bluuebunny/crossref_metadata_2025_split huggingface dataset:
Outcomes of the 2019 EMDataResource model challenge: validation of cryo-EM models at near-atomic resolution
Authors: Lawson Catherine L. , Kryshtafovych Andriy , Adams Paul D. , Afonine Pavel V. , Baker Matthew L. , Barad Benjamin A. , Bond Paul , Burnley Tom , Cao Renzhi , Cheng Jianlin , Chojnowski Grzegorz , Cowtan Kevin , Dill Ken A. , DiMaio Frank , Farrell Daniel P. , Fraser James S. , Herzik Mark A. , Hoh Soon Wen , Hou Jie , Hung Li-Wei , Igaev Maxim , Joseph Agnel P. , Kihara Daisuke , Kumar Dilip , Mittal Sumit , Monastyrskyy Bohdan , Olek Mateusz , Palmer Colin M. , Patwardhan Ardan , Perez Alberto , Pfab Jonas , Pintilie Grigore D. , Richardson Jane S. , Rosenthal Peter B. , Sarkar Daipayan , Schäfer Luisa U. , Schmid Michael F. , Schröder Gunnar F. , Shekhar Mrinal , Si Dong , Singharoy Abishek , Terashi Genki , Terwilliger Thomas C. , Vaiana Andrea , Wang Liguo , Wang Zhe , Wankowicz Stephanie A. , Williams Christopher J. , Winn Martyn , Wu Tianqi , Yu Xiaodi , Zhang Kaiming , Berman Helen M. , Chiu Wah 
Published: June 2020

AbstractThis paper describes outcomes of the 2019 Cryo-EM Map-based Model Metrics Challenge sponsored by EMDataResource (www.emdataresource.org). The goals of this challenge were (1) to assess the quality of models that can be produced using current modeling software, (2) to check the reproducibility of modeling results from different software developers and users, and (3) compare the performance of current metrics used for evaluation of models. The focus was on near-atomic resolution maps with an innovative twist: three of four target maps formed a resolution series (1.8 to 3.1 Å) from the same specimen and imaging experiment. Tools developed in previous challenges were expanded for managing, visualizing and analyzing the 63 submitted coordinate models, and several novel metrics were introduced. The results permit specific recommendations to be made about validating near-atomic cryo-EM structures both in the context of individual laboratory experiments and holdings of structure data archives such as the Protein Data Bank. Our findings demonstrate the relatively high accuracy and reproducibility of cryo-EM models derived from these benchmark maps by 13 participating teams, representing both widely used and novel modeling approaches. We also evaluate the pros and cons of the commonly used metrics to assess model quality and recommend the adoption of multiple scoring parameters to provide full and objective annotation and assessment of the model, reflective of the observed density in the cryo-EM map.
Cortical dynamics underlying social behavior in dominance hierarchy and spatial navigation
Authors: Lara-Vasquez Ariel , Espinosa Nelson , Morales Cristian , Moran Constanza , Billeke Pablo , Gallagher Joseph , Strohl Joshua J. , Huerta Patricio T. , Fuentealba Pablo 
Published: June 2020

AbstractRodents establish dominance hierarchy as a social ranking system in which one subject acts as dominant over all the other subordinate individuals. Dominance hierarchy regulates food access and mating opportunities, but little is known of its significance in collective behavior, for instance during navigation for foraging or migration. Here, we implemented a simplified goal-directed spatial navigation task in mice and found that the social context exerts significant influence on individual decision-making, even when efficient navigation rules leading to reward had been previously learned. Thus, decision-making and consequent task performance were strongly dependent on contingent social interactions arising during collective navigation, yet their influence on individual behavior was outlined by dominance hierarchy. Dominant animals did not behave as leaders during navigation; conversely, they were most sensitive to social context. Social ranking in turn was reflected in the neural activity and connectivity patterns of the prefrontal cortex and hippocampus, both in anesthetized and behaving mice. These results suggest that the interplay between contingent social interactions and dominance hierarchy can regulate behavioral performance, supported by the intrinsic matrix of coordinated activity in the hippocampal-prefrontal circuit.Significance StatementDecision-making is shaped by intrinsic features, such as memory-stored information, and external influences, such as social interactions, yet their interplay is not well understood. We studied decision-making during collective behavior and found that instead of prioritizing memory-based pertinent information, mice shifted their individual decisions according to contingent social interactions arising in the social context. Conversely, constitutive social interactions, such as dominance hierarchy, were relevant to outline the effect of the social environment on individual behavior. Our results suggest that intrinsic hippocampal-cortical activity and connectivity patterns define social interactions. Hence, intrinsic cortical dynamics underlie behavioral performance during social decision-making.
3D printed cell culture grid holders for improved cellular specimen preparation in cryo-electron microscopy
Authors: Fäßler Florian , Zens Bettina , Hauschild Robert , Schur Florian K.M. 
Published: June 2020

