bluuebunny/crossref_metadata_2025_split huggingface dataset:
XBP1s-Mediated ER Proteostasis Network Enhancement Can Selectively Improve the Folding and Secretion of an Osteogenesis Imperfecta-Causing Collagen-I Variant
Authors: DiChiara Andrew S. , Doan Ngoc-Duc , Bikovtseva Agata A. , Rowley Lynn , Butty Vincent L. , Weis MaryAnn E. , Eyre David R. , Lamandé Shireen R. , Bateman John F. , Shoulders Matthew D. 
Published: April 2021

ABSTRACTOsteogenesis imperfecta (OI) is typically caused by autosomal dominant mutations in genes encoding collagen type-I, most commonly resulting in Gly→Ser triple-helical domain substitutions that disrupt collagen folding and/or stability. Here, we test the hypothesis that upregulating the endoplasmic reticulum (ER) proteo-stasis network via the unfolded protein response (UPR) can improve the folding and secretion of the clinically severe, prototypical OI-causingCOL1A1p.G425S collagen-α1(I) variant. We first show that small molecules that activate the entire UPR by causing global ER protein misfolding stress severely ablate collagen-I secretion from both G425S Colα1(I)- and wild-type (WT) Colα1(I)-expressing primary fibroblasts. In contrast, stress-independent, specific induction of just the UPR’s XBP1s transcriptional response can enhance collagen-I secretion from G425S Colα1(I) patient primary fibroblasts up to ~300% of basal levels. Notably, the effect is selective – collagen-I secretion from WT Colα1(I)-expressing healthy donor primary fibroblasts is unaltered by XBP1s. XBP1s pathway activation appears to post-translationally enhance the folding/assembly and secretion of G425S Colα1(I), as only modest impacts on collagen-I transcription or synthesis are observed. Consistent with this notion, we find that the stable, triple-helical collagen-I secreted by XBP1s-activated G425S α1(I) patient fibroblasts includes a higher proportion of the mutant α1(I) polypeptide than the collagen-I secreted under basal ER proteostasis conditions. We note that consistent reproducibility of these results is dependent on as yet unascertained experimental variables. Still, these promising observations suggest the potential for ER proteo-stasis network modulation to improve mutant collagen proteostasis in the collagenopathies, motivating further investigation of the effect’s generality, underlying mechanism, and potential therapeutic benefits.
Multi-modal engineering ofBstDNA polymerase for thermostability in ultra-fast LAMP reactions
Authors: Paik Inyup , Ngo Phuoc H. T. , Shroff Raghav , Maranhao Andre C. , Walker David J.F. , Bhadra Sanchita , Ellington Andrew D. 
Published: April 2021

ABSTRACTDNA polymerase fromGeobacillus stearothermophilus, BstDNA polymerase (BstDNAP), is a versatile enzyme with robust strand-displacing activity that enables loop-mediated isothermal amplification (LAMP). Despite its exclusive usage in LAMP assay, its properties remain open to improvement. Here, we describe logical redesign ofBstDNAP by using multimodal application of several independent and orthogonal rational engineering methods such as domain addition, supercharging, and machine learning predictions of amino acid substitutions. The resulting Br512g3 enzyme is not only thermostable and extremely robust but it also displays improved reverse transcription activity and the ability to carry out ultrafast LAMP at 74 °C. Our study illustrates a new enzyme engineering strategy as well as contributes a novel engineered strand displacing DNA polymerase of high value to diagnostics and other fields.
Physiological Substrates and Ontogeny-Specific Expression of the Ubiquitin Ligases MARCH1 and MARCH8
Authors: Schriek Patrick , Liu Haiyin , Ching Alan C. , Huang Pauline , Gupta Nishma , Wilson Kayla R. , Tsai MinHsuang , Yan Yuting , Macri Christophe F. , Dagley Laura F. , Infusini Giuseppe , Webb Andrew I. , McWilliam Hamish , Ishido Satoshi , Mintern Justine D. , Villadangos Jose A. 
Published: April 2021

