bluuebunny/crossref_metadata_2025_split huggingface dataset:
A framework evaluating the utility of multi-gene, multi-disease population-based panel testing that accounts for uncertainty in penetrance estimates
Authors: Liang Jane W. , Christensen Kurt D. , Green Robert C. , Kraft Peter 
Published: August 2022

AbstractPanel germline testing allows for efficient detection of deleterious variants for multiple conditions, but the benefits and harms of identifying these variants are not always well-understood. We present a multi-gene, multi-disease aggregate utility formula that allows the user to consider adding or removing each gene in a panel based on variant frequency; estimated penetrances; and subjective disutilities for testing positive but not developing the disease and testing negative but developing the disease. We provide credible intervals for utility that reflect uncertainty in penetrance estimates. Rare, highly-penetrant deleterious variants tend to contribute positive net utilities for a wide variety of user-specified disutilities, even when accounting for parameter estimation uncertainty. However, the clinical utility of deleterious variants with moderate, uncertain penetrance depends more on assumed disutilities. The decision to include a gene on a panel depends on variant frequency, penetrance, and subjective utilities, and should account for uncertainties around these factors.
Endocannabinoid-dependent persistent decrease of GABAergic transmission on dopaminergic neurons underlies gene-environment interaction-induced susceptibility to cocaine sensitization
Authors: Serra Valeria , Traccis Francesco , Aroni Sonia , Bortolato Marco , Melis Miriam 
Published: August 2022

AbstractVulnerability to develop cocaine use disorder depends upon an unpredictable combination of genetic and non-genetic risk factors. Early life adversity and adolescence are critical non-genetic risk factors, and haplotypes of the monoamine oxidase (MAO) genes are among genetic variations increasing the risk of drug-related problems. However, data on the interactions between inheritable risk factors and early life stress (ES) with respect to predisposition to cocaine abuse are limited. Here, we show that a mouse model containing both genetic (low-activity alleles of theMAO Agene; MAOANeo) and environmental (i.e., ES) variables displays a long lasting increased sensitivity to repeatedin vivococaine psychomotor stimulant actions associated with a reduction of GABAA receptor-mediated inhibition of dopamine neurons of the ventral tegmental area (VTA). Depolarization-induced suppression of inhibition (DSI), a 2-arachidonoylglycerol (2-AG)-dependent form of short-term plasticity, also becomes readily expressed by dopamine neurons from MAOANeoES mice treated repeatedly with cocaine. Activation of either dopamine D2 or CB1 receptors is required for cocaine-induced DSI expression, decreased GABA synaptic efficacy, and hyperlocomotion. Next,in vivopharmacological enhancement of 2-AG signaling during repeated cocaine exposure occludes its actions bothin vivoandex vivo. This data extends our knowledge of the multifaceted sequelae imposed by this gene by environment interaction in VTA dopamine neurons of male pre-adolescent mice, contributing to our understanding of neural mechanisms of vulnerability for early onset cocaine use disorder.
Local brain oscillations and inter-regional connectivity differentially serve sensory and expectation effects on pain
Authors: Bott Felix S. , Nickel Moritz M. , Hohn Vanessa D. , May Elisabeth S. , Gil Ávila Cristina , Tiemann Laura , Gross Joachim , Ploner Markus 
Published: August 2022

AbstractPain emerges from the integration of sensory information about threats and contextual information such as an individual’s expectations. However, how sensory and contextual effects on pain are served by the brain is not fully understood so far. To address this question, we applied brief painful stimuli to 40 healthy human participants and independently varied stimulus intensity and expectations. Concurrently, we recorded electroencephalography. We assessed local oscillatory brain activity and inter-regional functional connectivity in a network of six brain regions playing key roles in the processing of pain. We found that sensory information predominantly influenced local brain oscillations. In contrast, expectations exclusively influenced inter-regional connectivity. Specifically, expectations altered connectivity at alpha (8-12 Hz) frequencies from prefrontal to somatosensory cortex. Moreover, discrepancies between sensory information and expectations, i.e., prediction errors, influenced connectivity at gamma (60-100 Hz) frequencies. These findings reveal how fundamentally different brain mechanisms serve sensory and contextual effects on pain.TeaserSensory and expectation effects on pain are implemented by fundamentally different brain mechanisms.
Tip-links serve as force-pass filter to fulfil the role of gating-springs
Authors: Arora Nisha , Hazra Jagadish P. , Roy Sandip , Bhati Gaurav K. , Gupta Sarika , Chaudhuri Abhishek , Sagar Amin , Rakshit Sabyasachi 
Published: August 2022

