bluuebunny/crossref_metadata_2025_split huggingface dataset:
At-home blood collection and stabilization in high temperature climates using homeRNA
Authors: Brown Lauren G. , Haack Amanda J. , Kennedy Dakota S. , Adams Karen N. , Stolarczuk Jennifer E. , Takezawa Meg G. , Berthier Erwin , Thongpang Sanitta , Lim Fang Yun , Chaussabel Damien , Garand Mathieu , Theberge Ashleigh B. 
Published: March 2022

ABSTRACTExpanding whole blood sample collection for transcriptome analysis beyond traditional phlebotomy clinics will open new frontiers for remote immune research and telemedicine. Determining the stability of RNA in blood samples exposed to high ambient temperatures (>30°C) is necessary for deploying home-sampling in settings with elevated temperatures (e.g., studying physiological response to natural disasters that occur in warm locations or in the summer). Recently, we have developed homeRNA, a technology that allows for self-blood sampling and RNA stabilization remotely. homeRNA consists of a lancet-based blood collection device, the Tasso-SST™ which collects up to 0.5 mL of blood from the upper arm, and a custom-built stabilization transfer tube containing RNAlater™. In this study, we investigated the robustness of our homeRNA kit in high temperature settings via two small pilot studies in Doha, Qatar (no. participants = 8), and the Western and South Central USA during the summer of 2021, which included a heatwave of unusually high temperatures in some locations (no. participants = 11). Samples collected from participants in Doha were subjected to rapid external temperature fluctuations from being moved to and from air-conditioned areas and extreme heat environments (up to 41°C external temperature during brief temperature spikes). In the USA pilot study, regions varied in outdoor temperature highs (between 25°C and 43.4°C). All samples that returned a RNA integrity number (RIN) value from the Doha, Qatar group had a RIN ≥7.0, a typical integrity threshold for downstream transcriptomics analysis. RIN values for the Western and South Central USA samples (n=12 samples) ranged from 6.9-8.7 with 9 out of 12 samples reporting RINs ≥7.0. Overall, our pilot data suggest that homeRNA can be used in some regions that experience elevated temperatures, opening up new geographical frontiers in disseminated transcriptome analysis for applications critical to telemedicine, global health, and expanded clinical research. Further studies, including our ongoing work in Qatar, USA, and Thailand, will continue to test the robustness of homeRNA.
bpRNA-align: Improved RNA Secondary Structure Global Alignment for Comparing and Clustering RNA Structures
Authors: Lasher Brittany , Hendrix David A. 
Published: March 2022

AbstractRibonucleic acid (RNA) is a polymeric molecule that is fundamental to biological processes, with structure being more highly conserved than primary sequence and often key to its function. Advances in RNA structure characterization have resulted in an increase in the number of accurate secondary structures. The task of uncovering common RNA structural motifs with a collective function through structural comparison remains challenging and could be used to discover new RNA families. In this work, we present a novel secondary structure alignment and clustering method, bpRNA-align. bpRNA-align is a customized global structural alignment method, utilizing an inverted (gap extend costs more than gap open) context-specific affine gap penalty and a structural, feature-specific substitution matrix to provide similarity scores. We evaluate our similarity scores in comparison to other methods, using affinity propagation clustering, applied to a benchmarking data set of known structure types.
StrainXpress: strain aware metagenome assembly from short reads
Authors: Kang Xiongbin , Luo Xiao , Schönhuth Alexander 
Published: March 2022

AbstractNext-generation sequencing based metagenomics has enabled to identify microorganisms in characteristic habitats without the need for lengthy cultivation. Importantly, clinically relevant phenomena such as resistance to medication, virulence or interactions with the environment can vary already within species. Therefore, a major current challenge is to reconstruct individual genomes from the sequencing reads at the level of strains, and not just the level of species. However, strains of one species can differ only by minor amounts of variants, which makes it difficult to distinguish them. Despite considerable recent progress, related approaches have remained fragmentary so far. Here, we present StrainXpress, as a comprehensive solution to the problem of strain aware metagenome assembly from next-generation sequencing reads. In experiments, StrainXpress reconstructs strain-specific genomes from metagenomes that involve up to more than 1000 strains, and proves to successfully deal with poorly covered strains. The amount of reconstructed strain-specific sequence exceeds that of the current state-of-the-art approaches by on average 26.75% across all data sets (first quartile: 18.51%, median: 26.60%, third quartile: 35.05%).
Effective holistic characterization of small molecule effects using heterogeneous biological networks
Authors: Mangione William , Falls Zackary , Samudrala Ram 
Published: March 2022