ABSTRACTMARCH1 and MARCH8 are ubiquitin ligases that control the expression and trafficking of critical immunoreceptors. Understanding of their function is hampered by three major knowledge gaps: (i) it is unclear which cell types utilize these ligases; (ii) their level of redundancy is unknown; and (iii) most of their putative substrates have been described in cell lines, often overexpressing MARCH1 or MARCH8, and it is unclear which substrates are regulated by either ligasein vivo. Here we address these questions by systematically analyzing the immune cell repertoire of MARCH1- or MARCH8-deficient mice, and applying unbiased proteomic profiling of the plasma membrane of primary cells to identify MARCH1 and MARCH8 substrates. Only CD86 and MHC II were unequivocally identified as immunoreceptors regulated by MARCH1 and MARCH8, but each ligase carried out its function in different tissues. MARCH1 regulated MHC II and CD86 in professional and “atypical” antigen presenting cells of hematopoietic origin, whereas MARCH8 only operated in non-hematopoietic cells. Our results reveal that the range of cells constitutively endowed with antigen-presentation capacity is wider than generally appreciated. They also establish MARCH1 and MARCH8 as specialized regulators of CD4+ T cell immunity in two ontogenically distinct cellular compartments.
Excitatory-inhibitory balance modulates the formation and dynamics of neuronal assemblies in cortical networks
Authors: Sadeh Sadra , Clopath Claudia 
Published: April 2021

AbstractRepetitive activation of subpopulation of neurons in cortical networks leads to the formation of neuronal assemblies, which can guide learning and behavior. Recent technological advances have made the artificial induction of such assemblies feasible, yet how various patterns of activation can shape their emergence in different operating regimes is not clear. Here we studied this question in large-scale cortical networks composed of excitatory (E) and inhibitory (I) neurons. We found that the dynamics of the network in which neuronal assemblies are embedded is important for their induction. In networks with strong E-E coupling at the border of E-I balance, increasing the number of perturbed neurons enhanced the potentiation of ensembles. This was, however, accompanied by off-target potentiation of connections from unperturbed neurons. When strong E-E connectivity was combined with dominant E-I interactions, formation of ensembles became specific. Counter-intuitively, increasing the number of perturbed neurons in this regime decreased the average potentiation of individual synapses, leading to an optimal assembly formation at intermediate sizes. This was due to potent lateral inhibition in this regime, which also slowed down the formation of neuronal assemblies, resulting in a speed-accuracy trade-off in the performance of the networks in pattern completion and behavioral discrimination. Our results therefore suggest that the two regimes might be suited for different cognitive tasks, with fast regimes enabling crude detections and slow but specific regimes favoring finer discriminations. Functional connectivity inferred from recent experiments in mouse cortical networks seems to be consistent with the latter regime, but we show that recurrent and top-down mechanisms can dynamically modulate the networks to switch between different states. Our work provides a framework to study how neuronal perturbations can lead to network-wide plasticity under biologically realistic conditions, and sheds light on the design of future experiments to optimally induce behaviorally relevant neuronal assemblies.
North America Insect Invades the World: the Case of the Flood Mosquito,Aedes vexans(Diptera: Culicidae), from Mitochondrial DNA
Authors: Vargas-Espinosa José Heriberto , Aguirre-Obando Oscar Alexander 
Published: April 2021