AbstractCryo-electron microscopy (cryo-EM) of cellular specimens provides insights into biological processes and structures within a native context. However, a major challenge still lies in the efficient and reproducible preparation of adherent cells for subsequent cryo-EM analysis. This is due to the sensitivity of many cellular specimens to the varying seeding and culturing conditions required for EM experiments, the often limited amount of cellular material and also the fragility of EM grids and their substrate. Here, we present low-cost and reusable 3D printed grid holders, designed to improve specimen preparation when culturing challenging cellular samples directly on grids. The described grid holders increase cell culture reproducibility and throughput, and reduce the resources required for cell culturing. We show that grid holders can be integrated into various cryo-EM workflows, including micro-patterning approaches to control cell seeding on grids, and for generating samples for cryo-focused ion beam milling and cryo-electron tomography experiments. Their adaptable design allows for the generation of specialized grid holders customized to a large variety of applications.
ComPotts: Optimal alignment of coevolutionary models for protein sequences
Authors: Talibart Hugo , Coste François 
Published: June 2020

AbstractTo assign structural and functional annotations to the ever increasing amount of sequenced proteins, the main approach relies on sequence-based homology search methods, e.g. BLAST or the current state-of-the-art methods based on profile Hidden Markov Models (pHMMs), which rely on significant alignments of query sequences to annotated proteins or protein families. While powerful, these approaches do not take coevolution between residues into account. Taking advantage of recent advances in the field of contact prediction, we propose here to represent proteins by Potts models, which model direct couplings between positions in addition to positional composition. Due to the presence of non-local dependencies, aligning two Potts models is computationally hard. To tackle this task, we introduce an Integer Linear Programming formulation of the problem and present ComPotts, an implementation able to compute the optimal alignment of two Potts models representing proteins in tractable time. A first experimentation on 59 low sequence identity pairwise alignments, extracted from 3 reference alignments from sisyphus and BaliBase3 databases, shows that ComPotts finds better alignments than the other tested methods in the majority of these cases.
High rates of genome rearrangements and pathogenicity ofShigellaspp
Authors: Seferbekova Zaira , Zabelkin Alexey , Yakovleva Yulia , Afasizhev Robert , Dranenko Natalia O. , Alexeev Nikita , Gelfand Mikhail S. , Bochkareva Olga O. 
Published: June 2020

AbstractShigellaare pathogens originating within theEscherichialineage but frequently classified as a separate genus.Shigellagenomes contain numerous insertion sequences (ISs) that lead to pseudogenization of affected genes and an increase of non-homologous recombination. Here, we study 414 genomes ofE. coliandShigellastrains to assess the contribution of genomic rearrangements toShigellaevolution. We found thatShigellaexperienced exceptionally high rates of intragenomic rearrangements and had a decreased rate of homologous recombination compared to pathogenic and non-pathogenicE. coli. The high rearrangement rate resulted in independent disruption of syntenic regions and parallel rearrangements in differentShigellalineages. Specifically, we identified two types of chromosomally encoded E3 ubiquitin-protein ligases acquired independently by allShigellastrains that also showed a high level of sequence conservation in the promoter and further in the 5’ intergenic region. In the only available enteroinvasiveE. coli(EIEC) strain, which is a pathogenicE. coliwith a phenotype intermediate betweenShigellaand non-pathogenicE. coli, we found a rate of genome rearrangements comparable to those in otherE. coliand no functional copies of the twoShigella-specific E3 ubiquitin ligases. These data indicate that accumulation of ISs influenced many aspects of genome evolution and played an important role in the evolution of intracellular pathogens. Our research demonstrates the power of comparative genomics-based on synteny block composition and an important role of non-coding regions in the evolution of genomic islands.ImportancePathogenicEscherichia colistrains frequently cause infections in humans. ManyE. coliexist in nature and their ability to cause disease is fueled by their ability to incorporate novel genetic information by extensive horizontal gene transfer of plasmids and pathogenicity islands. The emergence of antibiotic-resistantShigellaspp., which are pathogenic forms ofE. coli, coupled with the absence of an effective vaccine against them, highlights the importance of the continuing study of these pathogenic bacteria. Our study contributes to the understanding of genomic properties associated with molecular mechanisms underpinning the pathogenic nature ofShigella. We characterize the contribution of insertion sequences to the genome evolution of these intracellular pathogens and suggest a role of upstream regions of chromosomalipaHgenes in theShigellapathogenesis. The methods of rearrangement analysis developed here are broadly applicable to the analysis of genotype-phenotype correlation in historically recently emerging bacterial pathogens.
Fluoxetine rescues rotarod motor deficits inMecp2heterozygous mouse model of Rett syndrome via brain serotonin
Authors: Villani Claudia , Sacchetti Giuseppina , Carli Mirjana , Invernizzi Roberto W. 
Published: June 2020

