bluuebunny/crossref_metadata_2025_split huggingface dataset:
CRISPR-mediated deletion of the Protein tyrosine phosphatase, non-receptor type 22 (PTPN22) improves human T cell function for adoptive T cell therapy
Authors: Prade Sonja , Wright David , Logan Nicola , Teagle Alexandra R. , Stauss Hans , Zamoyska Rose 
Published: December 2020

AbstractAdoptive T cell transfer has improved the treatment of cancer patients. However, treatment of solid tumors is still challenging and new strategies that optimize T cell function and response duration in the tumor could be beneficial additions to cancer therapy. In this study, we deleted the intracellular phosphatase PTPN22 and the endogenous TCR α chain from human PBMC-derived T cells using CRISPR/Cas9 and transduced them with TCRs specific for a defined antigen. Deletion of PTPN22 in human T cells increased the secretion of IFNγ and GM-CSF in multiple donors. The cells retained a polyfunctional cytokine expression after re-stimulation and greater numbers of PTPN22KOT cells expressed inflammatory cytokines compared to unmutated control cells. PTPN22KOT cells seemed to be more polyfunctional at low antigen concentrations. Additionally, we were able to show that that PTPN22KOT cells were more effective in controlling tumor cell growth. This suggests that they might be more functional within the suppressive tumor microenvironment thereby overcoming the limitations of immunotherapy for solid tumors.
Investigating mechanisms underlying genetic resistance to Salmon Rickettsial Syndrome in Atlantic salmon using RNA sequencing
Authors: Moraleda Carolina P. , Robledo Diego , Gutiérrez Alejandro P. , del-Pozo Jorge , Yáñez José M. , Houston Ross D. 
Published: December 2020

ABSTRACTBackgroundSalmon Rickettsial Syndrome (SRS), caused byPiscirickettsia salmonis,is one of the primary causes of morbidity and mortality in Atlantic salmon aquaculture, particularly in Chile. Host resistance is a heritable trait, and functional genomic studies have highlighted genes and pathways important in the response of salmon to the bacteria. However, the functional mechanisms underpinning genetic resistance are not yet well understood. In the current study, a large population of salmon pre-smolts were challenged withP. salmonis, with mortality levels recorded and samples taken for genotyping. In parallel, head kidney and liver samples were taken from animals of the same population with high and low genomic breeding values for resistance, and used for RNA-Sequencing to compare their transcriptome profile both pre and post infection.ResultsA significant and moderate heritability (h2= 0.43) was shown for the trait of binary survival. Genome-wide association analyses using 38K imputed SNP genotypes across 2,251 animals highlighted that resistance is a polygenic trait. Several thousand genes were identified as differentially expressed between controls and infected samples, and enriched pathways related to the host immune response were highlighted. In addition, several networks with significant correlation with SRS resistance breeding values were identified, suggesting their involvement in mediating genetic resistance. These included apoptosis, cytoskeletal organisation, and the inflammasome.ConclusionsWhile resistance to SRS is a polygenic trait, this study has highlighted several relevant networks and genes that are likely to play a role in mediating genetic resistance. These genes may be future targets for functional studies, including genome editing, to further elucidate their role underpinning genetic variation in host resistance.
A Quadratic Model Captures the Human V1 Response to Variations in Chromatic Direction and Contrast
Authors: Barnett Michael A. , Aguirre Geoffrey K. , Brainard David H. 
Published: December 2020

AbstractAn important goal for vision science is to develop quantitative models for the representation of visual signals at post-receptoral sites. To this end, we develop the quadratic color model (QCM) and examine its ability to account for the BOLD fMRI response in human V1 to spatially-uniform temporal chromatic modulations, systematically varying in their chromatic directions and contrasts. We find that the QCM explains the same, cross-validated variance as a conventional GLM, with far fewer free parameters. The QCM generalizes to allow prediction of V1 responses to a large range of modulations. We replicated the results for each subject and find good agreement across both replications and subjects. We find that within the LM cone contrast plane, V1 is most sensitive to L-M contrast modulations and least sensitive to L+M contrast modulations. Within V1, we observe little to no change in chromatic sensitivity as a function of eccentricity.
Leveraging Affinity Interactions to Prolong Drug Delivery of Protein Therapeutics
Authors: Dogan Alan , Dabkowski Katherine , von Recum Horst 
Published: December 2020

