bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fyn kinase inhibition using AZD0530 improves recognition memory and reduces depressive-like behaviour in an experimental model of Parkinson’s disease
Authors: Guglietti Bianca , Carr Laura , Ellul Benjamin , Mustafa Sanam , Corrigan Frances , Collins-Praino Lyndsey E 
Published: June 2021

ABSTRACTFyn kinase has recently been established as a major upstream regulator of neuroinflammation in PD. This study aimed to determine if inhibition of Fyn kinase could lead to reduced neuroinflammation and improvements in motor and non-motor impairments in an early-stage model of PD. An experimental model of PD was produced using intra-striatal injection (4µl) of the neurotoxin 6-OHDA (5µg/µl). Sprague Dawley rats (n=42) were given either vehicle, 6mg/kg or 12mg/kg of Fyn kinase inhibitor (AZD0530) daily for 32 days via oral gavage and tested on a battery of tasks assessing motor, cognitive and neuropsychiatric outcomes. AZD 0530 administration led to improvement in volitional locomotion and recognition memory, as well as a reduction in depressive-like behaviour. Pathologically, an inflammatory response was observed; however, there were no significant differences in markers of neuroinflammation between treatment groups. Taken together, results indicate a potential therapeutic benefit for use of Fyn kinase inhibition to treat non-motor symptoms of PD, although mechanisms remain to be elucidated.HIGHLIGHTSFyn kinase has recently been proposed as a major upstream regulator of microglial activation in Parkinson’s disease (PD).This study was the first to evaluate the effects of Fyn kinase inhibition in a rodent model of PD.Fyn kinase inhibition using the Fyn kinase inhibitor AZD 0530 was capable of improving volitional locomotion and recognition memory and reducing depressive-like behaviour in a rodent model of PD.Interestingly, while increases in microglial activation were observed in this rodent model of PD, AZD 0530 did not significantly reduce this activation.This suggests that the behavioural improvements associated with Fyn kinase inhibition may occur independently of neuroinflammation and may be attributable to other brain mechanisms, including actions on NMDA or 5-HT6 receptors.
The Cost of Untracked Diversity in Brain-Imaging Prediction
Authors: Benkarim Oualid , Paquola Casey , Park Bo-yong , Kebets Valeria , Hong Seok-Jun , de Wael Reinder Vos , Zhang Shaoshi , Thomas Yeo B.T. , Eickenberg Michael , Ge Tian , Poline Jean-Baptiste , Bernhardt Boris , Bzdok Danilo 
Published: June 2021

AbstractBrain-imaging research enjoys increasing adoption of supervised machine learning for singlesubject disease classification. Yet, the success of these algorithms likely depends on population diversity, including demographic differences and other factors that may be outside of primary scientific interest. Here, we capitalize on propensity scores as a composite confound index to quantify diversity due to major sources of population stratification. We delineate the impact of population heterogeneity on the predictive accuracy and pattern stability in two separate clinical cohorts: the Autism Brain Imaging Data Exchange (ABIDE, n=297) and the Healthy Brain Network (HBN, n=551). Across various analysis scenarios, our results uncover the extent to which cross-validated prediction performances are interlocked with diversity. The instability of extracted brain patterns attributable to diversity is located preferentially to the default mode network. Our collective findings highlight the limitations of prevailing deconfounding practices in mitigating the full consequences of population diversity.
The chemical synthesis of knob domain antibody fragments
Authors: Macpherson Alex , Birtley James R. , Broadbridge Robert J. , Brady Kevin , Tang Yalan , Joyce Callum , Saunders Kenneth , Bogle Gregory , Horton John , Kelm Sebastian , Taylor Richard D. , Franklin Richard J. , Selby Matthew D. , Laabei Maisem , Wonfor Toska , Hold Adam , Vadysirisack Douangsone , Shi Jiye , van den Elsen Jean , Lawson Alastair D.G. 
Published: June 2021