AbstractTip-links as gating-spring in the mechanotransduction in hearing is still a debate. While the molecular elasticity of individual tip-link proteins warrants its candidature, the apparent rigidity from the heterotetrameric tip-links assembly refutes the claim. Using force-clamp experiments and simulations, we report that the heterotetrameric assembly is the natural selection for the gating-springs. Tip-links follow slip-ideal-slip bonds with increasing force. While in slip, the complex dissociates monotonously, ideal-bond interface responds indifferently to various auditory inputs. Insensitivity to forces renders tip-links as low-force pass filter, characteristic of gating-spring. Individual tip-links, however, forms slip-catch-slip bonds under tension. While catch bonds turn stronger with force from loud sound, our Langevin dynamics indicated the transition from slip-catch to slip-ideal bonds as cooperative effect of the dimers of individual protein complexes in tip-links. From molecular dynamics, we deciphered the molecular mechanism of catch bonds and its importance in deafness.
Optimizing InterProScan representation generates a surprisingly good protein function prediction method
Authors: Tiittanen Henri , Holm Liisa , Törönen Petri 
Published: August 2022

AbstractMotivationAutomated protein Function Prediction (AFP) is an intensively studied topic. Most of this research focuses on methods that combine multiple data sources, while fewer articles look for the most efficient ways to use a single data source. Therefore, we wanted to test how different preprocessing methods and classifiers would perform in the AFP task when we process the output from the InterProscan (IPS). Especially, we present novel preprocessing methods, less used classifiers and inclusion of species taxonomy. We also test classifier stacking for combining tested classifier results. Methods are tested with in-house data and CAFA3 competition evaluation data.ResultsWe show that including IPS localisation and taxonomy to the data improves results. Also the stacking improves the performance. Surprisingly, our best performing methods outperformed all international CAFA3 competition participants in most tests. Altogether, the results show how preprocessing and classifier combinations are beneficial in the AFP task.Contactpetri.toronen(AT)helsinki.fiSupplementary informationSupplementary text is available at the project web site http://ekhidna2.biocenter.helsinki.fi/AFP/ and at the end of this document.
A vast space of compact strategies for highly efficient decisions
Authors: Ma Tzuhsuan , Hermundstad Ann M 
Published: August 2022

ABSTRACTWhen foraging in dynamic and uncertain environments, animals can benefit from basing their decisions on smart inferences about hidden properties of the world. Typical theoretical approaches to understand the strategies that animals use in such settings combine Bayesian inference and value iteration to derive optimal behavioral policies that maximize total reward given changing beliefs about the environment. However, specifying these beliefs requires infinite numerical precision; with limited resources, this problem can no longer be separated into optimizing inference and optimizing action selections. To understand the space of behavioral policies in this constrained setting, we enumerate and evaluate all possible behavioral programs that can be constructed from just a handful of states. We show that only a small fraction of the top-performing programs can be constructed by approximating Bayesian inference; the remaining programs are structurally or even functionally distinct from Bayesian. To assess structural and functional relationships among all programs, we developed novel tree embedding algorithms; these embeddings, which are capable of extracting different relational structures within the program space, reveal that nearly all good programs are closely connected through single algorithmic “mutations”. We demonstrate how one can use such relational structures to efficiently search for good solutions via an evolutionary algorithm. Moreover, these embeddings reveal that the diversity of non-Bayesian behaviors originates from a handful of key mutations that broaden the functional repertoire within the space of good programs. The fact that this diversity of behaviors does not significantly compromise performance suggests a novel approach for studying how these strategies generalize across tasks.
Unified access to up-to-date residue-level annotations from UniProt and other biological databases for PDB data via PDBx/mmCIF files
Authors: Choudhary Preeti , Anyango Stephen , Berrisford John , Varadi Mihaly , Tolchard James , Velankar Sameer 
Published: August 2022

