bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cryo-EM structural studies of the agonist complexed human TRPV4 ion-channel reveals novel structural rearrangements resulting in an open-conformation
Authors: Botte Mathieu , Ulrich Alexander K. C. , Adaixo Ricardo , Gnutt David , Brockmann Andreas , Bucher Denis , Chami Mohamed , Bocquet Nicolas , Ebbinghaus-Kintscher Ulrich , Puetter Vera , Becker Andreas , Egner Ursula , Stahlberg Henning , Hennig Michael , Holton Simon J. 
Published: October 2020

ABSTRACTThe human transient receptor potential vanilloid 4 (hTRPV4) ion channel plays a critical role in a variety of biological processes. Whilst the activation of hTRPV4 gating properties has been reported for a broad spectrum of stimuli, including synthetic 4α-phorbols, the molecular basis of the activation is poorly understood. Here we report the novel cryo-EM structure of the hTRPV4 determined in the presence of the archetypical phorbol acid agonist, 4α-PDD. Complementary mutagenesis experiments support the EM-identified binding site as well as allowing rationalization of disruptive mutants located outside of the 4α-PDD binding site. This work represents the first structural information of hTRPV4 in a ligand-induced open conformation. Together, our data reveal the underlying molecular mechanisms resulting in the opening of the central pore and ion-channel activation and provide a structural template for designing inhibitors targeting the open-state conformation of hTRPV4.
In SituOptical Quantification of Extracellular Electron Transfer using Plasmonic Metal Oxide Nanocrystals
Authors: Graham Austin J. , Gibbs Stephen L. , Cabezas Camila A. Saez , Wang Yongdan , Green Allison M. , Milliron Delia J. , Keitz Benjamin K. 
Published: October 2020

AbstractExtracellular electron transfer (EET) is a critical form of microbial metabolism that enables respiration on a variety of inorganic substrates, including metal oxides. However, quantifying current generated by electroactive bacteria has been predominately limited to biofilms formed on electrodes. To address this, we developed a platform for quantifying EET flux from cell suspensions using aqueous dispersions of infrared plasmonic tin-doped indium oxide nanocrystals. Tracking the change in optical extinction during electron transfer enabled quantification of current generated by planktonicShewanella oneidensiscultures. Using this method, we differentiated between starved and actively respiring cells, between cells of varying genotype, and between cells engineered to differentially express a key EET gene using an inducible genetic circuit. Overall, our results validate the utility of colloidally stable plasmonic metal oxide nanocrystals as quantitative biosensors in native biological environments and contribute to a fundamental understanding of planktonicS. oneidensiselectrophysiology using simplein situspectroscopy.
Re-emergence and diversification of a specialised antennal lobe morphology in ithomiine butterflies
Authors: Morris Billy J , Couto Antoine , Aydin Asli , Montgomery Stephen H 
Published: October 2020

AbstractHow an organism’s sensory system functions is central to how it navigates its environment and meets the behavioural challenges associated with survival and reproduction. Comparing sensory systems across species can reveal how facets of behaviour and ecology promote adaptive shifts in the relative importance of certain environmental cues. The insect olfactory system is prominent model for investigating how ecological factors impact sensory reception and processing. Notably work in Lepidoptera led to the discovery of vastly expanded structures, termed a macroglomerular complex (MGC), within the primary olfactory processing centre. These structures typically process pheromonal cues and provide a classic example of how variation in size can influence the functional processing of sensory cues. Though prevalent across moths, the MGC was lost during the early evolution of butterflies, consistent with evidence that courtship initiation in butterflies is primarily reliant upon visual cues, rather than long distance olfactory signals like pheromones. However, a MGC has recently been reported to be present in a species of ithomiine,Godryis zavaleta, suggesting this once lost neural adaptation has re-emerged in this clade. Here, we show that MGC’s, or MGC-like morphologies, are indeed widely distributed across the ithomiine tribe, and vary in both structure and the prevalence of sexual dimorphism. Based on patterns of variation across species with different chemical ecologies, we suggest that this structure is involved in the processing of both plant and pheromonal cues, of interlinked chemical constitution, and has evolved in conjunction with the increased importance and diversification of plant derived chemicals cues in ithomiines.
ELOVL2 is required for robust visual function in zebrafish
Authors: Dasyani Manish , Gao Fangyuan , Xu Qianlan , Fossan Donald Van , Zhang Ellis , Pinto Antonio F. M. , Saghatelian Alan , Skowronska-Krawczyk Dorota , Chao Daniel L. 
Published: October 2020