AbstractWhile peptide and protein therapeutics have made tremendous advances in clinical treatments over the past few decades, they have been largely hindered by their ability to be effectively delivered to patients. While bolus parenteral injections have become standard clinical practice, they are insufficient to treat diseases that require sustained, local release of therapeutics. Cyclodextrin-based polymers (pCD) have been utilized as a platform to extend the local delivery of small-molecule hydrophobic drugs by leveraging hydrophobic-driven thermodynamic interactions between pCD and payload to extend its release, which has seen success bothin vitroandin vivo.Herein, we proposed the novel synthesis of protein-polymer conjugates that are capped with a “high affinity” adamantane. Using bovine serum albumin as a model protein, and anti-interleukin 10 monoclonal antibodies as a functional example, we outline the synthesis of novel protein-polymer conjugates that, when coupled with cyclodextrin delivery platforms, can maintain a sustained release of up to 65 days without largely sacrificing protein structure/function which has significant clinical applications in local antibody-based treatments for immune diseases, cancers, and diabetes.Graphical Abstract
Magnetic Tweezers with Magnetic Flux Density Feedback Control
Authors: Moghram Waddah I. , Kruger Anton , Sander Edward A. , Selby John C. 
Published: December 2020

ABSTRACTIn this work, we present a single-pole magnetic tweezers (MT) device designed for integration with substrate deformation tracking microscopy (DTM) and/or traction force microscopy (TFM) experiments intended to explore extracellular matrix rheology and human epidermal keratinocyte mechanobiology. Assembled from commercially available off-the-shelf electronics hardware and software, the MT device is amenable to replication in the basic biology laboratory. In contrast to conventional solenoid current-controlled MT devices, operation of this instrument is based on real-time feedback control of the magnetic flux density emanating from the blunt end of the needle core using a cascade control scheme and a digital proportional-integral-derivative (PID) controller. Algorithms that compensate for an apparent spatially non-uniform remnant magnetization of the needle core that develops during actuation are implemented into the feedback control scheme. Through optimization of PID gain scheduling, the MT device exhibits magnetization and demagnetization response times of less than 100 ms without overshoot over a wide range of magnetic flux density setpoints. Compared to current-based control, magnetic flux density-based control allows for more accurate and precise magnetic actuation forces by compensating for temperature increases within the needle core due to heat generated by the applied solenoid currents. Near field calibrations validate the ability of the MT device to actuate 4.5 μm-diameter superparamagnetic beads with forces up to 25 nN with maximum relative uncertainties of ±30% for beads positioned between 2.5 and 40 μm from the needle tip.
Automated Machine Learning for High-Throughput Image-Based Plant Phenotyping
Authors: Koh Joshua C.O. , Spangenberg German , Kant Surya 
Published: December 2020

AbstractAutomated machine learning (AutoML) has been heralded as the next wave in artificial intelligence with its promise to deliver high performance end-to-end machine learning pipelines with minimal effort from the user. AutoML with neural architecture search which searches for the best neural network architectures in deep learning has delivered state-of-the-art performance in computer vision tasks such as image classification and object detection. Using wheat lodging assessment with UAV imagery as an example, we compared the performance of an open-source AutoML framework, AutoKeras in image classification and regression tasks to transfer learning using modern convolutional neural network (CNN) architectures pretrained on the ImageNet dataset. For image classification, transfer learning with Xception and DenseNet-201 achieved best classification accuracy of 93.2%, whereas Autokeras had 92.4% accuracy. For image regression, transfer learning with DenseNet-201 had the best performance (R2=0.8303, RMSE=9.55, MAE=7.03, MAPE=12.54%), followed closely by AutoKeras (R2=0.8273, RMSE=10.65, MAE=8.24, MAPE=13.87%). Interestingly, in both tasks, AutoKeras generated compact CNN models with up to 40-fold faster inference times compared to the pretrained CNNs. The merits and drawbacks of AutoML compared to transfer learning for image-based plant phenotyping are discussed.
De novomacrocyclic peptides for inhibiting, stabilising and probing the function of the Retromer endosomal trafficking complex
Authors: Chen Kai-En , Guo Qian , Cui Yi , Kendall Amy K. , Hill Timothy A. , Hall Ryan J. , Sacharz Joanna , Norwood Suzanne J. , Xie Boyang , Leneva Natalya , Yang Zhe , Ghai Rajesh , Stroud David A. , Fairlie David , Suga Hiroaki , Jackson Lauren P. , Teasdale Rohan D. , Passioura Toby , Collins Brett M. 
Published: December 2020