AbstractCysteine-rich knob domains found in the ultralong complementarity determining regions of a subset of bovine antibodies, are capable of functioning autonomously as 3-6 kDa peptides. While they can be expressed recombinantly in cellular systems, in this paper we show that knob domains are also readily amenable to chemical synthesis, with a co-crystal structure of a chemically synthesised knob domain in complex with antigen showing structural equivalence to the biological product. For drug discovery, following immunisation of cattle, knob domain peptides can be synthesised directly from antibody sequence data, combining the power and diversity of the bovine immune repertoire with the ability to rapidly incorporate non-biological modifications. We demonstrate that, through rational design with non-natural amino acids, paratope diversity can be massively expanded, in this case improving the efficacy of an allosteric peptide. As a potential route to further improve stability, we also performed head-to-tail cyclisation, exploiting the unusual proximity of the N- and C-termini to synthesise functional, fully cyclic antibody fragments. Lastly, we highlight the stability of knob domains in plasma and, through pharmacokinetic studies, use palmitoylation as a route to extend the plasma half-life of knob domains in vivo. This study presents an antibody-derived medicinal chemistry platform, with protocols for solid-phase synthesis of knob domains; together with characterisation of their molecular structures, in vitro pharmacology and pharmacokinetics.
Memory B cells control SARS-CoV-2 variants upon mRNA vaccination of naive and COVID-19 recovered individuals
Authors: Sokal Aurélien , Barba-Spaeth Giovanna , Fernández Ignacio , Broketa Matteo , Azzaoui Imane , La Selle Andrea de , Vandenberghe Alexis , Fourati Slim , Roeser Anais , Meola Annalisa , Bouvier-Alias Magali , Crickx Etienne , Languille Laetitia , Michel Marc , Godeau Bertrand , Gallien Sébastien , Melica Giovanna , Nguyen Yann , Zarrouk Virginie , Canoui-Poitrine Florence , Noizat-Pirenne France , Megret Jérôme , Pawlotsky Jean-Michel , Fillatreau Simon , Bruhns Pierre , Rey Felix A. , Weill Jean-Claude , Reynaud Claude-Agnès , Chappert Pascal , Mahévas Matthieu 
Published: June 2021

SummaryHow a previous SARS-CoV-2 infection may amplify and model the memory B cell (MBC) response elicited by mRNA vaccines was addressed by a comparative longitudinal study of two cohorts, naive individuals and disease-recovered patients, up to 2 months after vaccination. The quality of the memory response was assessed by analysis of the VDJ repertoire, affinity and neutralization against variants of concerns (VOC), using unbiased cultures of 2452 MBCs. Upon boost, the MBC pool of recovered patients selectively expanded, further matured and harbored potent neutralizers against VOC. Maturation of the MBC response in naive individuals was much less pronounced. Nevertheless, and as opposed to their weaker neutralizing serum response, half of their RBD-specific MBCs displayed high affinity towards multiple VOC and one-third retained neutralizing potency against B.1.351. Thus, repeated vaccine challenges could reduce these differences by recall of affinity-matured MBCs and allow naive vaccinees to cope efficiently with VOC.
X-DPI: A structure-aware multi-modal deep learning model for drug-protein interactions prediction
Authors: Wang Penglei , Zheng Shuangjia , Jiang Yize , Li Chengtao , Liu Junhong , Wen Chang , Patronov Atanas , Qian Dahong , Chen Hongming , Yang Yuedong 
Published: June 2021

AbstractMotivationIdentifying the drug-protein interactions (DPIs) is crucial in drug discovery, and a number of machine learning methods have been developed to predict DPIs. Existing methods usually use unrealistic datasets with hidden bias, which will limit the accuracy of virtual screening methods. Meanwhile, most DPIs prediction methods pay more attention to molecular representation but lack effective research on protein representation and high-level associations between different instances. To this end, we presented here a novel structure-aware multi-modal DPIs prediction model, X-DPI, performing on a curated industry-scale benchmark dataset.ResultsWe built a high-quality benchmark dataset named GalaxyDB for DPIs prediction. This industry-scale dataset along with an unbiased training procedure resulted in a more robust benchmark study. For informative protein representation, we constructed a structure-aware graph neural network method from the protein sequence by combining predicted contact maps and graph neural networks. Through further integration of structure-based representation and high-level pre-trained embeddings for molecules and proteins, our model captured more effectively the feature representation of the interactions between them. As a result, X-DPI outperformed state-of-the-art DPIs prediction methods and obtained 5.30% Mean Square Error (MSE) improved in the DAVIS dataset and 8.89% area under the curve (AUC) improved in GalaxyDB dataset. Moreover, our model is an interpretable model with the transformer-based interaction mechanism, which can accurately reveal the binding sites between molecule and protein.
High heritabilities for antibiotic usage show potential to breed for disease resistance in finishing pigs
Authors: Gorssen Wim , Maes Dominiek , Meyermans Roel , Depuydt Jürgen , Janssens Steven , Buys Nadine 
Published: June 2021

