bluuebunny/crossref_metadata_2025_split huggingface dataset:
Biomedical Graph Visualizer for Identifying Drug Candidates
Authors: Teng Ashton , Villanueva Blanca , Jow Derek , Huang Shih-Cheng (Mars) , Piekos Samantha N. , Altman Russ B. 
Published: November 2020

1.AbstractMillions of Americans suffer from illnesses with non-existent or ineffective drug treatment. Identifying plausible drug candidates is a major barrier to drug development due to the large amount of time and resources required; approval can take years when people are suffering now. While computational tools can expedite drug candidate discovery, these tools typically require programming expertise that many biologists lack. Though biomedical databases continue to grow, they have proven difficult to integrate and maintain, and non-programming interfaces for these data sources are scarce and limited in capability. This creates an opportunity for us to present a suite of user-friendly software tools to aid computational discovery of novel treatments through de novo discovery or repurposing. Our tools eliminate the need for researchers to acquire computational expertise by integrating multiple databases and offering an intuitive graphical interface for analyzing these publicly available data. We built a computational knowledge graph focused on biomedical concepts related to drug discovery, designed visualization tools that allow users to explore complex relationships among entities in the graph, and served these tools through a free and user-friendly web interface. We show that users can conduct complex analyses with relative ease and that our knowledge graph and algorithms recover approved repurposed drugs. Our evaluation indicates that our method provides an intuitive, easy, and effective toolkit for discovering drug candidates. We show that our toolkit makes computational analysis for drug development more accessible and efficient and ultimately plays a role in bringing effective treatments to all patients.Our application is hosted at: https://biomedical-graph-visualizer.wl.r.appspot.com/
Machine learning-based clustering of nanosized fluorescent extracellular vesicles
Authors: Kuypers Sören , Smisdom Nick , Pintelon Isabel , Timmermans Jean-Pierre , Ameloot Marcel , Michiels Luc , Hendrix Jelle , Hosseinkhani Baharak 
Published: November 2020

ABSTRACTExtracellular vesicles (EV) are biological nanoparticles that play an important role in cell-to-cell communication. The phenotypic profile of EV populations is a promising reporter of disease, with direct clinical diagnostic relevance. Yet, robust methods for quantifying the biomarker content of EV have been critically lacking, and require a single-particle approach due to their inherent heterogeneous nature. Here, we used multicolor single-molecule burst analysis microscopy to detect multiple biomarkers present on single EV. We classified the recorded signals and applied the machine learning-based t-distributed stochastic neighbor embedding algorithm to cluster the resulting multidimensional data. As a proof of principle, we applied the method to assess both the purity and the inflammatory status of EV, and compared cell culture and plasma-derived EV isolated via different purification methods. We then applied this methodology to identify intercellular adhesion molecule-1 (ICAM-1) specific EV subgroups released by inflamed endothelial cells, and to prove that apolipoprotein-a1 is an excellent marker to identify the typical lipoprotein contamination in plasma. Our methodology can be widely applied on standard confocal microscopes, thereby allowing both standardized quality assessment of patient plasma EV preparations, and diagnostic profiling of multiple EV biomarkers in health and disease.
Precise spatial representations in the hippocampus of a food‑caching bird
Authors: Payne Hannah L. , Lynch Galen F. , Aronov Dmitriy 
Published: November 2020