ABSTRACTOmega-3 and omega-6 polyunsaturated fatty acids (PUFAs) play critical roles in membrane stability and cell signaling within the retina.Elovl2, an elongase involved in synthesis of long chain polyunsaturated fatty acids (LC-PUFAs), has recently been implicated in regulating aging in the mammalian retina. In this work, we characterize the expression and function ofelovl2in retina development in embryonic zebrafish. Whole mountin situhybridization showselovl2is expressed in the Müller glia in embryonic and adult zebrafish. Lipidomics analysis ofelovl2crispants whole embryos at day 2 and eyes at day 7 demonstrated significant changes in lipids composition, especially on the level of lipids containing docosahexaenoic acid (DHA). Histological analysis of zebrafish lackingelovl2revealed increased retinal thickness compared to controls at day 7 without gross disruptions of retinal architecture. Finally,elovl2crispants showed differences in the visual motor reflex light off (VMR-OFF) at day 7 compared to controls. In sum, inactivation ofelovl2in zebrafish embryos caused changes in lipid composition and in visual behavior further confirming the important role of LC-PUFAs in healthy vision.
Do auditory mismatch responses differ between acoustic features?
Authors: An HyunJung , Kei Shing Ho , Auksztulewicz Ryszard , Schnupp Jan W. 
Published: October 2020

AbstractMismatch negativity (MMN) is the electroencephalographic (EEG) waveform obtained by subtracting event-related potential (ERP) responses evoked by unexpected deviant stimuli from responses evoked by expected standard stimuli. While the MMN is thought to reflect an unexpected change in an ongoing, predictable stimulus, it is unknown whether MMN responses evoked by changes in different stimulus features have different magnitudes, latencies, and topographies. The present study aimed to investigate whether MMN responses differ depending on whether sudden stimulus change occur in pitch, duration, location or vowel identity respectively.To calculate ERPs to standard and deviant stimuli, EEG signals were recorded in normal-hearing participants (N=20; 13 males, 7 females) who listened to roving oddball sequences of artificial syllables. In the roving paradigm, any given stimulus is repeated several times to form a standard, and then suddenly replaced with a deviant stimulus which differs from the standard. Here, deviants differed from preceding standards along one of four features (pitch, duration, vowel or interaural level difference). The feature levels were individually chosen to match behavioral discrimination performance.We identified neural activity evoked by unexpected violations along all four acoustic dimensions. Evoked responses to deviant stimuli increased in amplitude relative to the responses to standard stimuli. A univariate (channel-by-channel) analysis yielded no significant differences between MMN responses following violations of different features. However, in a multivariate analysis (pooling information from multiple EEG channels), acoustic features could be decoded from the topography of mismatch responses, although at later latencies than those typical for MMN. These results support the notion that deviant feature detection may be subserved by a different process than general mismatch detection.
Aggregation of Cohorts for Histopathological Diagnosis with Deep Morphological Analysis
Authors: Park Jeonghyuk , Chung Yul Ri , Kong Seo Taek , Kim Yeong Won , Park Hyunho , Kim Kyungdoc , Kim Dong-Il , Jung Kyu-Hwan 
Published: October 2020

