bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bridging the translational neuroscience gap: Development of the ‘shiftability’ paradigm and an exemplar protocol to capture psilocybin-elicited ‘shift’ in neurobiological mechanisms in autism
Authors: Whelan Tobias P. , Daly Eileen , Puts Nicolaas A. , Malievskaia Ekaterina , Murphy Declan G.M. , McAlonan Grainne M. 
Published: May 2023

AbstractClinical trials of pharmacological approaches targeting the core features of autism have failed. This is despite evidence from preclinical studies, genetics, post-mortem studies and correlational analyses linking peripheral and central markers of multiple candidate neurochemical systems to brain function in autism. Whilst this has in part been explained by the heterogeneity of the autistic population, the field has largely relied upon association studies to link brain chemistry to function. The only way todirectlyestablish that a neurotransmitter or neuromodulator is involved in a candidate brain function is tochangeit and observe ashiftin that function. This experimental approach dominates preclinical neuroscience, but not human studies. There is very little direct experimental evidence describing how neurochemical systems modulate information processing in the living human brain. As a result, our understanding of how neurochemical differences contribute to neurodiversity is limited and impedes our ability to translate findings from animal studies into humans.Here, we begin by introducing our “shiftability” paradigm, an approach to bridge the translational gap in autism research. We then provide an overview of the methodologies used and explain our most recent choice of psilocybin as a pharmacological probe of the serotonin systemin vivo. Finally, we provide a summary of the protocol for ‘PSILAUT’, an exemplar “shiftability” study which uses psilocybin to directly test the hypothesis that the serotonin system functions differently in autistic and non-autistic adults.
In vivolong-term voltage imaging by genetically encoded voltage indicator reveals spatiotemporal dynamics of neuronal populations during development
Authors: Shiraishi Asuka , Hayashi Ayane , Fukuda Narumi , Hishinuma Mari , Miyazawa Hiroaki , Tsuda Sachiko 
Published: May 2023

AbstractA central question in brain development lies in how individual neurons emerge and organize communities to acquire various functions. Voltage imaging provides unique approaches to addressing this by enabling simultaneous, non-invasive, in vivo recording of voltage dynamics from a population of cells. Recently, genetically encoded voltage indicators (GEVIs) facilitate cell-type specific imaging of voltage dynamics. However, it has not been applied to brain development. Here, we applied ArcLight, a GEVI utilizing voltage-sensitive domain, to zebrafish and established experimental approaches for analyzing voltage and morphology of neuron populations during development, focusing on the spinal cord and cerebellum. We initially demonstrated that Arclight was widely distributed in the neural tissues. With voltage imaging, we successfully visualized the coordinated, spontaneous activity of spinal cord neurons in their early stage of development at a high spatiotemporal resolution, at subcellular and population levels. Hyperpolarization and subthreshold signals were also detected. Finally, long-term voltage imaging during development revealed the process of changes in voltage dynamics in neuron populations, accompanied by axonal outgrowth. Voltage imaging could greatly contribute to our understanding of the functional organization of the nervous system during development.
Ecological Inducers of the Yeast Filamentous Growth Pathway Reveal Environment-Dependent Roles for Pathway Components
Authors: Vandermeulen Matthew D. , Cullen Paul J. 
Published: May 2023

ABSTRACTSignaling modules, such as MAPK pathways, are evolutionarily conserved drivers of cell differentiation and stress responses. In many fungal species including pathogens, MAPK pathways control filamentous growth, where cells differentiate into an elongated cell type. The convenient model budding yeastSaccharomyces cerevisiaeundergoes filamentous growth by the filamentous growth (fMAPK) pathway; however, the inducers of the pathway remain unclear, perhaps because pathway activity has been mainly studied in laboratory conditions. To address this knowledge gap, an ecological framework was employed, which uncovered new fMAPK pathway inducers, including pectin, a material found in plants, and the metabolic byproduct ethanol. We also show that induction by a known inducer of the pathway, the non-preferred carbon source galactose, required galactose metabolism and induced the pathway differently than glucose limitation or other non-preferred carbon sources. By exploring fMAPK pathway function in fruit, we found induction of the pathway led to visible digestion of fruit rind through a known target,PGU1, which encodes a pectolytic enzyme. Different stimuli revealed different modes of pathway signaling. For example, combinations of inducers (galactose and ethanol) stimulated the pathway to near maximal levels, which showed dispensability of several fMAPK pathway components (e.g. mucin sensor, PAK), but not others (e.g. adaptor, MAPKKK) and required the Ras2-PKA pathway. This included a difference between the transcription factor binding partners for the pathway, as Tec1p, but not Ste12p, was partly dispensable for fMAPK pathway activity. Thus, by exploring ecologically-relevant stimuli, new modes of MAPK pathway signaling were uncovered, perhaps revealing how a pathway can respond differently to specific environments.Data Availability StatementAll data are in the manuscript and/or supporting information files.
Caenorhabditis elegansgerm granules are present in distinct configurations that differentially associate with RNAi-targeted RNAs
Authors: Uebel Celja J. , Rajeev Sanjana , Phillips Carolyn M. 
Published: May 2023

