bluuebunny/crossref_metadata_2025_split huggingface dataset:
Micromagnetic Stimulation (μMS) Dose-Response of the Rat Sciatic Nerve
Authors: Saha Renata , Sanger Zachary , Bloom Robert , Benally Onri J. , Wu Kai , Tonini Denis , Low Walter C. , Keirstead Susan A. , Netoff Theoden I. , Wang Jian-Ping 
Published: November 2022

AbstractObjectiveThe objective of this study was to investigate the effects of micromagnetic stimuli strength and frequency from theMagneticPen(MagPen) on the rat right sciatic nerve. The nerve’s response would be measured by recording muscle activity and movement of the right hind limb.ApproachThe MagPen was custom-built such that it can be held over the sciatic nerve in a stable manner. Rat leg muscle twitches were captured on video and movements were extracted using image processing algorithms. EMG recordings were also used to measure muscle activity.Main resultsThe MagPen prototype when driven by alternating current, generates time-varying magnetic field which as per Faraday’s Law of Electromagnetic Induction, induces an electric field for neuromodulation. The orientation dependent spatial contour maps for the induced electric field from the MagPen prototype has been numerically simulated. Furthermore, in thisin vivowork on μMS, a dose-response relationship has been reported by experimentally studying how the varying amplitude (Range: 25 mVp-pthrough 6 Vp-p) and frequency (Range: 100 Hz through 5 kHz) of the MagPen stimuli alters the hind limb movement. The primary highlight of this dose-response relationship is that at a higher frequency of the μMS stimuli, significantly smaller amplitudes can trigger hind limb muscle twitch. This frequency-dependent activation can be justified following directly from the Faraday’s Law as the magnitude of the induced electric field is directly proportional to frequency.SignificanceThis work reports that μMS can successfully activate the sciatic nerve in a dose-dependent manner. The MagPen probe, unlike electrodes, does not have a direct electrochemical interface with tissues rendering it much safer than an electrode. Magnetic fields create more precise activation than electrodes because they induce smaller volumes of activation. Finally, unique features of μMS such as orientation dependence, directionality and spatial selectivity have been demonstrated.
A preclinical model of THC edibles that produces high-dose cannabimimetic responses
Authors: English Anthony , Uittenbogaard Fleur , Torrens Alexa , Sarroza Dennis , Slaven Anna , Piomelli Danielle , Bruchas Michael R. , Stella Nephi , Land Benjamin B. 
Published: November 2022

AbstractNo preclinical experimental approach enables the study of voluntary oral consumption of high-concentration Δ9-tetrahydrocannabinol (THC) and its intoxicating effects, mainly owing to the aversive response of rodents to THC that limits intake. Here we developed a palatable THC formulation and an optimized access paradigm in mice to drive voluntary consumption. THC was formulated in chocolate gelatin (THC-E-gel). Adult male and female mice were allowedad libitumaccess for 1 and 2 h. Cannabimimetic responses (hypolocomotion, analgesia, and hypothermia) were measured following access. Levels of THC and its metabolites were measured in blood and brain tissue. Acute acoustic startle responses were measured to investigate THC-induced psychotomimetic behavior.When allowed access for 2 h to THC-E-gel on the second day of a three-day exposure paradigm, adult mice consumed up to ≈30 mg/kg over 2 h which resulted in robust cannabimimetic behavioral responses (hypolocomotion, analgesia and hypothermia). Consumption of the same gelatin decreased on the following 3rdday of exposure. Pharmacokinetic analysis show that THC-E-gel consumption led to parallel accumulation of THC and its psychoactive metabolite, 11-OH-THC, in brain, a profile that contrasts with the known rapid decline in brain 11-OH-THC levels following THC intraperitoneal (i.p.) injections. THC-E-gel consumption increased the acoustic startle response in males but not in females, demonstrating a sex-dependent effect of consumption. Thus, while voluntary consumption of THC-E-gel triggered equivalent cannabimimetic responses in male and female mice, it potentiated acoustic startle responses preferentially in males. We build a dose-prediction model that included cannabimimetic behavioral responses elicited byi.p.versus THC-E-gel to test the accuracy and generalizability of this experimental approach and found that it closely predicted the measured acoustic startle results in males and females. In summary, THC-E-gel offers a robust preclinical experimental approach to study cannabimimetic responses triggered by voluntary consumption in mice, including sex-dependent psychotomimetic responses.
More than just axons: A positive relationship between an intracellular isotropic diffusion signal and pubertal development in white matter regions in a massive adolescent cohort
Authors: Newman Benjamin T. , Patrie James T. , Druzgal T. Jason 
Published: November 2022

