bluuebunny/crossref_metadata_2025_split huggingface dataset:
Auto-inhibitory regulation of DNA binding by the C-terminal tails of the mitochondrial transcription factors Mtf1 and TFB2M
Authors: Basu Urmimala , Mishra Nandini , Farooqui Mohammed , Shen Jiayu , Johnson Laura C. , Patel Smita S. 
Published: March 2020

ABSTRACTThe structurally homologous Mtf1 and TFB2M proteins serve as transcription initiation factors of theSaccharomyces cerevisiaeand human mitochondrial RNA polymerases, respectively. These transcription factors directly interact with the non-template strand of the transcription bubble to drive promoter melting. Given the key roles of Mtf1 and TFB2M in promoter-specific transcription initiation, it is expected that the DNA binding activity of the mitochondrial transcription factors would be regulated to prevent DNA binding at inappropriate times. However, there is little information on how mitochondrial DNA transcription is regulated. While studying the C-tail deletion mutants of Mtf1 and TFB2M, we stumbled upon a new finding that suggested that the flexible C-tail region of these factors autoregulates their DNA binding activity. Quantitative DNA binding studies with fluorescence anisotropy-based titrations show that Mtf1 with an intact C-tail has no affinity for the DNA but the deletion of C-tail greatly increases the DNA binding affinity. Similar observations were made with TFB2M, although autoinhibition by the C-tail of TFB2M was not as absolute as in Mtf1. Analysis of available TFB2M structures show that the C-tail makes intramolecular interactions with the DNA binding groove in the free factor, which we propose masks the DNA binding activity. Further studies show that the RNA polymerase relieves autoinhibition by interacting with the C-tail and engaging it in complex formation. Thus, our biochemical and structural analysis identify previously unknown autoinhibitory and activation mechanisms of mitochondrial transcription factors that regulate the DNA binding activity and aid in specific assembly of the initiation complexes.
Embedding the de Bruijn graph, and applications to metagenomics
Authors: Menegaux Romain , Vert Jean-Philippe 
Published: March 2020

AbstractFast mapping of sequencing reads to taxonomic clades is a crucial step in metagenomics, which however raises computational challenges as the numbers of reads and of taxonomic clades increases. Besides alignment-based methods, which are accurate but computational costly, faster compositional approaches have recently been proposed to predict the taxonomic clade of a read based on the set ofk-mers it contains. Machine learning-based compositional approaches, in particular, have recently reached accuracies similar to alignment-based models, while being considerably faster. It has been observed that the accuracy of these models increases with the lengthkof thek-mers they use, however existing methods are limited to handlek-mers of lengths up tok= 12 or 13 because of their large memory footprint needed to store the model coefficients for each possiblek-mer. In order to explore the performance of machine learning-based compositional approaches for longerk-mers than currently possible, we propose to reduce the memory footprint of these methods by binning togetherk-mers that appear together in the sequencing reads used to train the models. We achieve this binning by learning a vector embedding for the vertices of a compacted de Bruijn graph, allowing us to embed any DNA sequence in a low-dimensional vector space where a machine learning system can be trained. The resulting method, which we callBrume, allows us to train compositional machine learning-based models withk-mers of length up tok= 31. We show on two metagenomics benchmark thatBrumereaches better performance than previously achieved, thanks to the use of longerk-mers.
Murine Radiation-Induced Stomach Pathology from Whole Thoracic Irradiation
Authors: McIlrath Daniel R. , Perez-Torres Carlos J. 
Published: March 2020