AbstractThe flood mosquito,Aedes vexans(Diptera: Culicidae), native of Canada, and currently present in all continents, has a vector competence for 30 arboviruses, being responsible for transmitting diseases, like West Nile fever, Rift Valley fever, Saint Louis Encephalitis and Eastern Equine Encephalitis. Hence, knowing the structure and gene flow ofA. vexansis important to develop adequate vector control strategies for this species. For this, from partial sequences of the mitochondrial COI gene available in Bold and GenBank, it was possible to determine the Haplotypic (Hd) and nucleotide (π) gene diversity, genetic structuring and gene flow at global, continental, and country levels. In total, 1184 sequences were recovered, distributed between America (88.60%), Europe (7.35%), Asia (3.89%), and Africa (0.17%). From these, 395 haplotypes (H) were detected without presence of pseudogenes (NUMTs), with H1 being the most frequent (24.58%) and between H12 - H395 the least frequent varying between 0.93% (H12) and 0.08% (H395). Phylogenetically, the haplotypes were grouped into six clades. Clade I grouped haplotypes from countries in America and Europe, while clades II and III presented haplotypes exclusively from Asia and Europe; clade IV grouped only one haplotype from Africa and the last ultimo clade V grouped haplotypes from America and Africa. The globalHdand π was 0.92 and 0.01, respectively. In addition, evidence was obtained of genetic structuring among continents (7.07%), countries (1.62%), and within countries (91.30%; FST= 0.08, p < 0.05) and no isolation by distance was detected (r = 0.003, p > 0.05). These results suggest that the mosquito populations that invaded other continents originate directly from the American continent, where possibly transcontinental commercial routes favored their long-distance dispersion.
Echocardiographic mitral valve association with morphometric measurements in Cavalier King Charles Spaniels via Inverse Probability Weighting analysis
Authors: Bagardi Mara , Ghilardi Sara , Locatelli Chiara , Bionda Arianna , Polli Michele , Bussadori Claudio M. , Colombo Fabio M. , Pazzagli Laura , Brambilla Paola G. 
Published: April 2021

AbstractDevelopment and progression of myxomatous mitral valve disease (MMVD) in Cavalier King Charles Spaniels (CKCS) are difficult to predict. Identification at a young age of dogs with a morphotype associated with more severe mitral disease is desirable. The aims of this study were to: 1) describe the physical, morphometric, and echocardiographic features of MMVD affected Cavalier King Charles Spaniels (CKCS) in American College of Veterinary Internal Medicine (ACVIM) class B1; 2) evaluate the influence of morphometric physical measurements on murmur intensity, mitral valve prolapse (MVP), regurgitant jet size and indexed mitral valve and annulus measurements. Fifty-two MMVD affected CKCS in ACVIM class B1 were included. This is a prospective clinical cross-sectional study. Morphometric measurements, which included body, thorax, and the head sizing of each dog, have been investigated to establish the association with heart murmur intensity, valvular and annular echocardiographic measurements, MVP and regurgitant jet size using inverse probability weighting (IPW) analyses to adjust for confounding. The IPW analyses showed that when head length and nose length decreased, dogs had more severe regurgitant jet size. Furthermore, subjects with more pronounced head stop angle had thicker anterior mitral valve leaflets. A brachycephalic morphotype, with dogs more similar to King Charles Spaniel breed in cephalic morphology, is associated with a more severe regurgitant jet size and with valvular characteristics related to worse forms of MMVD.
Time-series trend of pandemic SARS-CoV-2 variants visualized using batch-learning self-organizing map for oligonucleotide compositions
Authors: Abe Takashi , Furukawa Ryuki , Iwasaki Yuki , Ikemura Toshimichi 
Published: April 2021

ABSTRACTTo confront the global threat of coronavirus disease 2019, a massive number of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome sequences have been decoded, with the results promptly released through the GISAID database. Based on variant types, eight clades have already been defined in GISAID, but the diversity can be far greater. Owing to the explosive increase in available sequences, it is important to develop new technologies that can easily grasp the whole picture of the big-sequence data and support efficient knowledge discovery. An ability to efficiently clarify the detailed time-series changes in genome-wide mutation patterns will enable us to promptly identify and characterize dangerous variants that rapidly increase their population frequency. Here, we collectively analyzed over 150,000 SARS-CoV-2 genomes to understand their overall features and time-dependent changes using a batch-learning self-organizing map (BLSOM) for oligonucleotide composition, which is an unsupervised machine learning method. BLSOM can separate clades defined by GISAID with high precision, and each clade is subdivided into clusters, which shows a differential increase/decrease pattern based on geographic region and time. This allowed us to identify prevalent strains in each region and to show the commonality and diversity of the prevalent strains. Comprehensive characterization of the oligonucleotide composition of SARS-CoV-2 and elucidation of time-series trends of the population frequency of variants can clarify the viral adaptation processes after invasion into the human population and the time-dependent trend of prevalent epidemic strains across various regions, such as continents.
Glycine attenuates impairments of stimulus-evoked gamma oscillation in the ketamine model of schizophrenia
Authors: Haaf Moritz , Curic Stjepan , Steinmann Saskia , Rauh Jonas , Leicht Gregor , Mulert Christoph 
Published: April 2021