AbstractThe use of antimicrobials in animal production is under public debate, mainly due to the risk of transfer of resistance to pathogenic bacteria in humans. Therefore, measures have been taken during the last decades to reduce antibiotic usage in animals, for instance by national monitoring programmes and by improving animal health management. Although some initiatives exist in molecular genetic selection, quantitative genetic selection of animals towards decreased antibiotic usage is an underexplored area to reduce antibiotic usage. However, this strategy could yield cumulative effects.In this study we derived new phenotypes from on-farm parenteral antibiotic records from commercially grown crossbred finishing pigs used in the progeny test of Piétrain terminal sires to investigate the heritability of antibiotics usage. Parenteral antibiotic records, production parameters and pedigree records of 2238 fullsib pens from two experimental farms in Belgium between 2014 and 2020 were analysed. Heritability estimates were moderate (18-44%) for phenotypes derived from all antibiotic treatments, and low (1-15%) for phenotypes derived from treatments against respiratory diseases only. Moreover, genetic correlations between these new phenotypes and mortality were low to moderate (0.08-0.60) and no strong adverse genetic correlations with production traits were found.The high heritabilities and favourable genetic correlations suggest these new phenotypes derived from on-farm antibiotics records to be promising for inclusion in future pig breeding programs to breed for a decrease in antibiotics usage.
Psychophysiological Evidence for Fear Extinction Learning via Mental Imagery
Authors: Jiang Xinrui , Greening Steven 
Published: June 2021

AbstractImagery-based extinction procedures have long been used in the treatments of fear-related conditions. The assumption is that imagery can substitute for the perceptual stimuli in the extinction process. Yet, experimental validations of this assumption have been limited in number and some have relied exclusively on measures of autonomic reactivity without consideration of conscious feelings of fear. The current investigation sought to assess whether imagery-based exposure could lead to extinction of conditioned fear to the corresponding perceptual stimulus. Conditioned fear responses were measured by both a physiological (i.e., skin conductance response/SCR) and a subjective (i.e., self-reported fear) measure. Participants (N= 56) first underwent perceptual differential fear conditioning, then imagery extinction, then perceptual extinction. SCR evidence was found for successful fear conditioning, generalization of fear from viewing to imagery, and most importantly, the absence of differential fear after imagery extinction upon re-exposure to the conditioned perceptual stimulus. Self-reported fear confirmed the acquisition and generalization of fear and provided evidence of a significant reduction in differential fear conditioning across extinction. Consistent with clinical evidence of the efficacy of imagery extinction and the existing limited experimental literature, the current study offers support for fear extinction to perceptual stimuli via imagery exposure.
Increased brain growth in escaped rainbow trout
Authors: Laberge Frédéric , Gutgesell Marie , McCann Kevin S. 
Published: June 2021

AbstractRecent examples of rapid brain size plasticity in response to novel laboratory environments suggest that fish brain size is a flexible trait, allowing growth or shrinkage of brain tissue based on short term needs. Nevertheless, it remains to be seen if plasticity of fish brain size is relevant to natural environmental conditions. Here, using rainbow trout escaped from a farming operation as a natural experiment, we demonstrate that adult fish brain size can change rapidly in response to life in a natural lake environment. Specifically, escaped trout had on average 15% heavier brains relative to body size than captive trout after living for about 7 months in the lake. Because relative brain size of most escaped trout fell above the range of variation seen within the captive trout population, we conclude that increased brain size was achieved by plasticity after escape. Brain morphology analysis showed that the most anterior regions (olfactory bulbs and rest of telencephalon) contributed most to the increase in overall brain size in escaped trout. Relative size of the heart ventricle, another organ which can be subject to plastic changes under variable environmental conditions in fish, did not differ between escaped and captive trout. Massive and selective brain growth under the changed environmental conditions associated with escape from holding pens highlighted the plastic potential of fish brain size and suggests that a shift to increased complexity of life in the wild setting of a lake imposed greatly increased cognitive requirements on escaped trout.
IUCNN - deep learning approaches to approximate species’ extinction risk
Authors: Zizka Alexander , Andermann Tobias , Silvestro Daniele 
Published: June 2021

