secondary metabolites of the oocydin and zeamine families, respectively. A third cluster that we namedssmforsolanisecondarymetabolite had an unknown function. In this study, we constructed mutants impaired in each of the three secondary metabolite clustersssm, ooc, andzmsto compare first the phenotype of theD. solaniwild-type strain D s0432-1 with its associated mutants. We demonstrated the antimicrobial functions of these three PKS/NRPS clusters against bacteria, yeasts or fungi. The secondary metabolite clusterssm, conserved in several otherDickeyaspecies, produces a secondary metabolite inhibiting yeasts. Phenotyping and comparative genomics of differentD. solaniwild-type isolates revealed that the small regulatory RNA ArcZ plays a major role in the control of the clustersssmandzms. A single-point mutation, conserved in someDickeyawild-type strains, including the type strain IPO 2222, impairs the ArcZ function by affecting its processing into an active form.

AUTHOR SUMMARY

The development of new antibacterial molecules is critical in tackling the emergence of new pathogens or bacterial strains resistant to already available antibiotics. Bacterial phytopathogens can potentially synthesize novel compounds capable of targeting a specific type of microorganism.Dickeya solaniis the only of the twelve describedDickeyaspecies that has the three secondary metabolic pathwaysssm, oocandzms. An investigation of the functions of these three clusters allowed us to identify the anti-yeast activity of thessmcluster, a potential new molecule of clinical importance. By comparing the antimicrobial activity of severalDickeya solanistrains, we identified the small RNA regulator ArcZ as a critical regulator in the activation of thessmandzmsclusters. Our study showed that single-nucleotide polymorphisms of sRNA encoding genes can have huge impacts on bacterial phenotypes. It is thus critical to pay attention to the allele diversity of sRNA genes.
TGF-β-dependent Lymphoid Tissue Residency of Stem-like T cells Limits the Response to Tumor Vaccine
Authors: Li Guo , Wang Liwen , Ma Chaoyu , Liao Wei , Liu Yong , Mishra Shruti , Zhang Xin , Qiu Yuanzheng , Lu Qianjin , Zhang Nu
Published: July 2021

Stem-like CD8+T cells represent the key subset responding to multiple tumor immunotherapies, including tumor vaccination. However, the signals that control the differentiation of stem-like T cells are not entirely known. Most previous investigations on stem-like T cells are focused on tumor infiltrating T cells (TIL). The behavior of stem-like T cells in other tissues remains to be elucidated. Tissue-resident memory T cells (TRM) are often defined as a non-circulating T cell population residing in non-lymphoid tissues. TILs carrying TRMfeatures are associated with better tumor control. Here, we found that stem-like CD8+T cells differentiated into TRMs in a TGF-β and tumor antigen dependent manner almost exclusively in tumor draining lymph node (TDLN). TDLN-resident stemlike T cells were negatively associated with the response to tumor vaccine. In other words, after tumor vaccine, TDLN stem-like T cells transiently lost TRMfeatures, differentiated into migratory effectors and exerted tumor control.
Bayesian optimisation for yield in high-dimensional trait-space identifies crop ideotypes in Oil Seed Rape
Authors: Calderwood Alexander , Siles Laura , Eastmond Peter J. , Kurup Smita , Morris Richard J.
Published: July 2021

The improvement of crop yield has long been a major breeding target and is increasingly becoming a goal in many areas of plant research. Yield has been shown to be a complex trait, depending on multiple genes, plant architecture and plant-environment interactions. This complexity is frequently reduced by focussing on contributing factors to yield (yield traits). However, a quantitative understanding of the interplay between yield traits, and the effect of these relationships on yield is largely unexplored. Consequently, the extent to which crop varieties achieve their optimal morphology in a given environment and how this impacts on seed yield is unknown.