ABSTRACTThe Retromer complex (Vps35-Vps26-Vps29) is essential for endosomal membrane trafficking and signalling. Mutations in Retromer cause late-onset Parkinson’s disease, while viral and bacterial pathogens can hijack the complex during cellular infection. To modulate and probe its function we have created a novel series of macrocyclic peptides that bind Retromer with high affinity and specificity. Crystal structures show the majority of cyclic peptides bind to Vps29 via a Pro-Leu-containing sequence, structurally mimicking known interactors such as TBC1D5, and blocking their interaction with Retromerin vitroand in cells. By contrast, macrocyclic peptide RT-L4 binds Retromer at the Vps35-Vps26 interface and is a more effective molecular chaperone than reported small molecules, suggesting a new therapeutic avenue for targeting Retromer. Finally, tagged peptides can be used to probe the cellular localisation of Retromer and its functional interactions in cells, providing novel tools for studying Retromer function.
Modulation of motor cortex plasticity by repetitive paired-pulse TMS at late I-wave intervals is influenced by intracortical excitability
Authors: Opie George M , Sasaki Ryoki , Hand Brodie J , Semmler John G 
Published: December 2020

AbstractThe late indirect (I) waves recruited by transcranial magnetic stimulation (TMS) over primary motor cortex (M1) can be modulated using I-wave periodicity repetitive TMS (iTMS). The purpose of this study was to determine if the response to iTMS is influenced by different interstimulus intervals (ISIs) targeting late I-waves, and whether these responses were associated with individual variations in intracortical excitability. 17 young (27.2 ± 6.4 years, 12 females) healthy adults received iTMS at late I-wave intervals (4.0, 4.5 & 5.0 ms) in three separate sessions. Changes due to each intervention were examined with motor evoked potential (MEP) amplitudes and short-interval intracortical facilitation (SICF) using both posterior-anterior (PA) and anterior-posterior (AP) TMS current directions. Changes in MEP amplitude and SICF were influenced by iTMS ISI, with the greatest facilitation for ISIs at 4 and 5 ms with PA TMS, and 4 ms with AP TMS. Maximum SICF at baseline (irrespective of ISI) was associated with increased iTMS response, but only for PA stimulation. These results suggest that modifying iTMS parameters targeting late I-waves can influence M1 plasticity. They also suggest that maximum SICF may be a means by which responders to iTMS targeting the late I-waves could be identified.
SARS-CoV-2 Spike Protein Impairs Endothelial Function via Downregulation of ACE2
Authors: Lei Yuyang , Zhang Jiao , Schiavon Cara R. , He Ming , Chen Lili , Shen Hui , Zhang Yichi , Yin Qian , Cho Yoshitake , Andrade Leonardo , Shadel Gerry S. , Hepokoski Mark , Lei Ting , Wang Hongliang , Zhang Jin , Yuan Jason X.-J. , Malhotra Atul , Manor Uri , Wang Shengpeng , Yuan Zu-Yi , Shyy John Y-J. 
Published: December 2020

AbstractCoronavirus disease 2019 (COVID-19) includes the cardiovascular complications in addition to respiratory disease. SARS-CoV-2 infection impairs endothelial function and induces vascular inflammation, leading to endotheliitis. SARS-CoV-2 infection relies on the binding of Spike glycoprotein (S protein) to angiotensin converting enzyme 2 (ACE2) in the host cells. We show here that S protein alone can damage vascular endothelial cells (ECs) in vitro and in vivo, manifested by impaired mitochondrial function, decreased ACE2 expression and eNOS activity, and increased glycolysis. The underlying mechanism involves S protein downregulation of AMPK and upregulation of MDM2, causing ACE2 destabilization. Thus, the S protein-exerted vascular endothelial damage via ACE2 downregulation overrides the decreased virus infectivity.
Inhibition of the occipital face area modulates the electrophysiological signals of face familiarity positively: a combined cTBS-EEG study
Authors: Eick Charlotta Marina , Ambrus Géza Gergely , Kovács Gyula 
Published: December 2020