AbstractAlthough a substantial number of studies suggests some clinical benefit concerning negative symptoms in schizophrenia through the modulation of NMDA-receptor function, none of these approaches achieved clinical approval. Given the large body of evidence concerning glutamatergic dysfunction in a subgroup of patients, biomarkers to identify those with a relevant clinical benefit through glutamatergic modulation are urgently needed. A similar reduction of the early auditory evoked gamma-band response (aeGBR) as found in schizophrenia patients can be observed in healthy subjects in the ketamine-model, which addresses the putative excitation / inhibition (E/I) imbalance of the diseases. Moreover, this change in gamma-band oscillations can be related to the emergence of negative symptoms. Accordingly, this study investigated whether glycine-related increases of the aeGBR accompany an improvement concerning negative symptoms in the ketamine-model. The impact of subanesthetic ketamine doses and the pretreatment with glycine was examined in twenty-four healthy male participants while performing a cognitively demanding aeGBR paradigm with 64-channel electroencephalography. Negative Symptoms were assessed through the Positive and Negative Syndrome Scale (PANSS). Ketamine alone caused a reduction of the aeGBR amplitude associated with more pronounced negative symptoms compared to placebo. Pretreatment with glycine attenuated both, the ketamine-induced alterations of the aeGBR amplitude and the increased PANSS negative scores in glycine-responders, classified based on relative aeGBR increase. Thus, we propose that the aeGBR represents a possible biomarker for negative symptoms in schizophrenia related to insufficient glutamatergic neurotransmission. This would allow to identify patients with negative symptoms, who might benefit from glutamatergic treatment.
Stem cell-laden hydrogel bioink for generation of high resolution and fidelity engineered tissues with complex geometries
Authors: Jeon Oju , Lee Yu Bin , Lee Sang Jin , Guliyeva Nazilya , Lee Joanna , Alsberg Eben 
Published: April 2021

AbstractRecently, 3D bioprinting has been explored as a promising technology for biomedical applications with the potential to create complex structures with precise features. Cell encapsulated hydrogels composed of materials such as gelatin, collagen, hyaluronic acid, alginate and polyethylene glycol have been widely used as bioinks for 3D bioprinting. However, since most hydrogel-based bioinks may not allow rapid stabilization immediately after 3D bioprinting, achieving high resolution and fidelity to the intended architecture is a common challenge in 3D bioprinting of hydrogels. In this study, we have utilized shear-thinning and self-healing ionically crosslinked oxidized and methacrylated alginates (OMAs) as a bioink, which can be rapidly gelled by its self-healing property after bioprinting and further stabilized via secondary crosslinking. It was successfully demonstrated that stem cell-laden calcium-crosslinked OMA hydrogels can be bioprinted into complicated 3D tissue structures with both high resolution and fidelity. Additional photocrosslinking enables long-term culture of 3D bioprinted constructs for formation of functional tissue by differentiation of encapsulated human mesenchymal stem cells.
Organization and priming of long-term memory representations with two-phase plasticity
Authors: Luboeinski Jannik , Tetzlaff Christian 
Published: April 2021

AbstractSynaptic tagging and capture (STC) is a molecular mechanism that accounts for the consolidation of synaptic changes induced by plasticity. To link this mechanism to long-term memory and thereby to the level of behavior, its dynamics on the level of recurrent networks have to be understood. To this end, we employ a biologically detailed neural network model of spiking neurons featuring STC, which models the learning and consolidation of long-term memory representations. Using this model, we investigate the effects of different organizational paradigms of multiple memory representations, and demonstrate a proof of principle for priming on long timescales. We examine these effects considering the spontaneous activation of memory representations as the network is driven by background noise. Our first finding is that the order in which the memory representations are learned significantly biases the likelihood of spontaneous activation towards more recently learned memory representations. Secondly, we find that hub-like structures counter this learning order effect for representations with less overlaps. We show that long-term depression is the mechanism underlying these findings, and that intermediate consolidation in between learning the individual representations strongly alters the described effects. Finally, we employ STC to demonstrate the priming of a long-term memory representation on a timescale of minutes to hours. As shown by these findings, our model provides a mechanistic synaptic and neuronal basis for known behavioral effects.
Predicting synaptic connectivity for large-scale microcircuit simulations usingSnudda
Authors: Hjorth J J Johannes , Kotaleski Jeanette Hellgren , Kozlov Alexander 
Published: April 2021

