bluuebunny/crossref_metadata_2025_split huggingface dataset:
Preserved representations and decodability of diverse cognitive functions across the cortex, cerebellum, and subcortex
Authors: Nakai Tomoya , Nishimoto Shinji 
Published: December 2021

AbstractWhich part of the brain contributes to our complex cognitive processes? Studies have revealed contributions of the cerebellum and subcortex to higher-order cognitive functions; however it is unclear whether such functional representations are preserved across the cortex, cerebellum, and subcortex. In this study, we used functional magnetic resonance imaging data with 103 cognitive tasks and constructed three voxel-wise encoding and decoding models independently using cortical, cerebellar, and subcortical voxels. Representational similarity analysis revealed that the structure of task representations is preserved across the three brain parts. Principal component analysis visualized distinct organizations of abstract cognitive functions in each part of the cerebellum and subcortex. More than 90% of the cognitive tasks were decodable from the cerebellum and subcortical activities, even for the novel tasks not included in model training. Furthermore, we discovered that the cerebellum and subcortex have sufficient information to reconstruct activity in the cerebral cortex.
Single-cell profiling of healthy human kidney reveals features of sex-based transcriptional programs and tissue-specific immunity
Authors: McEvoy Caitriona M. , Murphy Julia M. , Zhang Lin , Clotet-Freixas Sergi , Mathews Jessica A. , An James , Karimzadeh Mehran , Pouyabahar Delaram , Su Shenghui , Zaslaver Olga , Röst Hannes , Arambewela Madhurangi , Liu Lewis Y. , Zhang Sally , Lawson Keith A. , Finelli Antonio , Wang Bo , MacParland Sonya A. , Bader Gary D. , Konvalinka Ana , Crome Sarah Q. 
Published: December 2021

AbstractMaintaining organ homeostasis requires complex functional synergy between distinct cell types, a snapshot of which is glimpsed through the simultaneously broad and granular analysis provided by single-cell atlases. Knowledge of the transcriptional programs underpinning the complex and specialized functions of human kidney cell populations at homeostasis is limited by difficulty accessing healthy, fresh tissue. Here, we present a single-cell perspective of healthy human kidney from 19 living donors, with equal contribution from males and females, profiling the transcriptome of 27677 high-quality cells to map healthy kidney at high resolution. Our sex-balanced dataset revealed sex-based differences in gene expression within proximal tubular cells, specifically, increased anti-oxidant metallothionein genes in females and the predominance of aerobic metabolism-related genes in males. Functional differences in metabolism were confirmed between male and female proximal tubular cells, with male cells exhibiting higher oxidative phosphorylation and higher levels of energy precursor metabolites. Within the immune niche, we identified kidney-specific lymphocyte populations with unique transcriptional profiles indicative of kidney-adapted functions and validated findings by flow cytometry. We observed significant heterogeneity in resident myeloid populations and identified an MRC1+ LYVE1+ FOLR2+ C1QC+ population as the predominant myeloid population in healthy kidney. This study provides a detailed cellular map of healthy human kidney, revealing novel insights into the complexity of renal parenchymal cells and kidney-resident immune populations.
Discovery of a new species of trichomonasvirus in the human parasite Trichomonas vaginalis using transcriptome mining
Authors: Manny Austin R. , Hetzel Carrie A. , Mizani Arshan , Nibert Max L. 
Published: December 2021