AbstractThe occipital face area (OFA) is hierarchically one of the first stages of the face processing network. It has originally been thought to be involved in early, structural processing steps, but currently more and more studies challenge this view and propose that it also takes part in higher face processing, such as identification and recognition. Here we tested whether the OFA is involved in the initial steps of recognition memory and plays a causal role in the differential processing of familiar and unfamiliar faces. We used an offline, inhibitory continuous theta-burst stimulation (cTBS) protocol over the right OFA and the vertex as control site. An electroencephalographic (EEG) recording of event-related potentials (ERPs), elicited by visually presented familiar (famous) and unfamiliar faces was performed before and after stimulation. We observed a difference in ERPs for famous and unfamiliar faces in a time-window corresponding to the N250 component. Importantly, this difference was significantly increased by cTBS of the right OFA, suggesting its causal role in the differential processing of familiar and unfamiliar faces. The enhancement occurred focally, at electrodes close to the right hemispheric cTBS site, as well as over similar occipito-temporal sites of the contralateral hemisphere. To the best of our knowledge, this is the first study showing the causal role of the rOFA in the differential processing of familiar and unfamiliar faces, using combined cTBS and EEG recording methods. These results are discussed with respect to the nature of familiar face representations, supported by an extensive, bilateral network.
First-described recently discovered non-toxic vegetal-derived furocoumarin preclinical efficacy against SARS-CoV-2: a promising antiviral herbal drug
Authors: Galindo-Cardiel Iván José , Núñez Adriana Toledo , Fernández María Celaya , Ramírez Labrada Ariel , Uranga-Murillo Iratxe , Cabrero Maykel Arias , Pardo Julian , Panzeri Ezio 
Published: December 2020

AbstractSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the aetiology of coronavirus disease 2019 (COVID19) pandemic. ICEP4 purified compound (ICEP4) is a recently discovered furocoumarin-related purified compound derived from the roots and seeds ofAngelica archangelica(herbal drug). ICEP4-related herbal preparations have been extensively used as active herbal ingredients in traditional medicine treatments in several European countries. Extraction method of patent pending ICEP4 (patent application no. GB2017123.7) has previously shown strong manufacturing robustness, long-lasting stability, and repeated chemical consistency. Here we show that ICEP4 presents a significantin vitrocytoprotective effect in highly virulent-SARS-CoV-2 challenged Vero E6 cellular cultures, using doses of 34.5 and 69 μM. No dose-related ICEP4 toxicity was observed in Vero E6 cells, M0 macrophages, B, CD4+ T and CD8+ T lymphocytes, Natural Killer (NK) or Natural Killer T (NKT) cells. No dose-related ICEP4 inflammatory response was observed in M0 macrophages quantified by IL6 and TNFα release in cell supernatant. No decrease in survival rate was observed after either 24 hr acute or 21-day chronic exposure inin vivotoxicity studies performed inC. elegans. Therefore, ICEP4 toxicological profile has demonstrated marked differences compared to others vegetal furocoumarins. Successful ICEP4 doses against SARS-CoV-2-challenged cells are within the maximum threshold of toxicity concern (TTC) of furocoumarins as herbal preparation, stated by European Medicines Agency (EMA). The characteristic chemical compounding of ICEP4, along with its safe TTC, allow us to assume that the first-observation of a natural antiviral compound has occurred. The potential druggability of a new synthetic ICEP4-related compound remains to be elucidated. However, well-established historical use of ICEP4-related compounds as herbal preparations may point towards an already-safe, widely extended remedy, which may be ready-to-go for large-scale clinical trials under the EMA emergency regulatory pathway. To the best of the authors’ knowledge, ICEP4-related herbal drug can be postulated as a promising therapeutic treatment for COVID19.
Recognition of Z-RNA by ADAR1 limits interferon responses
Authors: Tang Qiannan , Rigby Rachel E. , Young George R. , Korning-Hvidt Astrid , Tan Tiong Kit , Bridgeman Anne , Townsend Alain R. , Kassiotis George , Rehwinkel Jan 
Published: December 2020