AbstractSimulation of large-scale networks of neurons is an important approach to understanding and interpreting experimental data from healthy and diseased brains. Owing to the rapid development of simulation software and the accumulation of quantitative data of different neuronal types, it is possible to predict both computational and dynamical properties of local microcircuits in a ‘bottom-up’ manner. Simulated data from these models can be compared with experiments and ‘top-down’ modelling approaches, successively bridging the scales. Here we describe an open source pipeline, using the software Snudda, for predicting microcircuit connectivity and for setting up simulations using the NEURON simulation environment in a reproducible way. We also illustrate how to further ‘curate’ data on single neuron morphologies acquired from public databases. This model building pipeline was used to set up a first version of a full-scale cellular level model of mouse dorsal striatum. Model components from that work are here used to illustrate the different steps that are needed when modelling subcortical nuclei, such as the basal ganglia.
Computationally prioritized drugs inhibit SARS-CoV-2 infection and syncytia formation
Authors: Serra Angela , Fratello Michele , Federico Antonio , Ojha Ravi , Provenzani Riccardo , Tasnadi Ervin , Cattelani Luca , del Giudice Giusy , Kinaret Pia Anneli Sofia , Saarimäki Laura Aliisa , Pavel Alisa , Cerullo Vincenzo , Vapalahti Olli , Horvarth Peter , Di Lieto Antonio , Yli-Kauhaluoma Jari , Balistreri Giuseppe , Greco Dario 
Published: April 2021

AbstractNew affordable therapeutic protocols for COVID-19 are urgently needed despite the increasing number of effective vaccines and monoclonal antibodies. To this end, there is increasing attention towards computational methods for drug repositioning andde novodrug design.Here, we systematically integrated multiple data-driven computational approaches to perform virtual screening and prioritize candidate drugs for the treatment of COVID-19. From the set of prioritized drugs, we selected a subset of representative candidates to test in human cells. Two compounds, 7-hydroxystaurosporine and bafetinib, showed synergistic antiviral effects in ourin vitroexperiments, and strongly inhibited viral-induced syncytia formation. Moreover, since existing drug repositioning methods provide limited usable information forde novodrug design, we extracted and prioritized the chemical substructures of the identified drugs, providing a chemical vocabulary that may help to design new effective drugs.
Genomic organization of the autonomous regulatory domain ofeyelesslocus inDrosophila melanogaster
Authors: Verma Shreekant , Pathak Rashmi U , Mishra Rakesh K 
Published: April 2021

AbstractInDrosophila, expression ofeyeless(ey) gene is restricted to the developing eyes and central nervous system. However, the flanking genes,myoglianin(myo), and bent (bt) have different temporal and spatial expression patterns as compared to theey. How distinct regulation ofeyis maintained is mostly unknown. Earlier, we have identified a boundary element interveningmyoandeygenes (ME boundary) that prevents the crosstalk between thecis-regulatory elements ofmyoandeygenes. In the present study, we further searched for thecis-elements that define the domain ofeyand maintain its expression pattern. We identify another boundary element betweeneyandbt, the EB boundary. The EB boundary separates the regulatory landscapes ofeyandbtgenes. The two boundaries, ME and EB, show a long-range interaction as well as interact with the nuclear architecture. This suggests functional autonomy of theeylocus and its insulation from differentially regulated flanking regions. We also identify a new Polycomb Response Element, theey-PRE, within theeydomain. The expression state of theeygene, once established during early development is likely to be maintained with the help ofey- PRE. Our study proposes a general regulatory mechanism by which a gene can be maintained in a functionally independent chromatin domain in gene-rich euchromatin.