AbstractPurposeRadiation-induced lung injury is a common side effect in the treatment of lung and breast cancers. There is a large focus in the field on leveraging mouse models of radiation-induced lung injury to find novel treatments for the condition. While attempting to irradiate mouse lungs for purposes of creating a radiation-induced pulmonary fibrosis model, noticeable declines in health were observed at much earlier time points than recorded for lung pathology. This was later attributed to stomach pathology observed in CT images and ex vivo dissection.MethodsFor this study, we used longitudinal microCT to characterize male C57Bl/6 mice irradiated with a single dose of 20 Gy to the whole thoracic area delivered by an X-Rad cabinet irradiator. CT was performed with respiratory gating at 2 to 4 week timepoints to construct a timeline of pathology leading up to fibrosis and quantify severity of fibrosis afterwards. However, a mouse imaged at the 10 week timepoint showed evidence of stomach distention. These mice were sacrificed and their stomachs removed. Histology was performed on the stomachs using H&E staining.ResultsOn the CT images, we observed a large, spherical volume of hypointense signal, caudal to the lungs (Figure 1). This correlated with a distended stomach caused by constipation and gas build-up within the stomach. Statistical analysis showed 81% of mice (n=105) died prematurely after irradiation and before significant development of pulmonary fibrosis. Mice sacrificed and dissected showed unpassed bolus as contents of the stomach, and histology showed cell necrosis of the stomach walls.ConclusionThe histology indicated an inability for food to be digested and moved into the small intestine. This lead to a blockage and ensuing stomach distention. Given the severity of the pathology’s consequences, it lead to the mouse’s imminent mortality inhibiting the efficacy of the study. Future studies need to consider careful placement of shields or any beam contouring devices to ensure protection of the stomach given its higher radiosensitivity in contrast to the lungs.
Evidence accumulation and associated error-related brain activity as computationally-informed prospective predictors of substance use in emerging adulthood
Authors: Weigard Alexander S. , Brislin Sarah J. , Cope Lora M. , Hardee Jillian E. , Martz Meghan E. , Ly Alexander , Zucker Robert A. , Sripada Chandra , Heitzeg Mary M. 
Published: March 2020

AbstractRationaleSubstance use peaks during the developmental period known as emerging adulthood (ages 18–25), but not every individual who uses substances during this period engages in frequent or problematic use. Although individual differences in neurocognition appear to predict use severity, mechanistic neurocognitive risk factors with clear links to both behavior and neural circuitry have yet to be identified. Here we aim to do so with an approach rooted in computational psychiatry, an emerging field in which formal models are used to identify candidate biobehavioral dimensions that confer risk for psychopathology.ObjectivesWe test whether lower efficiency of evidence accumulation (EEA), a computationally-characterized individual difference variable that drives performance on the go/no-go and other neurocognitive tasks, is a risk factor for substance use in emerging adults.Methods and ResultsIn an fMRI substudy within a sociobehavioral longitudinal study (n=106), we find that lower EEA and reductions in a robust neural-level correlate of EEA (error-related activations in salience network structures) measured at ages 18–21 are both prospectively related to greater substance use during ages 22–26, even after adjusting for other well-known risk factors. Results from Bayesian model comparisons corroborated inferences from conventional hypothesis testing and provided evidence that both EEA and its neuroimaging correlates contain unique predictive information about substance use involvement.ConclusionsThese findings highlight EEA as a computationally-characterized neurocognitive risk factor for substance use during a critical developmental period, with clear links to both neuroimaging measures and well-established formal theories of brain function.
Mantis shrimp navigate home using celestial and idiothetic path integration
Authors: Patel Rickesh N. , Cronin Thomas W. 
Published: March 2020

SummaryPath integration is a robust mechanism that many animals employ to return to specific locations, typically their homes, during navigation. This efficient navigational strategy has never been demonstrated in a fully aquatic animal, where sensory cues used for orientation may differ dramatically from those available above the water’s surface. Here we report that the mantis shrimp,Neogonodactylus oerstedii, uses path integration informed by a hierarchical reliance on the sun, overhead polarization patterns, and idiothetic (internal) orientation cues to return home when foraging, making them the first fully aquatic path-integrating animals yet discovered. We show that mantis shrimp rely on navigational strategies closely resembling those used by insect navigators, opening a new avenue for the investigation of the neural basis of navigation behaviors and the evolution of these strategies in arthropods and potentially other animals as well.
locStra: Fast analysis of regional/global stratification in whole genome sequencing (WGS) studies
Authors: Hahn Georg , Lutz Sharon M. , Hecker Julian , Prokopenko Dmitry , Cho Michael H. , Silverman Edwin K. , Weiss Scott T. , Lange Christoph ,   the NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
Published: March 2020