ABSTRACTTrichomonas vaginalis is the most common nonviral cause of sexually transmitted infections globally, with an estimated quarter of a billion people infected around the world. Infection by the protozoan parasite results in the clinical syndrome trichomoniasis, which manifests as an inflammatory syndrome with acute and chronic consequences. Half or more of these parasites are themselves infected with one or more dsRNA viruses which can exacerbate the inflammatory disease. Four distinct viruses have been found in T. vaginalis to date, Trichomonas vaginalis virus 1 through 4 (or TVVs). Despite the global prevalence of these viruses, few coding-complete genome sequences have been determined. We conducted viral sequence mining in publicly available transcriptomes across 60 RNA-seq datasets representing 13 distinct T. vaginalis isolates. We assembled sequences for 27 new trichomonasvirus strains across all known TVV species, with 17 of these assemblies representing coding-complete genomes. Using a strategy of de novo sequence assembly followed by taxonomic classification, we discovered a fifth species of TVV that we term Trichomonas vaginalis virus 5 (TVV5). Six strains of TVV5 were assembled, including two coding-complete genomes. These TVV5 sequences exhibit high sequence identity to each other, but low identity to any strains of TVV1-4. Phylogenetic analysis corroborates the species-level designation. These results substantially increase the number of coding-complete TVV genome sequences and demonstrate the utility of mining publicly available transcriptomes for the discovery of RNA viruses in a critical human pathogen.
The Landscape-Based Protein Stability Analysis and Network Modeling of Multiple Conformational States of the SARS-CoV-2 Spike D614 Mutant: Conformational Plasticity and Frustration-Driven Allostery as Energetic Drivers of Highly Transmissible Spike Variant
Authors: Verkhivker Gennady , Agajanian Steve , Kassab Ryan , Krishnan Keerthi 
Published: December 2021

AbstractThe structural and functional studies of the SARS-CoV-2 spike protein variants revealed an important role of the D614G mutation that is shared across many variants of concern(VOCs), suggesting the effect of this mutation on the enhanced virus infectivity and transmissibility. The recent structural and biophysical studies provided important evidence about multiple conformational substates of the D614G spike protein. The development of a plausible mechanistic model which can explain the experimental observations from a more unified thermodynamic perspective is an important objective of the current work. In this study, we employed efficient and accurate coarse-grained simulations of multiple structural substates of the D614G spike trimers together with the ensemble-based mutational frustration analysis to characterize the dynamics signatures of the conformational landscapes. By combining the local frustration profiling of the conformational states with residue-based mutational scanning of protein stability and network analysis of allosteric interactions and communications, we determine the patterns of mutational sensitivity in the functional regions and sites of variants. We found that the D614G mutation may induce a considerable conformational adaptability of the open states in the SARS-CoV-2 spike protein without compromising folding stability and integrity of the spike protein. The results suggest that the D614G mutant may employ a hinge-shift mechanism in which the dynamic couplings between the site of mutation and the inter-protomer hinge modulate the inter-domain interactions, global mobility change and the increased stability of the open form. This study proposes that mutation-induced modulation of the conformational flexibility and energetic frustration at the inter-protomer interfaces may serve as an efficient mechanism for allosteric regulation of the SARS-CoV-2 spike proteins.
A correlation map of genome-wide DNA methylation patterns between paired human brain and buccal samples
Authors: Sommerer Yasmine , Ohlei Olena , Dobricic Valerija , Oakley Derek H. , Wesse Tanja , Sabet Sanaz Sedghpour , Demuth Ilja , Franke Andre , Hyman Bradley T. , Lill Christina M. , Bertram Lars 
Published: December 2021

AbstractEpigenome-wide association studies (EWAS) assessing the link between DNA methylation (DNAm) and phenotypes related to structural brain measures, cognitive function, and neurodegenerative diseases are becoming increasingly more popular. Due to the inaccessibility of brain tissue in humans, several studies use peripheral tissues such as blood, buccal swabs, and saliva as surrogates. To aid the functional interpretation of EWAS findings in such settings, there is a need to assess the correlation of DNAm variability across tissues in the same individuals. In this study, we performed a correlation analysis between DNAm data of a total of n=120 matched post-mortem buccal and prefrontal cortex samples. We identified nearly 25,000 (3% of approximately 730,000) cytosine-phosphate-guanine (CpG) sites showing significant (False Discovery Rate q < 0.05) correlations between buccal and PFC samples. Correlated CpG sites showed a preponderance to being located in promoter regions and showed a significant enrichment of being determined by genetic factors, i.e. methylation quantitative trait loci (mQTL), based on buccal and dorsolateral prefrontal cortex mQTL databases. Our novel buccal-brain DNAm correlation map will provide a valuable resource for future EWAS using buccal samples for studying DNAm effects on phenotypes relating to the brain. All correlation results are made freely available to the public online.
Aggregate trait evolvability and macroevolution in two sister species of the bryozoanStylopoma
Authors: Leventhal Sarah , Jamison-Todd Sarah , Simpson Carl 
Published: December 2021