AbstractPuberty is a key event in adolescent development that involves significant, hormone-driven changes to many aspects of physiology including the brain. Understanding how the brain responds during this time period is important for evaluating neuronal developments that affect mental health throughout adolescence and the adult lifespan. This study examines diffusion MRI scans from the cross-sectional ABCD Study baseline cohort, a large multi-site study containing thousands of participants, to describe the relationship between pubertal development and brain microstructure. Using advanced, 3-tissue constrained spherical deconvolution methods, this study is able to describe multiple tissue compartments beyond only white matter (WM) axonal qualities. After controlling for age, sex, brain volume, subject handedness, scanning site, and sibling relationships, we observe a positive relationship between an isotropic, intracellular diffusion signal fraction and pubertal development across a majority of regions of interest (ROIs) in the WM skeleton. We also observe regional effects from an intracellular anisotropic signal fraction compartment and extracellular isotropic free water-like compartment in several ROIs. This work suggests that changes during pubertal development elicit a complex response from brain tissue that cannot be completely described by traditional methods focusing only on WM axonal properties. This work brings in vivo human neuroimaging studies more into line with work performed on animal models, which describe an interaction between increased myelination, neurogenesis, angiogenesis, and glial cell proliferation in response to pubertal hormones.
Effect of tRNA maturase depletion on the levels and stabilities of ribosome assembly cofactor mRNAs inBacillus subtilis
Authors: Trinquier Aude , Condon Ciarán , Braun Frédérique 
Published: November 2022

AbstractThe impact of translation on mRNA stability can be varied, ranging from a protective effect of ribosomes that shield mRNA from ribonucleases (RNases), to preferentially exposing sites of RNase cleavage. These effects can change depending on whether ribosomes are actively moving along the mRNA or whether they are stalled at particular sequences, structures or awaiting charged tRNAs. We recently observed that depletingB. subtiliscells of its tRNA maturation enzymes RNase P or RNase Z, led to altered mRNA levels of a number of assembly factors involved in the biogenesis of the 30S ribosomal subunit. Here, we extend this study to other assembly factor mRNAs and identify multiple transcriptional and translational layers of regulation of therimMoperon mRNA that occur in response to the depletion of functional tRNAs.ImportanceThe passage of ribosomes across individual mRNAs during translation can have different effects on their degradation, ranging from a protective effect by shielding from ribonucleases, to in some cases, making the mRNA more vulnerable to RNase action. We recently showed that some mRNAs coding for proteins involved in ribosome assembly were highly sensitive to the availability of functional tRNA. Using strains depleted for the major tRNA processing enzymes RNase P and RNase Z, we expanded this observation to a wider set of mRNAs, including some unrelated to ribosome biogenesis. We characterize the impact of tRNA maturase depletion on therimMoperon mRNA and show it is highly complex, with multiple levels of transcriptional and post-transcriptional effects coming into play.
CURATE.AI – AI-derived personalized tacrolimus dosing for pediatric liver transplant: A retrospective study
Authors: Tan Shi-Bei , Kumar Kirthika Senthil , Gan Tiffany Rui Xuan , Truong Anh T. L. , Tan Lester W. J. , Blasiak Agata , Mali Vidyadhar Padmakar , Aw Marion M. , Ho Dean 
Published: November 2022