ABSTRACTThere have been substantial efforts in using deep learning (DL) to diagnose cancer from digital images of pathology slides. Existing algorithms typically operate by training deep neural networks (DNNs) either specialized in specific cohorts or an aggregate of all cohorts when there are only a few images available for the target cohort. A trade-off between decreasing the number of models and their cancer detection performance was evident in our experiments with The Cancer Genomic Atlas (TCGA) dataset, with the former approach achieving higher performance at the cost of having to acquire large datasets from the cohort of interest. Constructing annotated datasets for individual cohorts is extremely time-consuming, with the acquisition cost of such datasets growing linearly with the number of cohorts. Another issue associated with developing cohort-specific models is the difficulty of maintenance: all cohort-specific models may need to be adjusted when a new DL algorithm is to be used, where training even a single model may require a non-negligible amount of computation, or when more data is added to some cohorts. In resolving the sub-optimal behavior of a universal cancer detection model trained on an aggregate of cohorts, we investigated how cohorts can be grouped to augment a dataset without increasing the number of models linearly with the number of cohorts. This study introduces several metrics which measure the morphological similarities between cohort pairs and demonstrates how the metrics can be used to control the trade-off between performance and the number of models.
KlebsiellaMALDI TypeR: a web-based tool forKlebsiellaidentification based on MALDI-TOF mass spectrometry
Authors: Bridel Sébastien , Watts Stephen C. , Judd Louise M. , Harshegyi Taylor , Passet Virginie , Rodrigues Carla , Holt Kathryn E. , Brisse Sylvain 
Published: October 2020

AbstractMotivationKlebsiellaspecies are increasingly multidrug resistant pathogens affecting human and animal health and are widely distributed in the environment. Among these, theKlebsiella pneumoniaespecies complex (KpSC), which includes seven phylogroups, is an important cause of community and hospital infections. In addition, theKlebsiella oxytocaspecies complex (KoSC) also causes hospital infections and antibiotic-associated haemorrhagic colitis. The unsuitability of widely used clinical microbiology methods to distinguish species within each of these species complexes leads to high rates of misidentifications that are masking the true clinical significance and potential epidemiological specificities of individual species.ResultsWe developed a web-based tool,KlebsiellaMALDI TypeR, a platform-independent and user-friendly application that enables uploading raw data from MALDI-TOF mass spectrometer to identifyKlebsiellaisolates at the species complex and phylogroup levels. The tool is based on a database of previously identified biomarkers that are specific for either the species complex, individual phylogroups, or related phylogroups, and is available athttps://maldityper.pasteur.fr.
Agonist efficiency from concentration-response curves: structural implications and applications
Authors: Indurthi D. C. , Auerbach A. 
Published: October 2020

AbstractAgonists are evaluated by a concentration-response curve (CRC), with a midpoint (EC50) that indicates potency, a high-concentration asymptote that indicates efficacy and a low-concentration asymptote that indicates constitutive activity. A third agonist attribute, efficiency (η), is the fraction of binding energy that is applied to the conformational change that activates the receptor. We show that η can be calculated from EC50and the asymptotes of a CRC derived from either single-channel or whole-cell responses. For 20 agonists of skeletal muscle nicotinic receptors, the distribution of η values is bimodal with population means at 51% (including ACh, nornicotine and DMPP) and 40% (including epibatidine, varenicline and cytisine). The value of η is related inversely to the size of the agonist’s head-group, with high-versus low-efficiency ligands having an average volume of 70 Å3versus 102 Å3. Most binding site mutations have only a small effect on ACh efficiency except for αY190A (35%), αW149A (60%) and those at αG153 (42%). If η is known, the midpoint and high-concentration asymptote can be calculated from each other. Hence, an entire CRC can be estimated from the response to a single agonist concentration, and efficacy can be estimated from EC50of a CRC that has been normalized to 1. Given η, the level of constitutive activity can be estimated from a single CRC.Statement of significanceReceptors are molecular machines that convert chemical energy from agonist binding into mechanical energy of a global conformational change that generates a cell response. Agonists are distinguished by their potency (proportional to affinity) and efficacy, but also by the efficiency at which their binding energy is applied to receptor activation. Here we show that agonist efficiency can be estimated from a single concentrationresponse curve, and estimate efficiencies of 20 nicotinic receptor agonists. These have a bimodal distribution with larger agonists belonging to the lower-efficiency population. We further show that mutations of some binding site residues alter efficiency, and that knowledge of agonist efficiency simplifies and extends dose-response curve analysis.
Overexpression of MutS impairs DNA mismatch repair and causes cell division defect inE.coli
Authors: Iyer V Rajesh , Moharir Shivranjani C , Kumar Satish 
Published: October 2020