AbstractThe study of trait evolution in modular animals is more complicated than that in solitary animals, because a single genotype of a modular colony can express an enormous range of phenotypic variation. Furthermore, traits can occur either at the module level or at the colony level. However, it is unclear how the traits at the colony level evolve. We test whether colony-level aggregate traits, defined as the summary statistics of a phenotypic distribution, can evolve. To quantify this evolutionary potential, we use parent-offspring pairs in two sister species of the bryozoanStylopoma, grown and bred in a common garden breeding experiment. We find that the medians of phenotypic distributions are evolvable between generations of colonies. We also find that the structure of this evolutionary potential differs between these two species. Ancestral species align more closely with the direction of species divergence than the descendent species. This result indicates that aggregate trait evolvability can itself evolve.
Macroevolutionary dynamics of climatic niche space
Authors: Quintero Ignacio , Suchard Marc A. , Jetz Walter 
Published: December 2021

AbstractHow and why lineages evolve along niche space as they diversify and adapt to different environments is fundamental to evolution. Progress has been hampered by the difficulties of linking a comprehensive empirical characterization of species niches with flexible evolutionary models that describe their evolution. Consequently, the relative influence of external episodic and biotic factors remains poorly understood. Here we characterize species’ two-dimensional temperature and precipitation niche space occupied (i.e., species niche envelope) as complex geometries and assess their evolution across a large vertebrate radiation (all Aves) using a model that captures heterogeneous evolutionary rates on time-calibrated phylogenies. We find that extant birds coevolved from warm, mesic climatic niches into colder and drier environments and responded to the K-Pg boundary with a dramatic increase in disparity. Contrary to expectations of subsiding rates of niche evolution as lineages diversify, our results show that overall rates have increased steadily, with some lineages experiencing exceptionally high evolutionary rates, associated with colonization of novel niche spaces, and others showing niche stasis. Both competition- and environmental change-driven niche evolution transpire and result in highly heterogeneous rates near the present. Our findings share the limitations of all work based purely on extant taxa but highlight the growing ecological and conservation insights arising from the model-based integration of increasingly comprehensive and robust environmental and phylogenetic information.
Chronic AMPK inactivation slows SHH medulloblastoma progression by inhibiting mTORC1 signaling and depleting tumor stem cell populations
Authors: Dismuke Taylor , Malawsky Daniel Shiloh , Liu Hedi , Brenman Jay , Dasgupta Biplab , Tikunov Andrey , Gershon Timothy R. 
Published: December 2021

AbstractWe show that inactivating AMPKin vivoin a genetic model of medulloblastoma depletes tumor stem cell populations and slows tumor progression. Medulloblastoma, the most common malignant pediatric brain tumor, grows as heterogenous communities comprising diverse types of tumor and stromal cells. Previously, we showed that different populations in medulloblastomas show different sensitivities to specific targeted therapies. To determine if specific populations depend on AMPK, we analyzed mice with AMPK-inactivated medulloblastomas. We engineered mice with conditional deletion of the AMPK catalytic subunitsPrkaa1andPrkaa2and conditional expressionSmoM2, an oncogenicSmoallele that hyperactivates Sonic Hedgehog (SHH) signaling. We compared these medulloblastomas to SmoM2-driven medulloblastomas in AMPK-intact mice. AMPK-inactivation slowed tumor growth and progression, allowing longer event-free survival (EFS). scRNA-seq showed that AMPK inactivation altered cellular heterogeneity, increasing differentiation, decreasing tumor stem cell populations and reducing glio-neuronal multipotency. Surprisingly, AMPK-inactivated tumors showed decreased mTORC1 activation andHk2expression. GeneticHk2deletion in SmoM2-medulloblastomas similarly decreased stem cell populations, implicating reduced aerobic glycolysis in the tumor-suppressive effect of AMPK inactivation. Our results show that AMPK inactivation impairs tumor growth through mechanisms that disproportionately affect tumor stem cell populations that have proved refractory to conventional therapies.
Pharmacologic analysis of non-synonymous coding 5-HT2A SNPs reveals alterations psychedelic drug potencies and efficacies
Authors: Schmitz Gavin P. , Jain Manish K. , Slocum Samuel T. , Roth Bryan L. 
Published: December 2021