AbstractMore than 58,000 proteins have up-to-date correspondence between their amino acid sequence (UniProtKB) and their 3D structures (PDB), enabled by the Structure Integration with Function, Taxonomy and Sequences (SIFTS) resource. In addition to this fundamental mapping, SIFTS incorporates residue-level annotations from other biological resources such as Pfam, InterPro, SCOP, SCOP2, CATH, IntEnz, GO, PubMed, Ensembl, NCBI taxonomy database and Homologene. The SIFTS data is exported in XML format per individual PDB entry and is also accessible via the PDBe REST API. These mappings have always been maintained separately from the structure data (PDBx/mmCIF file) in the PDB archive. In this current work, taking advantage of the extensibility of the core PDBx/mmCIF framework, we extended the wwPDB PDBx/mmCIF data dictionary with additional categories to accommodate SIFTS data and added the UniProt, Pfam, SCOP2, and CATH mapping information directly into the PDBx/mmCIF files from the PDB archive. The integration of mapping data in the PDBx/mmCIF files provides consistent numbering of residues in different PDB entries allowing easy comparison of structure models. The extended PDBx/mmCIF format yields a more consistent, standardised metadata description without altering the core PDB information. This development enables up-to-date cross-reference information at residue level resulting in better data interoperability, supporting improved data analysis and visualisation.Availability and implementationWe expanded the PDBe release pipeline with a process that adds SIFTS annotations to the PDBx/mmCIF files for individual structures in the PDB archive. The scientific community can download these updated PDBx/mmCIF files from the PDBe entry pages(https://pdbe.org/7dr0) and through direct URLs(https://www.ebi.ac.uk/pdbe/static/entry/7o9f_updated.cif), using the PDBe download service(https://www.ebi.ac.uk/pdbe/download/api) or from the EMBL-EBI FTP area(https://ftp.ebi.ac.uk/pub/databases/msd/updated_mmcif/).
“It’s my job”: A qualitative study of the mediatization of science within the scientist-journalist relationship
Authors: Moorhead Laura L. , Fleerackers Alice , Maggio Lauren A. 
Published: August 2022

AbstractThrough 19 interviews with scientists, this study examines scientists’ use of media logic and their relationships with journalists using research as the focal point. The authors identified that the scientists shared a basic understanding of media logic classified in three patterns. Two patterns were previously identified by Olesk: 1) adaption (ability to explain research in a simple, engaging fashion but with a reactive approach to journalist interaction) and 2) adoption (proactively create and manage media interactions for strategic aims through a more active use of media logic). The other emerged as a new, third pattern, affiliation (enthusiastic contributors to journalists’ production practices and desire to engage in public outreach).
Automatic identification of drug-induced liver injury literature using natural language processing and machine learning methods
Authors: Oh Jung Hun , Tannenbaum Allen , Deasy Joseph O. 
Published: August 2022