ABSTRACTThe two most common reasons for attrition in therapeutic clinical trials are efficacy and safety. We integrated heterogeneous data to create a human interactome network that was used to comprehensively describe drug behavior in biological systems, with the goal of accurate therapeutic candidate generation. The Computational Analysis of Novel Drug Opportunities (CANDO) platform for shotgun multiscale therapeutic discovery, repurposing, and design was enhanced by integrating drug side effects, protein pathways, protein-protein interactions, protein-disease associations, and the Gene Ontology, complemented with its existing drug/compound, protein, and indication libraries. These integrated networks were reduced to a “multiscale interactomic signature” for each compound that describe its functional behavior as vectors of real values. These signatures are then used for relating compounds to each other with the hypothesis that similar signatures yield similar behavior. Our results indicated that there is significant biological information captured within our networks (particularly via side effects) which enhance the performance of our platform, as evaluated by performing all-against-all leave-one-out drug-indication association benchmarking. Further, drug impacts on pathways derived from computed compound-protein interaction scores served as the features for a random forest machine learning model trained to predict drug-indication associations, with applications to mental disorders and cancer metastasis highlighted. This interactomic pipeline highlights the ability of CANDO to accurately relate drugs in a multitarget and multiscale context, and paves the way for predicting novel putative drug candidates using the information gleaned from indirect data such as side effect profiles and protein pathway information.
SCAMPR: Single-Cell Automated Multiplex Pipeline for RNA Quantification and Spatial Mapping
Authors: Ghoddousi Ramin Ali Marandi , Magalong Valerie M. , Kamitakahara Anna K. , Levitt Pat 
Published: March 2022

SummarySpatial gene expression, achieved classically through in situ hybridization, is a fundamental tool for topographic phenotyping of cell types in the nervous system. Newly developed techniques allow for the visualization of multiple mRNAs at single-cell resolution, greatly expanding the ability to link gene expression to tissue topography. Yet, methods for efficient and accurate quantification and analysis of high dimensional in situ hybridization are limited. To this end, the Single-Cell Automated Multiplex Pipeline for RNA (SCAMPR) was developed, facilitating rapid and accurate segmentation of neuronal cell bodies using a dual immunohistochemistry-RNAscope protocol and quantification of low and high abundance mRNA signals using open-source image processing and automated segmentation tools. Proof of principle using SCAMPR focused on spatial mapping of gene expression by peripheral (vagal nodose) and central (visual cortex) neurons. The analytical effectiveness of SCAMPR is demonstrated by identifying the impact of early life stress on differential gene expression by vagal neuron subtypes.MotivationQuantitative analysis of spatial mRNA expression in neurons can lack accuracy and be both computationally and time intensive. Existing methods that rely on nuclear labeling (DAPI) to distinguish adjoining cells lack the precision to detect mRNA expression in the cytoplasm. In addition, quantification methods that rely on puncta counts can generate large, variable datasets that potentially undercount highly expressed mRNAs. To overcome these methodological barriers, we developed the SCAMPR pipeline that allows for fast, accurate segmentation of neuronal cell body boundaries, topographic gene expression mapping, and high dimensional quantification and analysis of mRNA expression in tissue sections.
A Spinal Circuit That Transmits Innocuous Cool Sensations
Authors: Horwitz Lorraine R , Lee Hankyu , Hor Chia Chun , Shen Fred Y , Cai Wei , Li Chen , Pai Emily Ling-Lin , Fung Tin Long Rex , Rovcanin Ilma , Pipe Kevin P , Xu X.Z. Shawn , Cai Dawen , Duan Bo 
Published: March 2022