AbstractSerotonin (5-Hydroxytryptamine; 5-HT) 2A receptor (5-HT2AR) signaling is essential for the actions of classical psychedelic drugs. In this study, we examined whether random sequence variations in the gene (single nucleotide polymorphisms, SNPs) encoding the 5-HT2AR affect the signaling of four commonly used psychedelic drugs. We examined the in vitro pharmacology of seven non-synonymous SNPs, which give rise to S12N, T25N, D48N, I197V, A230T, A447V, and H452Y variant 5-HT2A serotonin receptors. We found that these non-synonymous SNPs exert statistically significant, although modest, effects on the efficacy and potency of four therapeutically relevant hallucinogens. Significantly, the in vitro pharmacological effects of the SNPs drug actions at 5-HT2AR are drug specific.Table of Contents/Abstract Graphic
Quantitative Structural Analysis of Influenza Virus by Cryo-electron Tomography and Convolutional Neural Networks
Authors: Huang Qiu Yu , Song Kangkang , Xu Chen , Bolon Daniel N.A. , Wang Jennifer P. , Finberg Robert W. , Schiffer Celia A. , Somasundaran Mohan 
Published: December 2021

SummaryInfluenza viruses pose severe public health threats; they cause millions of infections and tens of thousands of deaths annually in the US. Influenza viruses are extensively pleomorphic, in both shape and size as well as organization of viral structural proteins. Analysis of influenza morphology and ultrastructure can help elucidate viral structure-function relationships as well as aid in therapeutics and vaccine development. While cryo-electron tomography (cryoET) can depict the 3D organization of pleomorphic influenza, the low signal-to-noise ratio inherent to cryoET and extensive viral heterogeneity have precluded detailed characterization of influenza viruses. In this report, we developed a cryoET processing pipeline leveraging convolutional neural networks (CNNs) to characterize the morphological architecture of the A/Puerto Rico/8/34 (H1N1) influenza strain. Our pipeline improved the throughput of cryoET analysis and accurately identified viral components within tomograms. Using this approach, we successfully characterized influenza viral morphology, glycoprotein density, and conduct subtomogram averaging of HA glycoproteins. Application of this processing pipeline can aid in the structural characterization of not only influenza viruses, but other pleomorphic viruses and infected cells.Graphical abstract
Nitrogen metabolism in Pseudomonas putida: functional analysis using random barcode transposon sequencing
Authors: Schmidt Matthias , Pearson Allison N. , Incha Matthew R. , Thompson Mitchell G. , Baidoo Edward E. K. , Kakumanu Ramu , Mukhopadhyay Aindrila , Shih Patrick M. , Deutschbauer Adam M. , Blank Lars M. , Keasling Jay D. 
Published: December 2021