AbstractTacrolimus is the cornerstone of immunosuppressive therapy after pediatric liver transplantation. However, reliance on the physician’s experience for dose titration, coupled with tacrolimus’s narrow therapeutic window and inter and intra-patient variability, often results in frequent under or over-dosing with detrimental patient outcomes. Existing predictive dose personalization models are not readily feasible for clinical implementation, as they require multiple measurements each day while the standard frequency is once daily. We developed CURATE.AI, a small-data artificial intelligence-derived platform, as a clinical decision support system to personalize doses using the patient’s own data obtained once a day. Retrospective dose personalization with CURATE.AI on 16 patients’ data demonstrated potential to enable patients to stay in the therapeutic range longer and reach the therapeutic range significantly earlier. Our findings support the testing of CURATE.AI in a prospective controlled trial as an aid for the physician’s decision on tacrolimus dose personalization after pediatric liver transplantation.
Inhibition of MLKL impairs abdominal aortic aneurysm development by attenuating smooth muscle cell necroptosis
Authors: Nemade Harshal N , Mehrkens Dennis , Lottermoser Hannah Sophia , Yilmaz Zeynep Ece , Schelemei Patrick , Picard Felix Ruben , Geißen Simon , Schwab Gülsah Fülgen , Hoyer Friedrich Felix , Guthoff Henning , Hof Alexander , Nettersheim Felix Sebastian , Sachinidis Agapios , Winkels Holger , Baldus Stefan , Pasparakis Manolis , Adam Matti , Mollenhauer Martin 
Published: November 2022

AbstractBackgroundReceptor-interacting serine/threonine-protein kinase 1 and 3 (RIPK1 and RIPK3) dependent cell death has been identified as a crucial mediator of abdominal aortic aneurysm (AAA) development. RIPK3 mediates phosphorylation of Mixed lineage kinase domain like pseudokinase (MLKL) thereby inducing its oligomerization and translocation to the cell membrane. Given the dual role of RIPKs being involved in necroptosis as well as in apoptosis induction, the specific role of MLKL-induced necroptotic cell death in AAA remains unclear.MethodsWe monitored elastase-perfusion (PPE) induced progression of AAA in C57BL/6N (WT), RIPK1 kinase-inactive (Ripk1D138N/D138N), MLKL knockout (Mlkl−/−) and MLKL phospho-deficient (MlklAA) mice by ultrasound measurements, histological analyses and bulk mRNA sequencing to assess structural and molecular aortic changes. Bone marrow transplantations in WT andMlklAAmice were utilized to dissect the role of MLKL in smooth muscle cells (SMCs) and myeloid cells in AAA development. MLKL expressing human SMCs were generated to investigate necroptosis-induced proinflammatory cytokine secretion and subsequent polymorphonuclear neutrophil (PMN) migration and activation in vitro.ResultsUltrasound analysis showed that ~70% of the WT animals developed PPE induced-AAA with significant aortic structural alterations and enhanced myeloid cell infiltration. In contrast,Ripk1D138N/D138N,MlklAA, andMlkl−/−mice were protected from AAA. This protection was associated with reduced adverse extracellular matrix (ECM) remodeling and leukocyte infiltration. MLKL deficiency was associated with a significant downregulation of genes involved in fibrinolysis, anti-inflammatory response, immune response and complement activation in aortic tissue in AAA. Bone marrow transplantation studies showed the lack of MLKL in SMCs to be the main driver of AAA protection. Proinflammatory cytokine secretion was elevated in necroptosis induced SMCs and resulted in a significant accumulation and activation of PMN.ConclusionsOverall, these findings indicate that MLKL-induced necroptotic SMC death and subsequent proinflammatory leukocyte activation play a causative role in AAA development and suggest that pharmacological inhibition of MLKL may represent a promising treatment strategy for AAA disease.
METTL17 is an Fe-S cluster checkpoint for mitochondrial translation
Authors: Ast Tslil , Itoh Yuzuru , Sadre Shayan , McCoy Jason G. , Namkoong Gil , Chicherin Ivan , Joshi Pallavi R. , Kamenski Piotr , Suess Daniel L. M. , Amunts Alexey , Mootha Vamsi K. 
Published: November 2022

AbstractFriedreich’s ataxia (FA) is the most common monogenic mitochondrial disease. FA is caused by a depletion of the mitochondrial protein frataxin (FXN), an iron-sulfur (Fe-S) cluster biogenesis factor. To better understand the cellular consequences of FA, we performed quantitative proteome profiling of human cells depleted for FXN. Nearly every known Fe-S cluster-containing protein was depleted in the absence of FXN, indicating that as a rule, cluster binding confers stability to Fe-S proteins. Proteomic and genetic interaction mapping identified impaired mitochondrial translation downstream of FXN loss, and specifically highlighted the methyltransferase-like protein METTL17 as a candidate effector. Using comparative sequence analysis, mutagenesis, biochemistry and cryogenic electron microscopy we show that METTL17 binds to the mitoribosomal small subunit during late assembly and harbors a previously unrecognized [Fe4S4]2+cluster required for its stability on the mitoribosome. Notably, METTL17 overexpression rescued the mitochondrial translation and bioenergetic defects, but not the cellular growth, of FXN null cells. Our data suggest that METTL17 serves as an Fe-S cluster checkpoint: promoting the translation and assembly of Fe-S cluster rich OXPHOS proteins only when Fe-S cluster levels are replete.
Integration of optic flow into the sky compass network in the brain of the desert locust
Authors: Zittrell Frederick , Pabst Kathrin , Carlomagno Elena , Rosner Ronny , Pegel Uta , Endres Dominik M. , Homberg Uwe 
Published: November 2022