SummaryThe hippocampus is an ancient neural circuit required for the formation of episodic memories. In mammals, this ability is thought to depend on well-documented patterns of neural activity, including place cells and sharp wave ripples. Notably, neither pattern has been found in non-mammals, despite compelling examples of episodic-like memory across a wide range of vertebrates. Does episodic memory nonetheless have a universal implementation across distant neural systems? We addressed this question by recording neural activity in the hippocampus of the tufted titmouse – an intense memory specialist from a food-caching family of birds. These birds cache large numbers of food items at scattered, concealed locations and use hippocampus-dependent memory to retrieve their caches. We found remarkably precise spatial representations akin to classic place cells, as well as sharp wave ripples, in the titmouse hippocampus. These patterns were organized along similar anatomical axes to those found in mammals. In contrast, spatial coding was weaker in a different, non-food-caching bird species. Our findings suggest a striking conservation of hippocampal mechanisms across distant vertebrates, in spite of vastly divergent anatomy and cytoarchitecture. At the same time, these results demonstrate that the exact implementation of such common mechanisms may conform to the unique ethological needs of different species.
Measuring stimulus-evoked neurophysiological differentiation in distinct populations of neurons in mouse visual cortex
Authors: Mayner William G. P. , Marshall William , Billeh Yazan N. , Gandhi Saurabh R. , Caldejon Shiella , Cho Andrew , Griffin Fiona , Hancock Nicole , Lambert Sophie , Lee Eric , Luviano Jennifer , Mace Kyla , Nayan Chelsea , Nguyan Thuyanh , North Kat , Seid Sam , Williford Ali , Cirelli Chiara , Groblewski Peter , Lecoq Jerome , Tononi Giulio , Koch Christof , Arkhipov Anton 
Published: November 2020

AbstractDespite significant progress in understanding neural coding, it remains unclear how the coordinated activity of large populations of neurons relates to what an observer actually perceives. Since neurophysiological differences must underlie differences among percepts, differentiation analysis—quantifying distinct patterns of neurophysiological activity—is an “inside out” approach that addresses this question. We used two-photon calcium imaging in mice to systematically survey stimulus-evoked neurophysiological differentiation in excitatory populations across 3 cortical layers (L2/3, L4, and L5) in each of 5 visual cortical areas (primary, lateral, anterolateral, posteromedial, and anteromedial) in response to naturalistic and phase-scrambled movie stimuli. We find that unscrambled stimuli evoke greater neurophysiological differentiation than scrambled stimuli specifically in L2/3 of the anterolateral and anteromedial areas, and that this effect is modulated by arousal state and locomotion. Contrariwise, decoding performance was far above chance and did not vary substantially across areas and layers. Differentiation also differed within the unscrambled stimulus set, suggesting that differentiation analysis may be used to probe the ethological relevance of individual stimuli.
Bi-directional control of a prelimbic somatostatin microcircuit decreases binge alcohol consumption
Authors: Dao Nigel C. , Brockway Dakota F. , Nair Malini Suresh , Crowley Nicole A. 
Published: November 2020

ABSTRACTSomatostatin neurons have been implicated in a variety of neuropsychiatric disorders such as depression and anxiety, but their role in substance abuse disorders, including alcohol use disorder (AUD), is not fully characterized. Here we found that repeat cycles of alcohol binge drinking in the Drinking-in-the-Dark (DID) model led to hypoactivity of somatostatin (SST) neuronal in the prelimbic (PL) cortex by diminishing their action potential firing capacity and excitatory/inhibitory transmission dynamic. We examined their role in regulating alcohol consumption via bidirectional chemogenetic manipulation. Both hM3Dq-induced excitation and KORD-induced silencing of PL SST neurons paradoxically reduced alcohol binge drinking in males and females, with no effect on sucrose consumption. This effect is mediated directly via monosynaptic connection from SST neurons onto pyramidal neurons and indirectly via an intermediate GABAergic source. Optogenetic-assisted circuit mapping revealed that PL SST neurons preferentially synapse onto pyramidal neurons over other GABAergic populations in males, whereas SST neuron-mediated inhibition is balanced across cell types in females. Alcohol binge drinking disinhibits pyramidal neurons by augmenting SST neurons-mediated GABA release and synaptic strength onto other GABAergic populations. Together these data suggest substantial interaction between alcohol binge drinking and SST neurons inhibitory circuit in the PL, as well as provide evidence for these neurons as a potential therapeutic candidate for the treatment of alcohol use disorders, including binge drinking.
Meiotic drive is associated with sexual incompatibility inNeurospora
Authors: Vogan Aaron , Svedberg Jesper , Grudzinska-Sterno Magdalena , Johannesson Hanna 
Published: November 2020