AbstractMotor skill is a specific area of disability of Rett syndrome (RTT), a rare disorder occurring almost exclusively in girls, caused by loss-of-function mutations of the X-linkedmethyl-CpG-binding protein2(MECP2) gene, encoding the MECP2 protein, a member of the methyl-CpG-binding domain nuclear proteins family. Brain 5-HT, which is defective in RTT patients andMecp2mutant mice, regulates motor circuits and SSRIs enhance motor skill learning and plasticity.In the present study, we used heterozygous (Het)Mecp2female andMecp2-null male mice to investigate whether fluoxetine, a SSRI with pleiotropic effects on neuronal circuits, rescues motor coordination deficits. Repeated administration of 10 mg/kg fluoxetine fully rescued rotarod deficit inMecp2Het mice regardless of age, route of administration or pre-training to rotarod. The motor improvement was confirmed in the beam walking test while no effect was observed in the hanging-wire test, suggesting a preferential action of fluoxetine on motor coordination. Citalopram mimicked the effects of fluoxetine, while the inhibition of 5-HT synthesis abolished the fluoxetine-induced improvement of motor coordination.Mecp2null mice, which responded poorly to fluoxetine in the rotarod, showed reduced 5-HT synthesis in the prefrontal cortex, hippocampus and striatum, and reduced efficacy of fluoxetine in raising extracellular 5-HT as compared to female mutants. No sex differences were observed in the ability of fluoxetine to desensitize 5-HT1Aautoreceptors upon repeated administration. These findings indicate that fluoxetine rescues motor coordination inMecp2Het mice through its ability to enhance brain 5-HT and suggest that drugs enhancing 5-HT neurotransmission may have beneficial effects on motor symptoms of RTT.
Understanding the host-microbe interactions using metabolic modeling
Authors: Jansma Jack , El Aidy Sahar 
Published: June 2020

AbstractThe human gut harbors an enormous number of symbiotic microbes, which is vital for human health. However, interactions within the complex microbiota community and between the microbiota and its host are challenging to elucidate, limiting development in the treatment for a variety of diseases associated with microbiota dysbiosis. UsingIn silicosimulation methods based on flux balance analysis, those interactions can be better investigated. Flux balance analysis uses an annotated genome-scale reconstruction of a metabolic network to determine the distribution of metabolic fluxes that represent the complete metabolism of a bacterium in a certain metabolic environment such as the gut. Simulation of a set of bacterial species in a shared metabolic environment can enable the study of the effect of numerous perturbations, such as dietary changes or addition of a probiotic species in a personalized manner. This review aims to introduce these applications of flux balance analysis to experimental biologists and discusses its potential use to improve human health.
Evidence of shifts towards neural states of stability during the retrieval of real-life episodic memories
Authors: Fuentemilla L , Nicolás B , Kastrinogiannis A , Silva M 
Published: June 2020