AbstractDrug-induced liver injury (DILI) is an adverse hepatic drug reaction that can potentially lead to life-threatening liver failure. Previously published work in the scientific literature on DILI has provided valuable insights for the understanding of hepatotoxicity as well as drug development. However, the manual search of scientific literature in PubMed is laborious. Natural language processing (NLP) techniques have been developed to decipher and understand the meaning of human language by extracting useful information from unstructured text data. In particular, NLP along with artificial intelligence (AI) / machine learning (ML) techniques may allow automatic processing of the DILI literature, but useful methods are yet to be demonstrated. To address this challenge, we have developed an integrated NLP/ML classification model to identify DILI-related literature using only paper titles and abstracts. We used 14,203 publications provided by the Critical Assessment of Massive Data Analysis (CAMDA) challenge, employing word vectorization techniques in NLP coupled with machine learning methods. Classification modeling was performed using 2/3 of the data for training and the remainder for testing in internal validation. The best performance was achieved using a linear support vector machine (SVM) model that combined vectors derived from term frequency-inverse document frequency (TF-IDF) and Word2Vec, achieving an accuracy of 95.0% and an F1-score of 95.0%. The final SVM model built using all 14,203 publications was tested on independent datasets, resulting in accuracies of 92.5%, 96.3%, and 98.3%, and F1-scores of 93.5%, 86.1%, and 75.6% for three test sets (T1-T3). The SVM model was tested on four external validation sets (V1-V4), resulting in accuracies of 92.0%, 96.2%, 98.3%, and 93.1%, and F1-scores of 92.4%, 82.9%, 75.0%, and 93.3%.
KAS-pipe2: a flexible toolkit for exploring KAS-seq and spKAS-seq data
Authors: Lyu Ruitu , Wu Tong , Park Gayoung , He Yu-Ying , He Chuan , Chen Mengjie 
Published: August 2022

AbstractKethoxal-assisted ssDNA sequencing (KAS-seq) is gaining popularity as a robust and effective approach to study the dynamics of transcriptionally engaged RNA polymerases through profiling of genome-wide single-stranded DNA (ssDNA). Its latest variant, spKAS-seq, a strand-specific version of KAS-seq, has been developed to map genome-wide R-loop structures by detecting imbalances of ssDNA on two strands. However, user-friendly, open-source analysis pipelines for KAS-seq data are still lacking. Here we present KAS-pipe2 as a flexible and integrated toolkit to facilitate the analysis and interpretation of KAS-seq data. KAS-pipe2 can perform standard analyses such as quality control, read alignment, and differential RNA polymerase activity analysis. In addition, KAS-pipe2 introduces many novel features, including, but not limited to: calculation of transcriptional indexes, identification of single-stranded transcribing enhancers, and high-resolution mapping of R-loops. We use benchmark datasets to demonstrate that KAS-pipe2 provides a powerful framework to study transient transcriptional regulatory programs. KAS-pipe2 is available at https://github.com/Ruitulyu/KAS-pipe2.
Screening the Medicines for Malaria Pandemic Response Box chemical library onCaenorhabditis elegansidentifies re-profiled candidate anthelmintic drug leads
Authors: Nick Marina , Partridge Frederick A , Forman Ruth , Bataille Carole JR , Else Kathryn J , Russell Angela J , Sattelle David B 
Published: August 2022

AbstractThe 3 major classes of soil transmitted helminths (whipworm, hookworm and Ascaris) affect 1.5 billion people worldwide mostly in poor countries, where they have adverse effects on child development, nutrition, and the work capacity of adults. Although there are drugs effective on Ascaris, notably the benzimidazoles, those same drugs show poor efficacy particularly against whipworm (Trichuris trichiura) and to a certain extent hookworm. Parasitic nematodes also infect farm livestock and companion animals. Resistance to currently deployed human and veterinary anthelmintic drugs is a growing problem. Therefore, new chemical anthelmintic lead compounds are urgently needed. One of the fastest routes to a novel therapeutic lead is to screen libraries of drugs which are either already approved for human use or have already been part of clinical trials. We have pursued this approach to anthelmintic lead discovery using an invertebrate automated phenotyping platform (INVAPP) for screening chemicals and the well-established nematode genetic model organismCaenorhabditis elegans. The 400 compound Medicines for Malaria Pandemic Response Box library was screened with each compound tested initially at 1.0 × 10−4M. We identified 6 compounds (MMV1593515 (vorapaxar), MMV102270 (diphyllin), MMV1581032 (ABX464), MMV1580796 (rubitecan), MMV1580505 and MMV1593531) active in both an L1-L4 growth / motility assay and in an L4 motility assay. For vorapaxar, an EC50of 5.7 × 10−7M was observed, a value comparable to some commercial anthelmintics. Although not a parasite, the ease with which high-throughput screens can be pursued on the free-living nematodeC. elegansmakes this a useful approach to identify chemical leads and complement the often lower-throughput experiments on parasitic nematode models.
3D Direttissima: A V1 Heresy
Authors: Arathorn David W 
Published: August 2022