AbstractMeiotic drive is the phenomenon whereby selfish elements bias their transmission to progeny at ratios above 50:50, violating Mendel’s law of equal segregation. The model fungusNeurosporacarries three different meiotic drivers, called Spore killers. Two of these,Sk-2andSk-3, are multilocus spore killers that constitute large haplotypes and are found in the speciesN. intermedia. Here we used molecular markers to determine that allN. intermediaisolates from New Zealand in fact belong to the sister speciesN. metzenbergii. Additionally, we use laboratory crosses to demonstrate thatSk-2andSk-3are involved in sexual incompatibility betweenN. intermediaandN. metzenbergii.. Our experiments revealed that while crosses between these two species normally produced viable progeny at appreciable rates, when strains ofN. intermediacarriedSk-2orSk-3the proportion of viable progeny dropped substantially and in some crosses, no viable progeny were observed. Backcrossings supported that the incompatibility is tightly linked to theSkhaplotype. Finally, it appears thatSk-2andSk-3have accumulated different incompatibility phenotypes when crossed withN. metzenbergiistrains, consistent with their independent evolutionary history. This research illustrates how meiotic drive can contribute to reproductive isolation between populations, and thereby speciation.
Genetically diverse populations spread faster in benign but not in challenging environments
Authors: Frederik Mortier , Stefano Masier , Dries Bonte 
Published: November 2020

AbstractPopulation spread from a limited pool of founding propagules is at the basis of biological invasions. The size and genetic variation of these propagules eventually affect whether the invasion is successful or not. The inevitable bottleneck at introduction decreases genetic diversity, and therefore should affect population growth and spread. However, many heavily bottlenecked invasive populations have been successful in nature. These negative effects of a genetic bottleneck are typically considered to be relaxed in benign environments because of a release from stress. Despite its relevance to understand and predict invasions, empirical evidence on the role of genetic diversity in relation to habitat quality is largely lacking. We use the mite Tetranychus urticae Koch as a model to experimentally assess spread rate and the size of genetically depleted inbred populations and enriched mixed populations. This was assessed in replicated linear patch systems consisting of benign (bean), challenging (tomato) or a gradient (bean to tomato) habitat. We find that genetic diversity increased population spread rates in the benign but not in the challenging habitat. Additionally, variance in spread was consistently higher in genetically poor populations and highest in the challenging habitat. Our experiment challenges the general view that a bottleneck in genetic variation decreases invasion success in challenging, but not in benign environments.
A Large-Scale Structural and Functional Connectome of Social Mentalizing
Authors: Wang Yin , Metoki Athanasia , Xia Yunman , Zang Yinyin , He Yong , Olson Ingrid R 
Published: November 2020

AbstractHumans have a remarkable ability to infer the mind of others. This mentalizing skill relies on a distributed network of brain regions but how these regions connect and interact is not well understood. Here we leveraged large-scale multimodal neuroimaging data to elucidate the connectome-level organization and brain-wide mechanisms of mentalizing processing. Key features of the mentalizing connectome have been delineated in exquisite detail and its relationship with the default mode network has been extensively scrutinized. Our study demonstrates that mentalizing processing unfolds across functionally heterogeneous regions with highly structured fiber tracts and unique hierarchical functional architecture, which make it distinguishable from the default mode network and other social brain networks.
Structural basis for variable IgE reactivities of Cor a 1 hazelnut allergens
Authors: Führer Sebastian , Kamenik Anna S. , Zeindl Ricarda , Nothegger Bettina , Hofer Florian , Reider Norbert , Liedl Klaus R. , Tollinger Martin 
Published: November 2020

AbstractA major proportion of allergic reactions to hazelnuts (Corylus avellana) are caused by immunologic cross-reactivity of IgE antibodies to pathogenesis-related class 10 (PR-10) proteins. Intriguingly, the four known isoforms of the hazelnut PR-10 allergen Cor a 1, denoted as Cor a 1.0401-Cor a 1.0404, share sequence identities exceeding 97 % but possess different immunologic properties. In this work we describe the NMR solution structures of these proteins and provide an in-depth study of their biophysical properties. Despite sharing highly similar three-dimensional structures, the four isoforms exhibit remarkable differences regarding structural flexibility, hydrogen bonding and thermal stability. Our experimental data reveal an inverse correlation between structural flexibility and IgE-binding, with the most flexible isoform having the lowest IgE-binding potential, while the isoform with the most rigid backbone scaffold displays the highest immunologic reactivity. These results point towards a significant entropic contribution to the process of antibody binding.
Validation of a novel associative transcriptomics pipeline in Brassica oleracea: Identifying candidates for vernalisation response
Authors: Woodhouse Shannon , He Zhesi , Woolfenden Hugh , Steuernagel Burkhard , Haerty Wilfried , Bancroft Ian , Irwin Judith A. , Morris Richard J. , Wells Rachel 
Published: November 2020