AbstractHow does one retrieve real-life episodic memories? Here, we tested the hypothesis, derived from computational models, that successful retrieval relies on neural dynamics patterns that rapidly shift towards stable states. We implemented cross-temporal correlation analysis of electroencephalographic (EEG) recordings while participants retrieved episodic memories cued by pictures collected with a wearable camera depicting real-life episodes taking place at “home” and at “the office”. We found that the retrieval of real-life episodic memories is supported by rapid shift towards brain states of stable activity, that the degree of neural stability is associated with the participants’ ability to recollect the episodic content cued by the picture, and that each individual elicits stable EEG patterns that were not shared with other participants. These results indicate that the retrieval of autobiographical memory episodes is supported by rapid shifts of neural activity towards stable states.
Pan-cancer detection of driver genes at the single-patient resolution
Authors: Nulsen Joel , Misetic Hrvoje , Yau Christopher , Ciccarelli Francesca D. 
Published: June 2020

ABSTRACTBackgroundIdentifying the complete repertoire of genes that drive cancer in individual patients is crucial for precision oncology. Most established methods identify driver genes that are recurrently altered across patient cohorts. However, mapping these genes back to patients leaves a sizeable fraction with few or no drivers, hindering our understanding of cancer mechanisms and limiting the choice of therapeutic interventions.ResultsWe present sysSVM2, a machine learning software that integrates cancer genetic alterations with gene systems-level properties to predict drivers in individual patients. Using simulated pan-cancer data, we optimise sysSVM2 for application to any cancer type. We benchmark its performance on real cancer data and validate its applicability to a rare cancer type with few known driver genes. We show that drivers predicted by sysSVM2 have a low false-positive rate, are stable and disrupt well-known cancer-related pathways.ConclusionssysSVM2 can be used to identify driver alterations in patients lacking sufficient canonical drivers or belonging to rare cancer types for which assembling a large enough cohort is challenging, furthering the goals of precision oncology. As resources for the community, we provide the code to implement sysSVM2 and the pre-trained models in all TCGA cancer types (https://github.com/ciccalab/sysSVM2).
High Content Screening and Proteomic Analysis Identify a Kinase Inhibitor that rescues pathological phenotypes in a Patient-Derived Model of Parkinson’s Disease
Authors: Antoniou Nasia , Prodromidou Kanella , Kouroupi Georgia , Samiotaki Martina , Panayotou George , Xilouri Maria , Stefanis Leonidas , Grailhe Regis , Taoufik Era , Matsas Rebecca 
Published: June 2020

AbstractCombining high throughput screening approaches with induced pluripotent stem cell (iPSC)-based disease modeling represents a promising unbiased strategy to identify therapies for neurodegenerative disorders. Here we applied high content imaging on iPSC-derived neurons from patients with familial Parkinson’s disease bearing the G209A (p.A53T) α-synuclein (αSyn) mutation and launched a screening campaign on a small kinase inhibitor library. We thus identified the multi-kinase inhibitor BX795 that at a single dose effectively restores disease-associated neurodegenerative phenotypes. Proteomics profiling mapped the molecular pathways underlying the protective effects of BX795, comprising a cohort of 118 protein-mediators of the core biological processes of RNA metabolism, protein synthesis, modification and clearance, and stress response, all linked to the mTORC1 signaling hub. In agreement, expression of human p.A53T-αSyn in neuronal cells affected key components of the mTORC1 pathway resulting in aberrant protein synthesis that was restored in the presence of BX795 with concurrent facilitation of autophagy. Taken together, we have identified a promising small molecule with neuroprotective actions as candidate therapeutic for PD and other protein conformational disorders.
ABA analogue produced byBacillus marisflavimodulates the physiological response of host-plant under drought stress
Authors: Gowtham H.G. , Duraivadivel P. , Ayusman S. , Sayani D. , Gholap S.L. , Niranjana S.R. , Hariprasad P. 
Published: June 2020