Here we use causal inference to model the hierarchically structured effects of 27 macro and micro yield traits on each other over the course of plant development, and on seed yield in Spring and Winter oilseed rape plants. We perform Bayesian optimisation on the modelled yield potential, identifying the morphology of ideotype plants which are expected to be higher yielding than the existing varieties in the studied panels. We find that existing Spring varieties occupy the optimal regions of trait-space, but that potentially high yielding strategies are unexplored in extant Winter varieties.

In addition to concrete recommendations for varietal improvement in oilseed rape, this work provides a novel, general methodological framework for the study of crop breeding as an optimisation problem.
The ASC Speck and NLRP3 Inflammasome Function Are Spatially and Temporally Distinct
Authors: Nagar Abhinit , Rahman Tabassum , Harton Jonathan A.
Published: July 2021

Although considered the ternary inflammasome structure, whether the singular, perinuclear NLRP3:ASC speck is synonymous with the NLRP3 inflammasome is unclear. Herein we report that the NLRP3:ASC speck is not required for nigericin-induced inflammasome activation, but facilitates and maximizes IL-1β processing. Further, the NLRP3 agonists H2O2 and MSU elicited IL-1β maturation without inducing specks. Notably, caspase-1 activity is spatially distinct from the speck, occurring at multiple cytoplasmic sites. Additionally, caspase-1 activity negatively regulates speck frequency and speck size while speck numbers and IL-1β processing are negatively correlated, cyclical, and can be uncoupled by NLRP3 mutations or inhibiting microtubule polymerization. Finally, when specks are present, caspase-1 is likely activated after leaving the speck structure. Thus, the speck is not the NLRP3 inflammasome itself, but is instead a dynamic structure which may amplify the NLRP3 response to weak stimuli by facilitating the formation and release of small NLRP3:ASC complexes which in turn activate caspase-1.
Energetics but not development is impacted in coral embryos exposed to ocean acidification
Authors: Chille EE , Strand EL , Scucchia F , Neder M , Schmidt V , Sherman MO , Mass T , Putnam HM
Published: July 2021

In light of the chronic stress and mass mortality reef-building corals face under climate change, it is critical to understand the processes essential to reef persistence and replenishment, including coral reproduction and development. Here we quantify gene expression and size sensitivity to ocean acidification across a set of developmental stages in the rice coral, Montipora capitata. Embryos and swimming larvae were exposed to pH treatments 7.8 (Ambient), 7.6 (Low) and 7.3 (Xlow) from fertilization to 9 days post-fertilization. Embryo and larval volume, and stage-specific gene expression were compared between treatments to determine the effects of acidified seawater on early development. While there was no measurable size differentiation between fertilized eggs and prawn chips exposed to pH 7.8, 7.6, and 7.3, early gastrula and planula raised in reduced pH treatments were significantly smaller than those raised in ambient seawater, suggesting an energetic cost to developing under low pH. However, no differentially expressed genes emerged until 9 days post-fertilization. Notably, gene expression patterns of larvae developing at pH 7.8 and pH 7.3 were more similar than those developing at pH 7.6. Larvae from pH 7.6 showed upregulation of genes involved in cell division, regulation of transcription, lipid metabolism, and oxidative stress in comparison to the other two treatments. While low pH appears to increase energetic demands and trigger oxidative stress, the developmental process is robust to this at a molecular level, with swimming larval stage reached in all pH treatments.

Summary statement

This developmental time series tracks the physiological and transcriptomic outcomes of early coral development under ambient pH (pH 7.8), and two low pH conditions (pH 7.6 and 7.3).
Residual dynamics resolves recurrent contributions to neural computation
Authors: Galgali Aniruddh R. , Sahani Maneesh , Mante Valerio
Published: July 2021