SUMMARYTemperature information is precisely processed in the nervous system. While progress has been made in identifying molecular thermosensors in the periphery, the neural circuits that process temperature information in the central nervous system remain unknown. Here we have identified an essential node in the neural circuitry for innocuous cool sensations. We found that a population of excitatory interneurons co-expressing Calbindin1 and Lbx1 (Calb1Lbx1) in the dorsal horn of the spinal cord is activated by innocuous cool temperatures. Genetic ablation or silencing of spinal Calb1Lbx1 neurons causes loss of innocuous cool but not noxious cold sensations. Further Brainbow labeling with expansion microscopy and electrophysiology showed that a small cluster of spinal Calb1Lbx1 interneurons in lamina I and the outer layer of lamina II represents the cooling-transmission neurons. These neurons receive monosynaptic connections from TRPM8+ primary sensory neurons and amplify the activity of cool-sensitive spinoparabrachial projection neurons. Our findings reveal a microcircuit in the dorsal spinal cord that specifically transmits innocuous cool sensations.
Polytypy and systematics: diversification ofPapilioswallowtail butterflies in the biogeographically complex Indo-Australian Region
Authors: Joshi Jahnavi , Kunte Krushnamegh 
Published: March 2022

ABSTRACTA long-standing problem in evolutionary biology and systematics is defining patterns of diversification and speciation, which is compounded by allopatric distributions of polytypic taxa in biogeographically fragmented landscapes. In this paper we revisit this enduring systematic challenge using Mormon swallowtail butterflies (PapiliosubgenusMenelaides)—an evolutionary and genetic model system.Menelaidesis speciose and intensively sampled, with nearly 260 years of systematic study complicated by polytypy resulting from discontinuous morphological variation. This variation is structured by the mainland-island matrix of the geologically complex Indo-Australian Region, where drawing species boundaries has been difficult. We sampled variation across the biogeographic range ofMenelaides, covering 97% of currently recognized species and nearly half of all subspecies. We generated a well-supported mito-nuclear phylogeny, on which we delineated species based on two species delimitation methods (GMYC and mPTP) and strongly supported reciprocal monophyly. These analyses showed that the true species diversity in this group may be up to 25% greater than traditional taxonomy suggests, and prompts extensive taxonomic restructuring. Biogeographic analyses showed thatMenelaideshave diversified largely in allopatry in Indo-Australian subregions by repeated dispersals across key biogeographic barriers. These results provide critical insights into the diversification process in this morphologically diverse and taxonomically complicated model group. These results will also be informative in future studies on systematics, biogeography, speciation and morphological diversification in the Indo-Australian Region—arguably the most complex geological land/seascape in the world.
Ecological diversity exceeds evolutionary diversity in model ecosystems
Authors: Rubin Ilan , Ispolatov Yaroslav , Doebeli Michael 
Published: March 2022

AbstractUnderstanding community saturation is fundamental to ecological theory. While investigations of the diversity of evolutionary stable states (ESSs) are widespread, the diversity of communities that have yet to reach an evolutionary endpoint is poorly understood. We use Lotka-Volterra dynamics and trait-based competition to compare the diversity of randomly assembled communities to the diversity of the ESS. We show that, with a large enough founding diversity (whether assembled at once or through sequential invasions), the number of long-time surviving species exceeds that of the ESS. However, the excessive founding diversity required to assemble a saturated community increases rapidly with the dimension of phenotype space. Additionally, traits present in communities resulting from random assembly are more clustered in phenotype space compared to random, though still markedly less ordered than the ESS. By combining theories of random assembly and ESSs we bring a new viewpoint to both the saturation and random assembly literature.
Extended longevity geometrically-inverted proximal tubule organoids for protein uptake studies
Authors: Parigoris Eric , Lee Ji-Hoon , Liu Amy Yunfan , Zhao Xueying , Takayama Shuichi 
Published: March 2022