ABSTRACTPresent study aims to understand the molecular mechanism involved in beneficial rhizobacteria mediated alleviation of drought stress in host plant.Bacillus marisflaviCRDT-EB-1 isolated from the rhizosphere soil was found effective in inducing resistance against drought stress in mustard seedlings. Among the different bacterial derivatives tested, the culture filtrate was found to contain bioactive molecules. Solvent extract of bacterial culture filtrate yielded seven distinct bands/ fractions on thin layer chromatography (TLC). The fraction four (F4) with Rfvalue 0.35-0.40 was significant in reducing adverse effect of drought stress in host plants. Application of F4 resulted in delayed drooping point and higher drought tolerance index (3.34), induced stomatal closure (9.648 μ), seed germination inhibition (12%), and reduced the GA3induced α-amylase activity in germinating barley seeds. On TLC, F4 turned colorless to orange color upon the spray of 2,4-dinitrophenylhydrazine reagent indicated the presence of aldehyde group. Supporting to this, the peaks between 9.8 to 10.0 ppm in1H-NMR chromatogram confirmed the presence of aldehyde group. Upon LC-MS/MS analysis of crude extract of culture filtrate and F4 revealed the presence of compounds with the molecular mass 250.33 and 266.33. By analyzing these data, the identity of the bioactive compounds were predicted as xanthoxin and xanthoxic acid, which are well-known precursor of Abscisic acid (ABA) in plants. The present study concludes the capability of ABA analogue (xanthoxin like compounds) production byB. marisflaviCRDT-EB-1 and its involvement in inducing drought stress tolerance in the host plant.
Functional Suppression of Premotor Activity in a Transient Model of Motor Cortex Injury
Authors: Elliott Kevin C. , Borrell Jordan A. , Barbay Scott , Nudo Randolph J. 
Published: June 2020

ABSTRACTCortical injuries (e.g. – strokes or traumatic brain injuries) can create a host of secondary events that further impair the brain’s sensory, motor, or cognitive capabilities. Here, we attempted to isolate the acute effects of the primary injury – the loss of cortical activity – on rodent motor cortex (caudal forelimb area, CFA) without the secondary effects that arise from damage to cortical tissue. We then observed the effects of this loss of activity on the rodent premotor cortex (rostral forelimb area, RFA). In anesthetized rats, CFA was temporarily inactivated with the GABA-A agonist muscimol, disrupting motor network function while leaving neural connectivity intact. Using intracortical microstimulation (ICMS) techniques, we found that CFA inactivation completely abolished ICMS-evoked forelimb movement from RFA yet spared some CFA evoked-movement. Neural recordings confirmed that neural suppression by muscimol was isolated to CFA and did not spread into RFA. We next observed how CFA inactivation suppressed RFA influence on forelimb muscles by obtaining intramuscular electromyographical (EMG) recordings from forelimb muscles during ICMS. EMG recordings showed that despite the presence of evoked movement in CFA, but not RFA, muscle activation in both areas were similarly reduced. These results suggest that the primary reason for the loss of ICMS-evoked movement in RFA is not reduced forelimb muscle activity, but rather a loss of the specific activity between RFA and CFA. Therefore, within the intact motor network of the rat, RFA’s influence on forelimb movement is mediated by CFA, similar to the premotor and motor organization observed in non-human primates.
Integrity of anterior corpus callosum is well related to language impairment after traumatic brain injury
Authors: Lee Hae In , Cho Minjae , Na Yoonhye , Hwang Yu Mi , Pyun Sung-Bom 
Published: June 2020

AbstractBackgroundThe corpus callosum (CC) serves as the bridge that relays information between the two cerebral hemispheres, and is one of the most commonly injured areas after traumatic brain injury (TBI). This study was designed to investigate the association between the CC integrity and language function after TBI.MethodsWe retrospectively enrolled 30 patients with TBI who underwent diffusion tensor imaging and language function evaluation using the Western Aphasia Battery. The CC was divided into five segments (C1-C5) according to its projecting fibers using Hofer’s method, and fractional anisotropy (FA) values were measured using DSI studio software. The FA values of the left arcuate fasciculus and cingulum for language function and executive function, respectively, were also evaluated. Twelve healthy controls were also enrolled to compare the FA values of these tracts.ResultsThe FA values of the cingulum and left arcuate fasciculus were significantly correlated with all language scores. The FA values of the entire CC were significantly correlated with the fluency, repetition, and aphasia quotient scores. The FA values of the anterior CC segment (C1 and C2) significantly correlated with the aphasia quotient score; C1 with the fluency score; and C2 with the fluency, comprehension, and repetition scores. However, the FA values of the posterior CC (C3-C5) were not significantly correlated with any of the language subset scores.ConclusionThe language function in patients with TBI is correlated with the integrity of the white matter tracts important for language and attention processes. Moreover, disruption of the CC is common after TBI, and the anterior CC segment plays an important role in language impairment after TBI. Therefore, analyzing CC integrity using diffusion tensor imaging can help predict language impairment in patients with TBI.