AbstractlocStrais anR-package for the analysis of regional and global population stratification in whole genome sequencing studies, where regional stratification refers to the substructure defined by the loci in a particular region on the genome. Population substructure can be assessed based on the genetic covariance matrix, the genomic relationship matrix, and the unweighted/weighted genetic Jaccard similarity matrix. Using a sliding window approach, the regional similarity matrices are compared to the global ones, based on user-defined window sizes and metrics, e.g. the correlation between regional and global eigenvectors. An algorithm for the specification of the window size is provided. As the implementation fully exploits sparse matrix algebra and is written in C++, the analysis is highly efficient. Even on single cores, for realistic study sizes (several thousand subjects, several million RVs per subject), the runtime for the genome-wide computation of all regional similarity matrices does typically not exceed one hour, enabling an unprecedented investigation of regional stratification across the entire genome. The package is applied to three WGS studies, illustrating the varying patterns of regional substructure across the genome and its beneficial effects on association testing.
Intergenerational transmission of the patterns of functional and structural brain networks
Authors: Takagi Yu , Okada Naohiro , Ando Shuntaro , Yahata Noriaki , Morita Kentaro , Koshiyama Daisuke , Kawakami Shintaro , Sawada Kingo , Koike Shinsuke , Endo Kaori , Yamasaki Syudo , Nishida Atsushi , Kasai Kiyoto , Tanaka Saori C 
Published: March 2020

AbstractThere is clear evidence of intergenerational transmission of life values, cognitive traits, psychiatric disorders, and even aspects of daily decision making. To investigate biological substrates of this phenomenon, brain has received increasing attention as a measurable biomarker and potential target for intervention. However, no previous study has quantitatively and comprehensively investigated the effects of intergenerational transmission on functional and structural brain networks from parents to their children. Here, by employing an unusually large cohort dataset, we show that patterns of functional and structural brain networks are preserved over a generation. We also demonstrate that several demographic and behavioural phenotypes have effects on brain similarity. Collectively, our results provide a comprehensive picture of neurobiological substrates of parent-child similarity, and demonstrate the usability of our dataset for investigating the neurobiological substrates of intergenerational transmission.
An autoinhibitory clamp of actin assembly constrains and directs synaptic endocytosis
Authors: Del Signore Steven J. , Kelley Charlotte F. , Messelaar Emily M. , Lemos Tania , Marchan Michelle F. , Ermanoska Biljana , Mund Markus , Fai Thomas G. , Kaksonen Marko , Rodal Avital A 
Published: March 2020

AbstractSynaptic membrane-remodeling events such as endocytosis require force-generating actin assembly. The endocytic machinery that regulates these actin and membrane dynamics localizes at high concentrations to large areas of the presynaptic membrane, but actin assembly and productive endocytosis are far more restricted in space and time. Here we describe a mechanism whereby autoinhibition clamps the presynaptic endocytic machinery to limit actin assembly to discrete functional events. We found that collective interactions between theDrosophilaendocytic proteins Nwk/FCHSD2, Dap160/Intersectin, and WASp relieve Nwk autoinhibition and promote robust membrane-coupled actin assemblyin vitro.Using automated particle tracking to quantify synaptic actin dynamicsin vivo, we discovered that Nwk-Dap160 interactions constrain spurious assembly of WASp-dependent actin structures. These interactions also promote synaptic endocytosis, suggesting that autoinhibition both clamps and primes the synaptic endocytic machinery, thereby constraining actin assembly to drive productive membrane remodeling in response to physiological cues.
Human-Genetic Ancestry Inference and False Positives in Forensic Familial Searching
Authors: Fortier Alyssa Lyn , Kim Jaehee , Rosenberg Noah A. 
Published: March 2020