ABSTRACTPseudomonas putida KT2440 has long been studied for its diverse and robust metabolisms, yet many genes and proteins imparting these growth capacities remain uncharacterized. Using pooled mutant fitness assays, we identified genes and proteins involved in the assimilation of 52 different nitrogen containing compounds. To assay amino acid biosynthesis, 19 amino acid drop- out conditions were also tested. From these 71 conditions, significant fitness phenotypes were elicited in 672 different genes including 100 transcriptional regulators and 112 transport-related proteins. We divide these conditions into 6 classes, and propose assimilatory pathways for the compounds based on this wealth of genetic data. To complement these data, we characterize the substrate range of three promiscuous aminotransferases relevant to metabolic engineering efforts in vitro. Furthermore, we examine the specificity of five transcriptional regulators, explaining some fitness data results and exploring their potential to be developed into useful synthetic biology tools. In addition, we use manifold learning to create an interactive visualization tool for interpreting our BarSeq data, which will improve the accessibility and utility of this work to other researchers.IMPORTANCEUnderstanding the genetic basis of P. putida’s diverse metabolism is imperative for us to reach its full potential as a host for metabolic engineering. Many target molecules of the bioeconomy and their precursors contain nitrogen. This study provides functional evidence linking hundreds of genes to their roles in the metabolism of nitrogenous compounds, and provides an interactive tool for visualizing these data. We further characterize several aminotransferases, lactamases, and regulators--which are of particular interest for metabolic engineering.
Rational domestication of a plant-based recombinant expression system expands its biosynthetic range
Authors: Jackson Mark A. , Chan Lai Yue , Harding Maxim D. , Craik David J. , Gilding Edward K. 
Published: December 2021

SummaryPlant molecular farming aims to provide a green, flexible, and rapid alternative to conventional recombinant expression systems, capable of producing complex biologics such as enzymes, vaccines, and antibodies. Historically, the recombinant expression of therapeutic peptides in plants has proven difficult, largely due to their small size and instability. However, some plant species harbour the capacity for peptide backbone cyclization, a feature inherent in stable therapeutic peptides. One obstacle to realizing the potential of plant-based therapeutic peptide production is the proteolysis of the precursor before it is matured into its final stabilized form. Here we demonstrate the rational domestication of Nicotiana benthamiana within two generations to endow this plant molecular farming host with an expanded repertoire of peptide sequence space. The in planta production of molecules including an insecticidal peptide, a prostate cancer therapeutic lead and an orally active analgesic are demonstrated.
Identification of genome-wide distribution of cyanobacterial group 2 sigma factor SigE accountable for its regulon
Authors: Kariyazono Ryo , Osanai Takashi 
Published: December 2021

AbstractSigma factors are the subunits of bacterial RNA polymerase that govern the expression of genes by recognizing the promoter sequence. Cyanobacteria, which are oxygenic phototrophic eubacteria, have multiple alternative sigma factors that respond to various environmental stresses. The subgroup highly homologous to the primary sigma factor (SigA) is called the group 2 sigma factor. The model cyanobacterium, Synechocystis sp. PCC 6803, has four group 2 sigma factors (SigB-E) conserved within the phylum Cyanobacteria. Among the group 2 sigma factors in Synechocystis sp. PCC 6803, SigE is unique because it alters metabolism by inducing the expression of genes related to sugar catabolism and nitrogen metabolism. However, the features of promoter sequence of the SigE regulon remains elusive. Here, we identified the direct targets of SigA and SigE by chromatin immunoprecipitation sequencing (ChIP-seq). We then showed that the binding sites of SigE and SigA overlapped substantially, but SigE exclusively localized to SigE-dependent promoters. We also found consensus sequences from SigE-dependent promoters and confirmed their importance. ChIP-seq analysis showed both the redundancy and specificity of SigE compared with SigA, integrating information obtained from a previously adopted genetic approach and in vitro assays. The features of SigE elucidated in our study indicate its similarity with group 2 sigma factors of other bacteria, even though they are evolutionally irrelevant. Our approach is also applicable to other organisms and organelles, such as plant plastids, which have multiple group 2 sigma factors.ImportanceGroup 2 sigma factors are alternative sigma factors highly homologous to primary sigma factors. Cyanobacteria, which are photosynthetic eubacteria, are unique because they have multiple group 2 sigma factors. Although each sigma factor induces the expression of specific genes, the redundancy and complicated network of the primary and group 2 sigma factors hinder the identification of their regulons via a genetic approach. Here, we identified the binding sites of SigE (group 2 sigma factor) and SigA (primary sigma factor) using chromatin immunoprecipitation sequencing and identified the minimal element of SigE-dependent promoters by subsequent promoter assays. Our study provides insights into the common features of group 2 sigma factors, which, though evolutionarily irrelevant, are widespread among eubacteria and plant plastids.