ABSTRACTRNA silencing pathways are complex, highly conserved, and perform widespread, critical regulatory roles. InC. elegansgermlines, RNA surveillance occurs through a series of perinuclear germ granule compartments—P granules, Z granules, SIMR foci, andMutatorfoci—multiple of which form via phase separation and exhibit liquid-like properties. The functions of individual proteins within germ granules are well-studied, but the spatial organization, physical interaction, and coordination of biomolecule exchange between compartments within germ granule “nuage” is less understood. Here we find that key proteins are sufficient for compartment separation, and that the boundary between compartments can be reestablished after perturbation. Using super-resolution microscopy, we discover a toroidal P granule morphology which encircles the other germ granule compartments in a consistent exterior-to-interior spatial organization. Combined with findings that nuclear pores primarily interact with P granules, this nuage compa rtment organization has broad implications for the trajectory of an RNA as it exits the nucleus and enters small RNA pathway compartments. Furthermore, we quantify the stoichiometric relationships between germ granule compartments and RNA to reveal discrete populations of nuage that differentially associate with RNAi-targeted transcripts, possibly suggesting functional differences between nuage configurations. Together, our work creates a more spatially and compositionally accurate model ofC. elegansnuage which informs the conceptualization of RNA silencing through different germ granule compartments.
Contrasting synaptic roles of MDGA1 and MDGA2
Authors: Bemben Michael A. , Sandoval Matthew , Le Aliza A. , Won Sehoon , Chau Vivian N. , Lauterborn Julie C. , Incontro Salvatore , Li Kathy H. , Burlingame Alma L. , Roche Katherine W. , Gall Christine M. , Nicoll Roger A. , Diaz-Alonso Javier 
Published: May 2023

AbstractNeurodevelopmental disorders are frequently linked to mutations in synaptic organizing molecules. MAM domain containing glycosylphosphatidylinositol anchor 1 and 2 (MDGA1 and MDGA2) are a family of synaptic organizers suggested to play an unusual role as synaptic repressors, but studies offer conflicting evidence for their localization. Using epitope-tagged MDGA1 and MDGA2 knock-in mice, we found that native MDGAs are expressed throughout the brain, peaking early in postnatal development. Surprisingly, endogenous MDGA1 was enriched at excitatory, but not inhibitory, synapses. Both shRNA knockdown and CRISPR/Cas9 knockout of MDGA1 resulted in cell-autonomous, specific impairment of AMPA receptor- mediated synaptic transmission, without affecting GABAergic transmission. Conversely, MDGA2 knockdown/knockout selectively depressed NMDA receptor-mediated transmission butenhancedinhibitory transmission. Our results establish that MDGA2 acts as a synaptic repressor, but only at inhibitory synapses, whereas both MDGAs are required for excitatory transmission. This nonoverlapping division of labor between two highly conserved synaptic proteins is unprecedented.TeaserMDGAs 1 and 2 independently localize to and modulate excitatory and inhibitory hippocampal synapses by different mechanisms.
Discovery of reactive peptide inhibitors of human papillomavirus oncoprotein E6
Authors: Ye Xiyun , Zhang Peiyuan , Tao Jason , Wang John C. K. , Mafi Amirhossein , Grob Nathalie M. , Quartararo Anthony J. , Baddock Hannah T. , Foe Ian , Loas Andrei , Eaton Dan L. , Hao Qi , Nile Aaron H. , Pentelute Bradley L. 
Published: May 2023

ABSTRACTHuman papillomavirus (HPV) infections account for nearly all cervical cancer cases, which is the fourth most common cancer in women worldwide. High-risk variants, including HPV16, drive tumorigenesis in part by promoting the degradation of the tumor suppressor p53. This degradation is mediated by the HPV early protein 6 (E6), which recruits the E3 ubiquitin ligase E6AP and redirects its activity towards ubiquitinating p53. Targeting the protein interaction interface between HPV E6 and E6AP is a promising modality to mitigate HPV-mediated degradation of p53. In this study, we designed a covalent peptide inhibitor, termed reactide, that mimics the E6AP LXXLL binding motif by selectively targeting cysteine 58 in HPV16 E6 with quantitative conversion. This reactide provides a starting point in the development of covalent peptidomimetic inhibitors for intervention against HPV-driven cancers.
Anterior chamber depth in mice is controlled by several quantitative trait loci
Authors: Larson Demelza R. , Kimber Allysa J. , Meyer Kacie J. , Anderson Michael G. 
Published: May 2023