AbstractMutS and its homologues, from prokaryotes to humans, recognize and bind to DNA mismatches generated during DNA replication, initiate DNA mismatch repair and ensures 100-200 fold increase in replication fidelity. InE.coli, through post transcriptional regulation, at least three mechanisms mediate decline of MutS intracellular concentrations during stress conditions. To understand the significance of this multifold regulation, we overexpressed MutS inE.coliand found that it led to impairment of DNA mismatch repair as reflected by preferential accumulation of transition mutations in spontaneous base pair substitution spectrum. This phenomenon was dependent on MutS-mismatch affinity and interaction. Higher MutS overexpression levels promoted DNA double strand breaks, inhibited cell division and resultantly caused a manifold increase inE.colicell length. This cell division defect involved a novel MutS-FtsZ interaction and impediment of FtsZ ring function. Our findings may have relevance for cancers where mismatch proteins are known to be overexpressed.
CRISPR-enhanced human adipocyte “browning” as cell therapy for metabolic disease
Authors: Tsagkaraki Emmanouela , Nicoloro Sarah , De Souza Tiffany , Solivan-Rivera Javier , Desai Anand , Shen Yuefei , Kelly Mark , Guilherme Adilson , Henriques Felipe , Ibraheim Raed , Amrani Nadia , Luk Kevin , Maitland Stacy , Friedline Randall H. , Tauer Lauren , Hu Xiaodi , Kim Jason K. , Wolfe Scot A. , Sontheimer Erik J. , Corvera Silvia , Czech Michael P. 
Published: October 2020

AbstractObesity and type 2 diabetes (T2D) are associated with poor tissue responses to insulin1,2, disturbances in glucose and lipid fluxes3–5and comorbidities including steatohepatitis6and cardiovascular disease7,8. Despite extensive efforts at prevention and treatment9,10, diabetes afflicts over 400 million people worldwide11. Whole body metabolism is regulated by adipose tissue depots12–14, which include both lipid-storing white adipocytes and less abundant “brown” and “brite/beige” adipocytes that express thermogenic uncoupling protein UCP1 and secrete factors favorable to metabolic health15–18. Application of clustered regularly interspaced short palindromic repeats (CRISPR) gene editing19,20to enhance “browning” of white adipose tissue is an attractive therapeutic approach to T2D. However, the problems of cell-selective delivery, immunogenicity of CRISPR reagents and long term stability of the modified adipocytes are formidable. To overcome these issues, we developed methods that deliver complexes of SpyCas9 protein and sgRNAex vivoto disrupt the thermogenesis suppressor geneNRIP121,22with near 100% efficiency in human or mouse adipocytes.NRIP1gene disruption at discrete loci strongly ablated NRIP1 protein and upregulated expression of UCP1 and beneficial secreted factors, while residual Cas9 protein and sgRNA were rapidly degraded. Implantation of the CRISPR-enhanced human or mouse brown-like adipocytes into high fat diet fed mice decreased adiposity and liver triglycerides while enhancing glucose tolerance compared to mice implanted with unmodified adipocytes. These findings advance a therapeutic strategy to improve metabolic homeostasis through CRISPR-based genetic modification of human adipocytes without exposure of the recipient to immunogenic Cas9 or delivery vectors.
Multiscale and multimodal reconstruction of cortical structure and function
Authors: Turner Nicholas L. , Macrina Thomas , Bae J. Alexander , Yang Runzhe , Wilson Alyssa M. , Schneider-Mizell Casey , Lee Kisuk , Lu Ran , Wu Jingpeng , Bodor Agnes L. , Bleckert Adam A. , Brittain Derrick , Froudarakis Emmanouil , Dorkenwald Sven , Collman Forrest , Kemnitz Nico , Ih Dodam , Silversmith William M. , Zung Jonathan , Zlateski Aleksandar , Tartavull Ignacio , Yu Szi-chieh , Popovych Sergiy , Mu Shang , Wong William , Jordan Chris S. , Castro Manuel , Buchanan JoAnn , Bumbarger Daniel J. , Takeno Marc , Torres Russel , Mahalingam Gayathri , Elabbady Leila , Li Yang , Cobos Erick , Zhou Pengcheng , Suckow Shelby , Becker Lynne , Paninski Liam , Polleux Franck , Reimer Jacob , Tolias Andreas S. , Reid R. Clay , da Costa Nuno Maçarico , Seung H. Sebastian 
Published: October 2020