AbstractIn forensic familial search methods, a query DNA profile is tested against a database to determine if the query profile represents a close relative of a database entrant. One challenge for familial search is that the calculations may require specification of allele frequencies for the unknown population from which the query profile has originated. Allele-frequency misspecification can substantially inflate false-positive rates compared to use of allele frequencies drawn from the same population as the query profile. Here, we use ancestry inference on the query profile to circumvent the high false-positive rates that result from highly misspecified allele frequencies. In particular, we perform ancestry inference on the query profile and make use of allele frequencies based on its inferred genetic ancestry. In a test for sibling matches on profiles that represent unrelated individuals, we demonstrate that false-positive rates for familial search with use of ancestry inference to specify the allele frequencies are similar to those seen when allele frequencies align with the population of origin of a profile. Because ancestry inference is possible to perform on query profiles, the extreme allele-frequency misspecifications that produce the highest false-positive rates can be avoided. We discuss the implications of the results in the context of concerns about the forensic use of familial searching.
Data Processing Pipeline for Multiband Diffusion-, T1- and Susceptibility Weighted MRI to Establish Structural Connectivity of the Human Basal Ganglia and Thalamus
Authors: Gilani Irtiza A. , Oguz Kader K. , Boyaci Huseyin , Doerschner Katja 
Published: March 2020

AbstractThe basal ganglia and thalamus play an important role in cognition, procedural learning, eye movements, control of voluntary motor movements, emotional control, habit development, and are structures that are severely impacted by neurological disorders such as Parkinson’s disease, or Tourette syndrome. To understand the structural connectivity of cortical and subcortical circuits in the healthy human brain could thus be of pivotal importance for detecting changes in this circuitry and to start early intervention, to assess the progress of movement rehabilitation, or the effectiveness of therapeutic approaches in neuropsychiatry. While conventional clinical magnetic resonance imaging (MRI) is able to provide detailed information about connectivity at the macro level, the sensitivity and specificity of such structural imaging methods put limits on the amount of detail one can obtain when measuringin vivoconnectivity of human basal ganglia and thalamus at routine clinical magnetic field strengths. In contrast, the multiband diffusion echo planar imaging method, which acquires multiple slices simultaneously, enables high resolution imaging of these abovementioned brain structures with only short acquisition times at 3-Tesla and higher magnetic field strengths. To unleash the greater potential of information embedded in data acquired with this technique, complementary data processing pipelines are required. Here, we use a protocol composed of multiband diffusion-, T1- and susceptibility weighted data acquisition sequences and introduce an associated pipeline based on combined manual and automated processing. The design of this data processing pipeline allows us to generate comprehensivein vivoparticipant-specific probabilistic patterns and visualizations of the structural connections that exist within basal ganglia and thalamic nuclei. Moreover, we are able to map specific parcellations of these nuclei into sub-territories based on their connectivity with primary motor-, and somatosensory cortex. This data processing strategy enables detailed subcortical structural connectivity mapping which could benefit early intervention and therapy methods for human movement rehabilitation and for treating neuropsychiatric disorders.
Association Study based on Topological Constraints of Protein-Protein Interaction Networks
Authors: Guo Hao-Bo , Qin Hong 
Published: March 2020

AbstractThe non-random interaction pattern of a protein-protein interaction network (PIN) is biologically informative but its potentials have not been fully utilized in omics studies. Here, we propose a network-permutation-based association study (NetPAS) method that gauges the observed interactions between two sets of genes based on the comparison between permutation null models and the empirical networks. This enables NetPAS to evaluate relationships, constrained by network topology, between gene sets related to different phenotypes. We demonstrated the utility of NetPAS in 50 well-curated gene sets and comparison of association studies using Z-scores, p-values or overrepresentations. Using NetPAS, a weighted human disease network was generated from the association scores of 19 gene sets from OMIM. We also applied NetPAS in gene sets derived from gene ontology and pathway annotations and showed that NetPAS uncovered functional terms missed by DAVID and other network-based enrichment tools. Overall, we show that NetPAS can take topological constraints of molecular networks into account and offer new perspectives than existing methods.
Insights into chloroplast genome variation across Opuntioideae (Cactaceae)
Authors: Köhler Matias , Reginato Marcelo , Souza-Chies Tatiana T. , Majure Lucas C. 
Published: March 2020