AbstractAimThe global Red List (RL) from the International Union for the Conservation of Nature is the most comprehensive global quantification of extinction risk, and widely used in applied conservation as well as in biogeographic and ecological research. Yet, due to the time- consuming assessment process, the RL is biased taxonomically and geographically, which limits its application on large scales, in particular for understudied areas such as the tropics, or understudied taxa, such as most plants and invertebrates. Here we present IUCNN, an R- package implementing deep learning models to predict species RL status from publicly available geographic occurrence records (and other traits if available).InnovationWe implement a user-friendly workflow to train and validate neural network models, and subsequently use them to predict species RL status. IUCNN contains functions to address specific issues related to the RL framework, including a regression-based approach to account for the ordinal nature of RL categories and class imbalance in the training data, a Bayesian approach for improved uncertainty quantification, and a target accuracy threshold approach that limits predictions to only those species whose RL status can be predicted with high confidence. Most analyses can be run with few lines of code, without prior knowledge of neural network models. We demonstrate the use of IUCNN on an empirical dataset of ∼14,000 orchid species, for which IUCNN models can predict extinction risk within minutes, while outperforming comparable methods.Main conclusionsIUCNN harnesses innovative methodology to estimate the RL status of large numbers of species. By providing estimates of the number and identity of threatened species in custom geographic or taxonomic datasets, IUCNN enables large-scale analyses on the extinction risk of species so far not well represented on the official RL.
Expression and function of SLC38A5, an amino acid-coupled Na+/H+ exchanger, in triple-negative breast cancer and its relevance to macropinocytosis
Authors: Ramachandran Sabarish , Sennoune Souad , Sharma Monica , Thangaraju Muthusamy , Suresh Varshini , Bhutia Yangzom D. , Pruitt Kevin , Ganapathy Vadivel 
Published: June 2021

AbstractMetabolic reprogramming in cancer cells necessitates increased amino acid uptake, which is accomplished by upregulation of specific amino acid transporters. Since amino acid transporters differ in substrate selectivity, mode of transport, and driving forces, not all tumors rely on any single amino acid transporter for this purpose. Here we report on the differential upregulation of the amino acid transporter SLC38A5 in triple-negative breast cancer (TNBC). The upregulation is evident in primary TNBC tumors, conventional TNBC cell lines, patient-derived xenograft TNBC cell lines, and a mouse model of spontaneous mammary tumor representing TNBC. The upregulation is confirmed by functional assays. SLC38A5 is an amino acid-dependent Na+/H+ exchanger which transports Na+ and amino acids into cells coupled with H+ efflux. Since the traditional Na+/H+ exchanger is an established inducer of macropinocytosis, an endocytic process for cellular uptake of bulk fluid and its components, we examined the impact of SLC38A5 on macropinocytosis in TNBC cells. We found that the transport function of SLC38A5 is coupled to induction of macropinocytosis. Surprisingly, the transport function of SLC38A5 is inhibited by amilorides, the well-known inhibitors of Na+/H+ exchanger, possibly related to the amino acid-dependent Na+/H+ exchange function of SLC38A5. The Cancer Genome Atlas database corroborates SLC38A5 upregulation in TNBC. This represents the first report on the selective expression of SLC38A5 in TNBC and its role as an inducer of macropinocytosis, thus revealing a novel, hitherto unsuspected, function for an amino acid transporter that goes beyond amino acid delivery but is still relevant to cancer cell nutrition.Summary StatementSLC38A5 is an amino acid-coupled Na+/H+ exchanger that is upregulated in triple-negative breast cancer, and its function in cancer cells goes beyond amino acid delivery; it promotes macropinocytosis, a distinct form of endocytic process for cellular uptake of proteins and other nutrients present in extracellular fluid.
vWCluster: A Network Based Clustering of Multi-omics Breast Cancer Data Based on Vector-Valued Optimal Transport
Authors: Zhu Jiening , Oh Jung Hun , Deasy Joseph O. , Tannenbaum Allen 
Published: June 2021