AbstractAssociative transcriptomics has been used extensively in Brassica napus to enable the rapid identification of markers correlated with traits of interest. However, within the important vegetable crop species, Brassica oleracea, the use of associative transcriptomics has been limited due to a lack of fixed genetic resources and the difficulties in generating material due to self-incompatibility. Within Brassica vegetables, the harvestable product can be vegetative or floral tissues and therefore synchronisation of the floral transition is an important goal for growers and breeders. Vernalisation is known to be a key determinant of the floral transition, yet how different vernalisation treatments influence flowering in B. oleracea is not well understood.Here, we present results from phenotyping a diverse set of 69 B. oleracea accessions for heading and flowering traits under different environmental conditions. We developed a new associative transcriptomics pipeline, and inferred and validated a population structure, for the phenotyped accessions. A genome-wide association study identified miR172D as a candidate for the vernalisation response. Gene expression marker association identified variation in expression of BoFLC.C2 as a further candidate for vernalisation response.This study provides insights into the genetic basis of vernalisation response in B. oleracea through associative transcriptomics and confirms its characterisation as a complex G x E trait. Candidate leads were identified in miR172D and BoFLC.C2. These results could facilitate marker-based breeding efforts to produce B. oleracea lines with more synchronous heading dates, potentially leading to improved yields.
CRISPR/Cas9 targeting Ttc30a mimics ciliary chondrodysplasia with polycystic kidney disease
Authors: Getwan Maike , Hoppmann Anselm , Schlosser Pascal , Grand Kelli , Song Weiting , Diehl Rebecca , Schroda Sophie , Heeg Florian , Deutsch Konstantin , Hildebrandt Friedhelm , Lausch Ekkehart , Köttgen Anna , Lienkamp Soeren S. 
Published: November 2020

AbstractSkeletal ciliopathies (e.g. Jeune syndrome, short rib polydactyly syndrome, Sensenbrenner syndrome) are frequently associated with cystic kidney disease and other organ manifestations, but a common molecular mechanism has remained elusive.We established two models for skeletal ciliopathies (ift80andift172) inXenopus tropicalis, which exhibited severe limb deformities, polydactyly, cystic kidneys, and ciliogenesis defects, closely matching the phenotype of affected patients.Employing data-mining and anin silicoscreen we identified candidate genes with similar molecular properties to genetically validated skeletal ciliopathy genes. Among four genes experimentally validated, CRISPR/Cas9 targeting ofttc30areplicated all aspects of the phenotypes observed in the models of genetically confirmed disease genes, including ciliary defects, limb deformations and cystic kidney disease.Our findings establish three new models for skeletal ciliopathies (ift80,ift172,ttc30a) and identify TTC30A/B as an essential node in the network of ciliary chondrodysplasia and nephronophthisis-like disease proteins implicating post-translational tubulin modifications in its pathogenesis.
Rate of immune complex cycling in follicular dendritic cell determines the extent of protecting antigen integrity and availability to germinal center B cells1
Authors: Arulraj Theinmozhi , Binder Sebastian C. , Meyer-Hermann Michael 
Published: November 2020