AbstractWhile some in vitro platforms have been adapted to study proteinuric kidney disease, organoids have been challenging to study the disease. This is because apical access is historically difficult, and this is the surface on which megalin (LRP2), an endocytic receptor responsible for tubular reabsorption of filtered plasma proteins, resides. Based on our previous geometrically-inverted organoids, this study established high-throughput basal-in and apical-out proximal tubule organoids to study proteinuric kidney disease in a more physiologically consistent manner. Organoids successfully formed around a minimal Matrigel scaffold, and were maintained in culture for 90+ days, the longest reported hanging drop culture to date. The proximal tubule organoids exhibited good polarization, showed upregulation of maturity markers, such as aquaporin-1 and megalin, and experienced less epithelial-to-mesenchymal (EMT) transition compared to 2D cells. To assess protein uptake, fluorescent albumin was placed in the surrounding media, facing the apical surface, and organoids demonstrated functional protein uptake even at 90 days. To mimic proteinuric conditions, organoids were exposed to human serum albumin and released kidney injury molecule-1 (KIM-1), a common biomarker for kidney injury, in both dose- and time-dependent manners. While this study focuses on applications for modeling proteinuric kidney disease conditions, these organoids are envisioned to have broad utility where apical proximal tubule cell access is required.
A global high-density chromatin interaction network reveals functional long-range and trans-chromosomal relationships
Authors: Lohia Ruchi , Fox Nathan , Gillis Jesse 
Published: March 2022

Chromatin contacts are essential for gene-expression regulation, however, obtaining a high-resolution genome-wide chromatin contact map is still prohibitively expensive owing to large genome sizes and the quadratic scale of pairwise data. Chromosome conformation capture (3C) based methods such as Hi-C have been extensively used to obtain chromatin contacts. However, since the sparsity of these maps increases with an increase in genomic distance between contacts, long-range or trans chromatin contacts are especially challenging to sample.Here, we created a high density reference genome-wide chromatin contact map using a meta-analytic approach. We integrate 3600 Human, 6700 Mouse, and 500 Fly 3C experiments to create species-specific meta-3C contact maps with 304 billion, 193 billion, and 19 billion contacts in respective species. We validate that meta-3C are uniquely powered to capture functional chromatin contacts in both cis and trans. Unlike individual experiments, meta-3C gene contacts predict gene coexpression for long-range and trans chromatin contacts. Similarly, for long-range cis-regulatory interactions, meta-3C contacts outperform all individual experiments, providing an improvement over the conventionally used linear genomic distance-based association. Assessing between species, we find patterns of chromatin contacts conservation in both cis and trans and strong associations with coexpression even in species for which 3C data is lacking.We have generated an integrated chromatin interaction network which complements a large number of methodological and analytic approaches focused on improved specificity or interpretation. This high-depth “super-experiment” is surprisingly powerful in capturing long-range functional relationships of chromatin interactions, which are now able to predict coexpression, expression quantitative trait loci (eQTL), and cross-species relationships.
Environmental response in gene expression and DNA methylation reveals factors influencing the adaptive potential ofArabidopsis lyrata
Authors: Hämälä Tuomas , Ning Weixuan , Kuittinen Helmi , Aryamanesh Nader , Savolainen Outi 
Published: March 2022

AbstractUnderstanding what factors influence plastic and genetic variation is valuable for predicting how organisms respond to changes in the selective environment. Here, using gene expression and DNA methylation as molecular phenotypes, we study environmentally induced variation amongArabidopsis lyrataplants grown at lowland and alpine field sites. Our results show that gene expression is highly plastic, as many more genes are differentially expressed between the field sites than between populations. These environmentally responsive genes evolve under strong selective constraint – the strength of purifying selection on the coding sequence is high, while the rate of adaptive evolution is low. We find, however, that positive selection oncis-regulatory variants has likely contributed to the maintenance of genetically variable environmental responses, but such variants segregate only between distantly related populations. In contrast to gene expression, DNA methylation at genic regions is largely insensitive to the environment, and plastic methylation changes are not associated with differential gene expression. Besides genes, we detect environmental effects at transposable elements (TEs): TEs at the high-altitude field site have higher expression and methylation levels, suggestive of a broad-scale TE activation. Compared to the lowland population, plants native to the alpine environment harbor an excess of recent TE insertions, and we observe that specific TE families are enriched within environmentally responsive genes. Together, our findings provide insight into selective forces shaping plastic and genetic variation. We also highlight how plastic responses at TEs can rapidly create novel heritable variation in stressful conditions.
Multi-omic analysis of the cardiac cellulome defines a vascular contribution to cardiac diastolic dysfunction in obese female mice
Authors: Dona Malathi S. I. , Hsu Ian , Meuth Alex I. , Brown Scott M. , Bailey Chastidy , Aragonez Christian G. , Chandrasekar Bysani , Martinez-Lemus Luis A. , DeMarco Vincent G. , Grisanti Laurel A. , Jaffe Iris Z. , Pinto Alexander R. , Bender Shawn B. 
Published: March 2022