AbstractIn this paper, we present a network-based clustering method based on the vector-valued Wasserstein distance derived from optimal mass transport (OMT) theory. This distance allows for the natural integration of multi-layer representations of data in a given network from which one derives clusters via a hierarchical clustering approach. In this study, we applied the methodology, called vector Wasserstein clustering (vW-cluster), to multi-omics data from the two largest breast cancer studies. The resultant clusters showed significantly different survival rates in Kaplan-Meier analysis in both datasets. CIBERSORT scores were compared among the identified clusters. Out of the 22 CIBERSORT immune cell types, 9 were commonly significantly different in both datasets, suggesting the difference of tumor immune microenvironment in the cluster. vWCluster can aggregate multi-omics data represented as a vectorial form in a network with multiple layers, taking into account the concordant effect of heterogeneous data, and further identify subtypes of tumors with different survival rates.
Post-Infection Entry Mechanism of Ricin A Chain-Pokeweed Antiviral Proteins (RTA-PAPs) Chimeras is Mediated by Viroporins
Authors: Hassan Yasser 
Published: June 2021

AbstractThe limitations of virus-specific antiviral drugs became apparent during the current COVID-19 pandemic. The search for broad range antiviral proteins of a new kind to answer current and future pandemics has become an even more pressing matter. Here, the author further describes the expected anti-SARS-CoV-2 mechanisms of a novel broad range antiviral chimeric protein constructed between ricin A chain and pokeweed antiviral proteins. The latest in protein-ligand docking software were used to determine binding affinity of RTA-PAPs to SARS-CoV-2 frameshift stimulation element and elucidate the preferential post-infection entry mechanisms of RTA-PAPs into virus infected cells over non-infected ones, by doing a comparative analysis between in vitro and in silico results on numerous viruses. The results obtained strongly suggest that the post-infection preferential entry of RTA-PAPs into infected cells is mediated by the presence of viroporins integrated into the host cell membrane. The discovery of this mechanism revealed RTA-PAPs, and proteins like them, to be a new class of broad range antivirals that target with high specificity viroporin producing viruses, and with gain of functions in antiviral activities, post-infection.
Demographic Inferences and Loci Under Selection in a Recently Expanded Coral Population
Authors: Fifer James E. , Yasuda Nina , Yamakita Takehisa , Davies Sarah W. 
Published: June 2021

AbstractCoral poleward range expansions in response to warming oceans have been historically observed, however contemporary expansion rates of some coral species have become more rapid as global temperatures rise at unprecedented rates. Range expansion can lead to reduced genetic diversity and surfing of deleterious mutations in expanding populations, potentially limiting the ability for adaption and persistence in novel environments. Successful expansions that overcome these founder effects and colonize new habitat have been attributed to multiple introductions from different sources, hybridization with native populations, or rapid adaptive evolution. Here, we investigate population genomic patterns of the reef-building coralAcropora hyacinthusalong a latitudinal cline that includes a well-established range expansion front in Japan using 2b-RAD sequencing. A total of 184 coral samples were collected across seven sites spanning from ∼24°N to near its northern range front at ∼33°N. We uncover the presence of three cryptic lineages ofA. hyacinthus, which occupy discrete areas within this region. Only one lineage is present at the expansion front and we find evidence of its historical occupation of marginal habitats. Within this lineage we also find evidence of bottleneck pressures associated with expansion events including higher clonality, increased linkage disequilibrium, and lower genetic diversity in range edge populations compared to core populations. Asymmetric migration between populations was also detected with lower migration from edge sites. Lastly, we describe genomic signatures of local adaptation potentially attributed to lower winter temperatures experienced at the more recently expanded northern populations. Together these data illuminate the genomic consequences of range expansion in a coral and highlight how adaptation to colder temperatures along the expansion front may facilitate further range expansion in this coral lineage.