AbstractChloroplast genomes (plastomes) are frequently treated as highly conserved among land plants. However, many lineages of vascular plants have experienced extensive structural rearrangements, including inversions and modifications to the size and content of genes. Cacti are one of these lineages, containing the smallest plastome known for an obligately photosynthetic angiosperm, including the loss of one copy of the inverted repeat (∼25 kb) and thendhgenes suite, but only a few cacti from the subfamily Cactoideae have been sufficiently characterized. Here, we investigated the variation of plastome sequences across the second-major lineage of the Cactaceae, the subfamily Opuntioideae, to address 1) how variable is the content and arrangement of chloroplast genome sequences across the subfamily, and 2) how phylogenetically informative are the plastome sequences for resolving major relationships among the clades of Opuntioideae. Ourde novoassembly of theOpuntia quimiloplastome recovered an organelle of 150,347 bp in length with both copies of the inverted repeats and the presence of all thendhgenes suite. An expansion of the large single copy unit and a reduction of the small single copy was observed, including translocations and inversion of genes as well as the putative pseudogenization of numerous loci. Comparative analyses among all clades within Opuntioideae suggested that plastome structure and content vary across taxa of this subfamily, with putative independent losses of thendhgene suite and pseudogenization of genes across disparate lineages, further demonstrating the dynamic nature of plastomes in Cactaceae. Our plastome dataset was robust in determining relationships among major clades and subclades within Opuntioideae, resolving three tribes with high support: Cylindropuntieae, Tephrocacteae and Opuntieae. A plastome-wide survey for highly informative phylogenetic markers revealed previously unused regions for future use in Sanger-based studies, presenting a valuable dataset with primers designed for continued evolutionary studies across Cactaceae. These results bring new insights into the evolution of plastomes in cacti, suggesting that further analyses should be carried out to address how ecological drivers, physiological constraints and morphological traits of cacti may be related with the common rearrangements in plastomes that have been reported across the family.
Differential RNA editing between epithelial and mesenchymal tumors impacts mRNA abundance in immune response pathways
Authors: Chan Tracey , Fu Ting , Bahn Jae Hoon , Jun Hyun-Ik , Lee Jae-Hyung , Quinones-Valdez Giovanni , Cheng Chonghui , Xiao Xinshu 
Published: March 2020

AbstractRecent studies revealed global shifts in RNA editing, the modification of RNA sequences, across many cancers. Besides a few sites implicated in tumorigenesis or metastasis, most tumor-associated sites, predominantly in noncoding regions, have unknown function. Here, we characterize editing profiles between epithelial (E) and mesenchymal (M) phenotypes in seven cancer types, as epithelial-mesenchymal transition (EMT) is a key paradigm for metastasis. We observe distinct editing patterns between E and M tumors and EMT induction upon loss of ADAR enzymes in cultured cells. E-M differential sites are highly enriched in genes involved in immune and viral processes, some of which regulate mRNA abundance of their respective genes. We identify a novel mechanism in which ILF3 preferentially stabilizes edited transcripts. Among editing-dependent ILF3 targets is the transcript encoding PKR, a crucial player in immune response. Our study demonstrates the broad impact of RNA editing in cancer and relevance of editing to cancer-related immune pathways.
Large scale analysis of smoking-induced changes in the tumor immune microenvironment
Authors: Alisoltani Arghavan , Qiu Xinru , Jaroszewski Lukasz , Sedova Mayya , Li Zhanwen , Godzik Adam 
Published: March 2020

AbstractTobacco smoke is a known carcinogen, mostly due to its genotoxicity, but its effects on the host immune system are also playing an important role. Here, we leveraged recent results on the immune landscape of cancer based on The Cancer Genomic Atlas (TCGA) data analysis and compared the proportions of major classes of tumor-infiltrating immune cells (TIICs) between smokers and never smokers in ten TCGA cancer types. We show that statistically significant changes can be identified in all ten cancers, with increased plasma cell populations and the modified ratio of activated to resting TIICs being the most consistent features distinguishing smokers and never-smokers across different cancers, with both being correlated with survival outcomes. Analysis of existing single-cell RNA-seq data further showed that smoking differentially affects the gene expression profile of cancer patients based on the immune cell type. The smoking-induced changes in the patterns of immune cells and their correlations to survival outcomes are stronger in female smokers.