ABSTRACTFlexible orientation through any environment requires a sense of current relative heading that is updated based on self-motion. Global external cues originating from the sky or the earth’s magnetic field and local cues provide a reference frame for the sense of direction. Locally, optic flow may inform about turning maneuvers, travel speed and covered distance. The central complex in the insect brain is associated with orientation behavior and largely acts as a navigation center. Visual information from global celestial cues and local landmarks are integrated in the central complex to form an internal representation of current heading. However, it is largely unclear which neurons integrate optic flow in the central-complex network. We recorded intracellularly from neurons in the locust central complex while presenting lateral grating patterns that simulated translational and rotational motion to identify these sites of integration. Certain types of central-complex neurons were sensitive to visual self-motion independent of the type and direction of simulated motion. Columnar neurons innervating the noduli, paired central-complex substructures, were tuned to the direction of simulated horizontal turns. Modelling the connectivity of these neurons with a system of proposed compass neurons can account for rotation-direction specific shifts in the activity profile in the central complex corresponding to turn direction. Our model is similar but not identical to the mechanisms proposed for angular velocity integration in the navigation compass of the flyDrosophila.
Multiplexed selectivity screening of anti-GPCR antibodies
Authors: Dahl Leo , Kotliar Ilana B. , Bendes Annika , Dodig-Crnković Tea , Fromm Samuel , Elofsson Arne , Uhlén Mathias , Sakmar Thomas P. , Schwenk Jochen M. 
Published: November 2022

ABSTRACTG protein-coupled receptors (GPCRs) control critical cellular signaling pathways. Therapeutic agents, such as antibodies (Abs), are being developed to modulate GPCR signaling pathways. However, validating the selectivity of anti-GPCR Abs is challenging due to sequence similarities of individual receptors within GPCR subfamilies. To address this, we developed a multiplexed immunoassay to test >400 anti-GPCR Abs from the Human Protein Atlas targeting a customized library of 215 expressed and solubilized GPCRs representing all GPCR subfamilies. We found that ~61% of Abs were selective for their intended target, ~11% to bind off-target, and ~28% not to bind any GPCR. Antigens of on-target Abs were, on average, significantly longer, more disordered, and less likely to be buried in the interior of the GPCR protein than the other Abs. These results provide important insights into the immunogenicity of GPCR epitopes and form a basis for the design of therapeutic Abs and the detection of pathological auto-antibodies.TEASERA multiplexed library-to-library selectivity analysis of 400 anti-GPCR antibodies within subfamilies of 200 solubilized receptors.
3DProtDTA: the deep learning model for drug-target affinity prediction based on the residue-level protein graphs
Authors: Voitsitskyi Taras , Stratiichuk Roman , Koleiev Ihor , Popryho Leonid , Ostrovsky Zakhar , Henitsoi Pavel , Khropachev Ivan , Vozniak Volodymyr , Zhytar Roman , Nechepurenko Diana , Yesylevskyy Semen , Nafiev Alan , Starosyla Serhii 
Published: November 2022

AbstractAccurate prediction of the drug-target affinity (DTA)in silicois of critical importance for modern drug discovery. Computational methods of DTA prediction, applied in the early stages of drug development, are able to speed it up and cut its cost significantly. A wide range of approaches based on machine learning was recently proposed for DTA assessment. The most promising of them are based on deep learning techniques and graph neural networks to encode molecular structures. The recent breakthrough in protein structure prediction made by AlphaFold made an unprecedented amount of proteins without experimentally defined structures accessible for computational DTA prediction. In this work, we propose a new deep learning DTA model 3DProtDTA, which utilises AlphaFold structure predictions in conjunction with the graph representation of proteins. The model is superior to its rivals on common benchmarking datasets and has a potential for further improvement.
SCALA: A web application for multimodal analysis of single cell next generation sequencing data
Authors: Tzaferis Christos , Karatzas Evangelos , Baltoumas Fotis A. , Pavlopoulos Georgios A. , Kollias George , Konstantopoulos Dimitris 
Published: November 2022