SummaryWe present a semi-automated reconstruction of L2/3 mouse primary visual cortex from 3 million cubic microns of electron microscopic images, including pyramidal and inhibitory neurons, astrocytes, microglia, oligodendrocytes and precursors, pericytes, vasculature, mitochondria, and synapses. Visual responses of a subset of pyramidal cells are included. The data are being made publicly available, along with tools for programmatic and 3D interactive access. The density of synaptic inputs onto inhibitory neurons varies across cell classes and compartments. We uncover a compartment-specific correlation between mitochondrial coverage and synapse density. Frequencies of connectivity motifs in the graph of pyramidal cells are predicted quite accurately from node degrees using the configuration model of random graphs. Cells receiving more connections from nearby cells exhibit stronger and more reliable visual responses. These example findings illustrate the resource’s utility for relating structure and function of cortical circuits as well as for neuronal cell biology.
Multi-objective TMA management optimization using the point merge system
Authors: Cecen Ramazan Kursat 
Published: October 2020

Purpose
The purpose of this study is to provide conflict-free operations in terminal manoeuvre areas (TMA) using the point merge system (PMS), airspeed reduction (ASR) and ground holding (GH) techniques. The objective is to minimize both total aircraft delay (TD) and the total number of the conflict resolution manoeuvres (CRM).

Design/methodology/approach
The mixed integer linear programming (MILP) is used for both single and multi-objective optimization approaches to solve aircraft sequencing and scheduling problem (ASSP). Compromise criterion and ε-constraint methods were included in the methodology. The results of the single objective optimization approach results were compared with baseline results, which were obtained using the first come first serve approach, in terms of the total number of the CRM, TD, the number of aircraft using PMS manoeuvres, ASR manoeuvres, GH manoeuvres, departure time updates and on-time performance.

Findings
The proposed single-objective optimization approach reduced both the CRM and TD considerably. For the traffic flow rates of 15, 20 and 25 aircraft, the improvement of CRM was 53.08%, 41.12% and 32.6%, the enhancement of TD was 54.2%, 48.8% and 31.06% and the average number of Pareto-optimal solutions were 1.26, 2.22 and 3.87, respectively. The multi-objective optimization approach also exposed the relationship between the TD and the total number of CRM.

Practical implications
The proposed mathematical model can be implemented considering the objectives of air traffic controllers and airlines operators. Also, the mathematical model is able to create conflict-free TMA operations and, therefore, it brings an opportunity for air traffic controllers to reduce frequency occupancy time.

Originality/value
The mathematical model presents the total number of CRM as an objective function in the ASSP using the MILP approach. The mathematical model integrates air traffic controllers’ and airline operators’ perspective together with new objective functions.
Responsibilities of archivist now and in the future as the result of COVID – 19; Case of ICA-SUV
Authors: Netshakhuma Nkholedzeni Sidney 
Published: October 2020

Purpose
The purpose of this study was to examine the strategies for the preservation of archival materials in the International Council on Archives Section on University and Research Institution Archives (ICA SUV) by the members and to make recommendations for the digital archival preservation to continue its accessibility during the national lockdown because of COVID–19.

Design/methodology/approach
This study is based on the survey conducted on the ICA SUV members during the national lockdown. The study used a survey research methodology through e-mails as data collection instruments.

Findings
The key findings revealed that most of the sections on university and research institution archives lack digitization preservation strategies and most of their records are not accessible online, as most of their collections are still preserved manually through the paper-based system; furthermore, archivists are not fully trained on digital management. The paper recommends universities to develop preservation strategies to migrate records from the paper-based system to electronic records management system.

Research limitations/implications
The population of the study comprised ICA SUV members, who responded to the survey. Therefore, the sample size and geographical spread were inadequate for generalization of the findings. In conclusion, the study demonstrated that accessibility of the archives was dependent on the quality of digitized archives.

Practical implications
This study demonstrates that the development of a preservation strategy enhances access to archival materials during the national lockdown because of COVID–19.

Social implications
This paper highlights the plight of university archives and reiterates the need for urgent digitization of their archives of universities all over the world.

Originality/value
To the best of author’s knowledge, this paper appears to be the first to review the responsibilities of archivists now and in the future as the result of COVID–19. This study is confirmed to be on the positive side of COVID–19 and change the archive sector by adapting to information communication technology.