Relating neural activity to behavior requires an understanding of how neural computations arise from the coordinated dynamics of distributed, recurrently connected neural populations. However, inferring the nature of recurrent dynamics from partial recordings of a neural circuit presents significant challenges. Here, we show that some of these challenges can be overcome by a fine-grained analysis of the dynamics of neural residuals, i.e. trial-by-trial variability around the mean neural population trajectory for a given task condition. Residual dynamics in macaque pre-frontal cortex (PFC) in a saccade-based perceptual decision-making task reveals recurrent dynamics that is time-dependent, but consistently stable, and suggests that pronounced rotational structure in PFC trajectories during saccades is driven by inputs from upstream areas. The properties of residual dynamics restrict the possible contributions of PFC to decision-making and saccade generation, and suggest a path towards fully characterizing distributed neural computations with large-scale neural recordings and targeted causal perturbations.
Tissue-Specific Biochemical Differences Between Chronic Wasting Disease Prions Isolated From Free Ranging, White-Tailed Deer (Odocoileus virginianus)
Authors: Wagner Kaitlyn , Pierce Robyn , Gordon Elizabeth , Ballard Jennifer R. , Moreno Julie A. , Zabel Mark D.
Published: July 2021

Chronic wasting disease (CWD) is an invariably fatal prion disease affecting cervid species world-wide. Prions can manifest as distinct strains that can influence disease pathology and transmission. CWD is profoundly lymphotropic and most infected cervids likely shed peripheral prions replicated in lymphoid organs. However, CWD is a neurodegenerative disease and most research on prion strains has focused on neurogenic prions. Thus, a knowledge gap exists comparing prions in the brain to prions in the lymph node. In this study we compared prions from the obex and lymph node of naturally exposed white-tailed deer to identify potential biochemical strain differences. Here, we report biochemical evidence of strain differences between the brain and lymph node from these animals. Future work should examine the biological and zoonotic impact of these biochemical differences and examine more cervids from multiple locations to see if these differences are conserved across species and locations.
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

Evolution 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

It 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

Cocaine 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

Mediation 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

Fibrogenic 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

Abstract

We 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

Water 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 Statement

As 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

Hemispheric 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

Synthetic 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

De 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

Echinoids 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

The 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

A 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

Abstract

Humans 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.
Patterns of mesozooplankton community composition and vertical fluxes in the global ocean
Authors: Soviadan Yawouvi Dodji , Benedetti Fabio , Brandão Manoela C. , Ayata Sakina-Dorothée , Irisson Jean-Olivier , Jamet Jean Louis , Kiko Rainer , Lombard Fabien , Gnandi Kissao , Stemmann Lars
Published: July 2021

Vertical variations in physical and chemical conditions drive changes in marine zooplankton community diversity and composition. In turn, zooplankton communities play a critical role in regulating the transfer of organic matter produced in the surface ocean to deeper layers. Yet, the links between zooplankton community composition and the strength of vertical fluxes of particles remain elusive, especially on a global scale. Here, we provide a comprehensive analysis of variations in zooplankton community composition and vertical particle flux in the upper kilometer of the global ocean. Zooplankton samples were collected across five depth layers and vertical particle fluxes were assessed using continuous profiles of the Underwater Vision Profiler (UVP5) at 57 stations covering seven ocean basins. Zooplankton samples were analysed using a Zooscan and individual organisms were classified into 19 groups for the quantitative analyses. Zooplankton abundance, biomass and vertical particle flux decreased from the surface to 1000m depth at all latitudes. The zooplankton abundance decrease rate was stronger at sites characterised by oxygen minima (< 5µmol O2.kg−1) where most zooplankton groups showed a marked decline in abundance, except the jellyfishes, molluscs, annelids, large protists and a few copepod families. The attenuation rate of vertical particle fluxes was weaker at such oxygen-depleted sites. Canonical redundancy analyses showed that the epipelagic zooplankton community composition depended on the community structure of surface phytoplankton and the quantity and the quality of the produced particulate organic matter. We provide a consistent baseline of plankton community structure together with estimates of vertical flux and a contribution to our understanding of global zooplankton dynamics in the upper kilometer of the global ocean. Our results further suggest that future changes in surface phytoplankton composition and mesopelagic oxygen loss might lead to profound changes in zooplankton abundance and community structure in both the euphotic and mesopelagic ocean. These changes may affect the vertical export and hereby the strength of the biological carbon pump