AbstractCoronary microvascular dysfunction (CMD) is associated with cardiac dysfunction and predictive of cardiac mortality in obesity, especially in females. Emerging evidence suggests development of heart failure with preserved ejection fraction in females with CMD and that mineralocorticoid receptor (MR) antagonism may be more efficacious in obese female, versus male, HFpEF patients. Accordingly, we examined the hypothesis that smooth muscle cell (SMC)-specific MR deletion prevents obesity-associated coronary and cardiac diastolic dysfunction in females. Obesity was induced in female mice via western diet (WD) feeding alongside littermates fed standard diet. Initial studies revealed that global MR blockade with spironolactone prevented impaired coronary vasodilation and diastolic dysfunction in obese females. Importantly, specific deletion of SMC-MR similarly prevented obesity-associated coronary and cardiac dysfunction. Cardiac gene expression profiling suggested reduced cardiac inflammation in WD-fed mice with SMC-MR deletion independent of blood pressure, aortic stiffening, and cardiac hypertrophy. Further mechanistic studies utilizing single-cell RNA sequencing of non-cardiomyocyte cell populations revealed novel impacts of SMC-MR deletion on the cardiac cellulome in obese mice. Specifically, WD feeding induced inflammatory gene signatures in multiple non-myocyte populations (B/T cells, macrophages, and endothelium), independent of cardiac fibrosis, that was prevented by SMC-MR deletion. Further, SMC-MR deletion induced a basal reduction in cardiac mast cells and prevented WD-induced cardiac pro-inflammatory chemokine expression and leukocyte recruitment. These data reveal a central role for SMC-MR signaling in obesity-associated coronary and cardiac dysfunction thus supporting the emerging paradigm of a vascular origin of cardiac dysfunction in obesity.
TCGADEPMAP– Mapping Translational Dependencies and Synthetic Lethalities within The Cancer Genome Atlas
Authors: Shi Xu , Gekas Christos , Verduzco Daniel , Petiwala Sakina , Jeffries Cynthia , Lu Charles , Murphy Erin , Anton Tifani , Vo Andy H. , Xiao Zoe , Narayanan Padmini , Barnes J. Matthew , Roy Somdutta , Ramathal Cyril , Flister Michael J. , Dezso Zoltan 
Published: March 2022

ABSTRACTThe Cancer Genome Atlas (TCGA) has yielded unprecedented genetic and molecular characterization of the cancer genome, yet the functional consequences and patient-relevance of many putative cancer drivers remain undefined. TCGADEPMAPis the first hybrid map of translational tumor dependencies that was built from machine learning of gene essentiality in the Cancer Dependency Map (DEPMAP) and then translated to TCGA patients. TCGADEPMAPcaptured well-known and novel cancer lineage dependencies, oncogenes, and synthetic lethalities, demonstrating the robustness of TCGADEPMAPas a translational dependency map. Exploratory analyses of TCGADEPMAPalso unveiled novel synthetic lethalities, including the dependency ofPAPSS1driven by loss ofPAPSS2which is collaterally deleted with the tumor suppressor genePTEN. Synthetic lethality ofPAPSS1/2was validated in vitro and in vivo, including the underlying mechanism of synthetic lethality caused by the loss of protein sulfonation that requiresPAPSS1orPAPSS2. Moreover, TCGADEPMAPdemonstrated that patients with predictedPAPSS1/2synthetic lethality have worse overall survival, suggesting that these patients are in greater need of drug discovery efforts to targetPAPSS1. Other map “extensions” were built to capture unique aspects of patient-relevant tumor dependencies using the flexible analytical framework of TCGADEPMAP, including translating gene essentiality to drug response in patient-derived xenograft (PDX) models (i.e., PDXEDEPMAP) and predicting gene tolerability within normal tissues (GTEXDEPMAP). Collectively, this study demonstrates how translational dependency maps can be used to leverage the rapidly expanding catalog of patient genomic datasets to identify and prioritize novel therapeutic targets with the best therapeutic indices.