AbstractThe heretical conjecture offered here is that a 3-space scene reconstruction of sequences of visual fixations is constructed directly in V1 in a head-centered frame. “Direttissima” is a climbing term designating the shortest, most direct route to the objective of a climb. The “heresy” here is the claim that the construction of the first 3D representation of the scene before one’s eyes takes place in V1 rather than further up the visual pathways. The inputs to the neural process proposed for such construction are the V1 retinotopic projections from each eye and the vergence angle. Absolute disparities are not encoded as a separate data set in a distinct set of neurons, but rather are emergent properties of the neurons that implement the construction of the 3D representation of one or a sequence of fixations on elements of the scene. In this conjecture, the conscious “picture” we take as vision is a projection of the 3D construction, not a view of the retinal image. One of the critical psychophysical clues to the nature of such a mechanism is the well known visual size constancy phenomenon. Another property of the proposed mechanism is that it is plausibly fast enough to enable such spatially and temporally demanding tasks as a human batting a fastball or a bobcat swatting the head of a striking rattlesnake.
Widespread perturbation of ETS factor binding sites in cancer
Authors: Carrasco Pro S , Hook H , Bray D , Berenzy D , Moyer D , Yin M , Labadorf AT , Tewhey R , Siggers T , Fuxman Bass JI 
Published: August 2022

AbstractAlthough >90% of somatic mutations reside in non-coding regions, few have been reported as cancer drivers. To predict driver non-coding variants (NCVs), we present a novel transcription factor (TF)-aware burden test (TFA-BT) based on a model of coherent TF function in promoters. We applied our TFA-BT to NCVs from the Pan-Cancer Analysis of Whole Genomes cohort and predicted 2,555 driver NCVs in the promoters of 813 genes across 20 cancer-types. These genes are enriched in cancer-related gene ontologies, essential genes, and genes associated with cancer prognosis. We found that 765 candidate driver NCVs alter transcriptional activity, 510 lead to differential binding of TF-cofactor regulatory complexes, and that they primarily impact the binding of ETS factors. Finally, we show that different NCVs within a promoter often affect transcriptional activity through shared mechanisms. Our integrated computational and experimental approach shows that cancer NCVs are widespread and that ETS factors are commonly disrupted.
Seasonal polyphenism of wing colors and its influence on sulphur butterfly diversification
Authors: Fenner Jennifer , Ficarrotta Vincent , Colombara Alexandra , Smith Heather , Evans Kymberlee , Range Ryan , Counterman Brian A. 
Published: August 2022

AbstractSeasonal variation of color patterns on butterfly wings are iconic examples of developmentally plastic traits that can influence adaptation and speciation. Yet, there are few examples of such seasonal polyphenisms that have characterized the environmental cues, ecological consequences, or genetic mechanisms involved in generating the plastic variation of wing color. Further, there is a lack of support that such plasticity may impact the adaptive diversification of butterfly wing patterns. Here, we report a case of seasonal polyphenism in pigment and structurally-based color patterns ofZerene cesoniathat are strikingly similar to the color pattern divergence seen on the wings of sulphur butterflies. We show that (i) coordinated changes in temperature and photoperiod drive the plasticity, (ii) the plastic color changes impact how fast the butterflies can warm, (iii) identifyspaltas likely be involved in the genetic coupling of the pigment and structurally-based color plastic response. We further show that this plastic wing changes phenocopy wing pattern divergence betweenZerenespecies, as well as the color pattern differences known to be commonly involved in sexual selection and speciation across sulphur butterflies. Together, our results demonstrate that shared environmental cues and genetic basis for pigment and structural color plasticity may result in conditions that may have facilitated species diversification of sulphur butterflies.