AbstractNucleic acids are powerful triggers of innate immunity and can adopt the unusual Z-conformation. The p150 isoform of adenosine deaminase acting on RNA 1 (ADAR1) prevents aberrant interferon (IFN) induction and contains a Z-nucleic acid binding (Zα) domain. We report that knock-in mice bearing two point mutations in the Zαdomain of ADAR1, which abolish binding to Z-form nucleic acids, spontaneously induced type I IFNs and IFN-stimulated genes (ISGs) in multiple organs. This included the lung where both stromal and haematopoietic cells displayed ISG induction inAdar1mZα/mZαmice. Concomitantly,Adar1mZα/mZαmice showed improved control of influenza A virus. The spontaneous IFN response inAdar1mZα/mZαmice required MAVS, implicating cytosolic RNA sensing. Finally, analysis of A-to-I changes revealed a specific requirement of ADAR1’s Zαdomain in editing of a subset of RNAs. In summary, our results reveal that endogenous RNAs in Z-conformation have immunostimulatory potential that is curtailed by ADAR1.
Inhibition of phosphodiesterase - 10A by Papaverine protects human cortical neurons from quinolinic acid induced oxidative stress and synaptic proteins alterations
Authors: Bhat Abid , Tan Vanessa , Heng Benjamin , Essa Musthafa M. , Chidambaram Saravana B. , Guillemin Gilles J. 
Published: December 2020

AbstractPhosphodi esterase-10A (PDE10A) hydrolyse the secondary messengers cGMP and cAMP which play critical role in neurodevelopment and brain functions. PDE10A is linked to progression of neurodegenerative diseases like Alzheimer’s, Parkinson’s, Huntington’s diseases etc and a critical role in cognitive functions. The present study was undertaken to determine the possible neuroprotective effects and the associated mechanism of papaverine (PAP) against quinolinic acid (QUIN) induced excitotoxicity using human primary cortical neurons. Cytotoxicity potential of PAP was analysed using MTS assay. Reactive oxygen species (ROS) and mitochondrial membrane potential were measured by DCF-DA and JC10 staining, respectively. Caspase 3/7 and cAMP levels using ELISA kits. Effect of PAP on the CREB, BNDF and synaptic proteins such as SAP-97, synaptophysin, synapsin-I, PSD-95 expression was analysed by Western blotting technique. Pre-treatment with PAP increased intracellular cAMP and nicotinamide adenine dinucleotide (NAD+) levels, restored mitochondrial membrane potential (ΔΨm), and decreased ROS and caspase3/7 content in QUIN exposed neurons. PAP up-regulated CREB and BDNF, and synaptic proteins expression. In summary, these data indicate that PDE10A involves in QUIN mediated neurotoxicity and its inhibition can elicit neuroprotection by reducing the oxidative stress and protecting synaptic proteins via upregulation of cAMP signalling cascade.
Homeostatic Synaptic Scaling Establishes the Specificity of an Associative Memory
Authors: Wu Chi-Hong , Ramos Raul , Katz Donald B , Turrigiano Gina G 
Published: December 2020

AbstractAccurate memory formation has been hypothesized to depend on both rapid Hebbian plasticity for initial encoding, and slower homeostatic mechanisms that prevent runaway excitation and subsequent loss of memory specificity. Here, we tested the role of synaptic scaling in shaping the specificity of conditioned taste aversion (CTA) memory, a Hebbian plasticity-dependent form of associative learning. We found that CTA memory initially generalized to non-conditioned tastants (generalized aversion), becoming specific to the conditioned tastant only over the course of many hours. Blocking synaptic scaling in the gustatory cortex (GC) prolonged the duration of the initial generalized aversion and enhanced the persistence of synaptic strength increases observed after CTA. Taken together, these findings demonstrate that synaptic scaling is important for sculpting the specificity of an associative memory and suggest that the relative strengths of Hebbian and homeostatic plasticity can modulate the balance between stable memory formation and generalization.