AbstractFollicular Dendritic Cells (FDCs) retain immune complexes (ICs) for prolonged time periods and are important for germinal center (GC) reactions. ICs undergo periodic cycling in FDCs, a mechanism supporting an extended half-life of antigen. Based on experimental data we estimated that the average residence time of Phycoerythrin-ICs (PE-ICs) on FDC surface and interior were 21 and 36 minutes, respectively. GC simulations show that antigen cycling might impact GC dynamics due to redistribution of antigen on the FDC surface and by protecting antigen from degradation. Antigen protection and influence on GC dynamics varied with antigen cycling time and total antigen concentration. Simulations predict that blocking antigen cycling terminates the GC reaction and decreases plasma cell production. Considering that cycling of antigen could be a target for the modulation of GC reactions, our findings highlight the importance of understanding the mechanism and regulation of IC cycling in FDCs.
Neural excitability and sensory input determine intensity perception with opposing directions in initial cortical responses
Authors: Stephani T. , Hodapp A. , Idaji M. Jamshidi , Villringer A. , Nikulin V. V. 
Published: November 2020

AbstractPerception of sensory information is determined by stimulus features (e.g., intensity) and instantaneous neural states (e.g., excitability). Commonly, it is assumed that both are reflected similarly in evoked brain potentials, that is, higher evoked activity leads to a stronger percept of a stimulus. We tested this assumption in a somatosensory discrimination task in humans, simultaneously assessing (i) single-trial excitatory post-synaptic currents inferred from short-latency somatosensory evoked potentials (SEP), (ii) pre-stimulus alpha oscillations (8-13 Hz), and (iii) peripheral nerve measures. Fluctuations of neural excitability shaped the perceived stimulus intensity already during the very first cortical response (at ∼20 ms) yet demonstrating opposite neural signatures as compared to the effect of presented stimulus intensity. We reconcile this discrepancy via a common framework based on modulations of electro-chemical membrane gradients linking neural states and responses, which calls for reconsidering conventional interpretations of brain potential magnitudes in stimulus intensity encoding.
Recurrent dynamics of prefrontal cortex during context-dependent decision-making
Authors: Cohen Zach , DePasquale Brian , Aoi Mikio C. , Pillow Jonathan W. 
Published: November 2020

AbstractA key problem in systems neuroscience is to understand how neural populations integrate relevant sensory inputs during decision-making. Here, we address this problem by training a structured recurrent neural network to reproduce both psychophysical behavior and neural responses recorded from monkey prefrontal cortex during a context-dependent per-ceptual decision-making task. Our approach yields a one-to-one mapping of model neurons to recorded neurons, and explicitly incorporates sensory noise governing the animal’s performance as a function of stimulus strength. We then analyze the dynamics of the resulting model in order to understand how the network computes context-dependent decisions. We find that network dynamics preserve both relevant and irrelevant stimulus information, and exhibit a grid of fixed points for different stimulus conditions as opposed to a one-dimensional line attractor. Our work provides new insights into context-dependent decision-making and offers a powerful framework for linking cognitive function with neural activity within an artificial model.
Dichotic listening deficits in amblyaudia are characterized by aberrant neural oscillations in auditory cortex
Authors: Momtaz Sara , Moncrieff Deborah W. , Bidelman Gavin M. 
Published: November 2020

ABSTRACTChildren diagnosed with auditory processing disorder (APD) show deficits in processing complex sounds that are associated with difficulties in higher-order language, learning, cognitive, and communicative functions. Amblyaudia (AMB) is a subcategory of APD characterized by abnormally large ear asymmetries in dichotic listening tasks. Here, we examined frequency-specific neural oscillations and functional connectivity via high-density EEG in children with and without AMB during passive listening of nonspeech stimuli. Time-frequency maps of these “brain rhythms” revealed stronger phase-locked beta-gamma (∼35 Hz) oscillations in AMB participants within bilateral auditory cortex for sounds presented to the right ear, suggesting a hypersynchronization and imbalance of auditory neural activity. Brain-behavior correlations revealed neural asymmetries in cortical responses predicted the larger than normal right-ear advantage seen in participants with AMB. Additionally, we found weaker functional connectivity in the AMB group from right to left auditory cortex, despite their stronger neural responses overall. Our results reveal abnormally large auditory sensory encoding and an imbalance in communication between cerebral hemispheres (ipsi-to -contralateral signaling) in AMB. These neurophysiological changes might lead to the functionally poorer behavioral capacity to integrate information between the two ears in children with AMB.