ABSTRACTAnalysis and interpretation of high-throughput transcriptional and chromatin accessibility data at single cell resolution are still open challenges in the biomedical field. In this article, we present SCALA, a bioinformatics tool for analysis and visualization of single cell RNA sequencing (scRNA-seq) and Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) datasets. SCALA combines standard types of analysis by integrating multiple software packages varying from quality control to identification of distinct cell population and cell states. Additional analysis options enable functional enrichment, cellular trajectory inference, ligand-receptor analysis and regulatory network reconstruction. SCALA is fully parameterizable at every step of the analysis, presenting data in tabular format and produces publication-ready 2D and 3D visualizations including heatmaps, barcharts, scatter, violin and volcano plots. We demonstrate the functionality of SCALA through two use-cases related to TNF-driven arthritic mice, handling data from both scRNA-seq and scATAC-seq experiments. SCALA is mainly developed in R, Shiny and JavaScript and is available as a web application athttp://scala.pavlopouloslab.infoorhttps://scala.fleming.gr.
Mechanical wounding impacts the growth versus defence balance in tomato (Solanum lycopersicum)
Authors: Aparecida Cunha Ana Flavia , Duarte Rodrigues Pedro Henrique , Anghinoni Ana Clara , de Paiva Vinicius Juliani , da Silva Pinheiro Daniel Gonçalves , Campos Marcelo Lattarulo 
Published: November 2022

AbstractPlants have evolved elaborate surveillance systems that allow them to perceive the attack by pests and pathogens and activate the appropriate defences. Mechanical stimulation, such as mechanical wounding, represents one of the most reliable cues for the perception of potential herbivore aggressors. Here we demonstrate that mechanical wounding disturbs the growth versus defence balance in tomato, a physiological condition where growth reduction arises as a pleiotropic consequence of the activation of defence responses (or vice-versa). We observed that consecutive lesions on tomato leaves impairs the formation of several growth-related traits, including shoot elongation, leaf expansion and time for flowering set, while concomitantly activating the production of defence responses such as trichome formation and the upregulation of defence-related genes. We also provide genetic evidence that this wound-induced growth repression is a consequence of tomato plants sensing the injuries via jasmonates (JAs), a class of plant hormones known to be master regulators of the plant growth versus defence balance. Besides providing a mechanistic explanation on how the growth and defence balance is shifted when plants are subjected to a specific type of mechanical stimulus, our results may offer a practical explanation for why tomato productivity is so negatively impacted by herbivore attack.HighlightAntagonism between growth and defence responses was observed in tomato plants subject to mechanical wounding, a treatment that hinders development while promoting the activation of anti-herbivore traits.
A meta-analysis of operational interactions between pinnipeds and fisheries
Authors: Jackson J , Arlidge W , Oyanedel R , Davis KJ 
Published: November 2022

AbstractThe global recovery of pinniped populations is a conservation success. However, pinniped population recovery has increased human-wildlife conflict with fisheries, an issue often reported and requiring management, but one that lacks global synthesis. We conduct a meta-analysis to estimate the impacts of operational interactions (specifically, lost catch) between pinnipeds and fisheries. Where quantifiable interactions are reported (n = 36), on average fishers have a 33.7% chance of interacting with pinnipeds on any given fishing day, and 13.8% lost catch. We find a large degree of heterogeneity between studies, with some fisheries experiencing much more negative interactions than others. Specifically, smaller-scale fisheries using nets are up to twice as likely to have negative interactions and lose up to five times more catch compared to large-scale fisheries. We conclude that pinniped-fishery conflict is a substantial global issue, but its impacts are not uniform. To successfully manage long-term coexistence between pinnipeds and humans, explicit data quantifying operational interactions is required. Population recoveries can have unintended consequences for fisheries, and management of ecological, social and economic outcomes is needed for long-term coexistence.TeaserPinniped population recoveries have led to significant impacts on fisheries, but small-scale fisheries lose out most.