ABSTRACTPURPOSEAnterior chamber depth (ACD) is a quantitative trait associated with primary angle closure glaucoma (PACG). Although ACD is highly heritable, known genetic variations explain a small fraction of the phenotypic variability. The purpose of this study was to identify additional ACD-influencing loci using strains of mice.METHODSCohorts of 86 N2 and 111 F2 mice were generated from crosses between recombinant inbred BXD24/TyJ and wild-derived CAST/EiJ mice. Using anterior chamber optical coherence tomography, mice were phenotyped at 10-12 weeks of age, genotyped based on 93 genome-wide SNPs, and subjected to quantitative trait locus (QTL) analysis.RESULTSIn an analysis of ACD among all mice, six loci passed the significance threshold ofp= 0.05 and persisted after multiple regression analysis. These were on chromosomes 6, 7, 11, 12, 15 and 17 (namedAcdq6,Acdq7,Acdq11,Acdq12,Acdq15, andAcdq17, respectively).CONCLUSIONSOur findings demonstrate a quantitative multi-genic pattern of ACD inheritance in mice and identify six previously unrecognized ACD-influencing loci. We have taken a unique approach to studying the anterior chamber depth phenotype by using mice as genetic tool to examine this continuously distributed trait.
Voltage dynamics of dendritic integration and back-propagationin vivo
Authors: Wong-Campos J. David , Park Pojeong , Davis Hunter , Qi Yitong , Tian He , Itkis Daniel G. , Kim Doyeon , Grimm Jonathan B. , Plutkis Sarah E. , Lavis Luke , Cohen Adam E. 
Published: May 2023

AbstractNeurons integrate synaptic inputs within their dendrites and produce spiking outputs, which then propagate down the axon and back into the dendrites where they contribute to plasticity. Mapping the voltage dynamics in dendritic arbors of live animals is crucial for understanding neuronal computation and plasticity rules. Here we combine patterned channelrhodopsin activation with dual-plane structured illumination voltage imaging, for simultaneous perturbation and monitoring of dendritic and somatic voltage in Layer 2/3 pyramidal neurons in anesthetized and awake mice. We examined the integration of synaptic inputs and compared the dynamics of optogenetically evoked, spontaneous, and sensory-evoked back-propagating action potentials (bAPs). Our measurements revealed a broadly shared membrane voltage throughout the dendritic arbor, and few signatures of electrical compartmentalization among synaptic inputs. However, we observed spike rate acceleration-dependent propagation of bAPs into distal dendrites. We propose that this dendritic filtering of bAPs may play a critical role in activity-dependent plasticity.
A Long COVID Risk Predictor Focused on Clinical Workflow Integration
Authors: Bhattacharya Biplab S. , Mitchell Elliot G. , Shetty Gaurav , Delong Grant , Munia Tamanna T. K. , Tariq Abdul A. 
Published: May 2023

AbstractFor the NIH Long COVID Computational Challenge (L3C) in the Fall of 2022, we developed a machine learning model to predict who is at high risk for developing Long COVID, optimized for clinical deployment. Our submission won second prize in the competition. We present lessons learned, with details on the features, model selection and performance, fairness analysis, limitations, and deployment implications.
Selenium supplementation and clinical outcomes: an umbrella review protocol
Authors: Mosanya Adaobi Uchenna , Umeh Ifeoma , Abdullahi Abba Khalid , Ukoha-Kalu Blessing Onyinye , Adibe Maxwell Ogochukwu , Sanmartin Grijalba Carmen 
Published: May 2023

AbstractBackgroundSelenium is a trace element essential for the normal functions of different human body systems and its deficiency has been associated with different disease states. In recent years, many systematic reviews of randomized clinical trials in humans have demonstrated various properties of selenium such as antioxidant, anti-inflammatory, increased immunity, blocking tumour invasion and metastasis in various pathological conditions. Therefore, there is need to summarize these recent findings in one single paper to facilitate the decision making of clinicians and policy makers regarding the inclusion of selenium supplementation in routine clinical practice, treatment guidelines and essential medicine list. This study would guide researchers towards future research and design of clinical trials.ObjectivesThe objective of this umbrella review is to assess the clinical outcomes of selenium supplementation in different disease states and to determine its therapeutic implications.Eligibility criteriaOnly systematic reviews of randomized clinical trials reporting clinical outcomes after the use of selenium alone as a supplement in the management of diseases will be included. While primary studies, systematic reviews that involved the administration of selenium in combination with other trace elements for the prevention or treatment of diseases will be excluded.MethodsThe following databases will be searched by three independent reviewers: MEDLINE, PUBMED, EMBASE, COCHRANE database of systematic reviews, CINAHL, JBI Evidence synthesis, EPISTEMONIKOS, SCOPUS, Web of Science and TRIP PRO. Unpublished reviews will be searched using ProQuest for dissertations and Theses, Canadian Agency for drugs and Technologies in Health (CADTH) database of Grey matters and GOOGLE scholar. Systematic reviews published in the last 10 years (2013 to 2023). There will be no language restriction. The services of a translator will be employed if studies in other languages were found. Selection of reviews and data extraction will be done by 3 independent reviewers. Summary of findings will be presented in tables accompanied by texts where necessary.Strengths and limitations of this studyThis is the first umbrella review on the use of selenium supplements for disease management. Secondly, the findings from this study would facilitate the decision making of clinicians and policy makers regarding the inclusion of selenium supplementation in routine clinical practice, treatment guidelines and essential medicine list. Nevertheless, a major limitation of this umbrella review would be a reduced scope of eligible studies because only systematic reviews/ or meta-analysis that included randomized clinical trials will be considered.
An intra-oral flavor discrimination task in freely moving mice
Authors: Shiotani Kazuki , Tanisumi Yuta , Osako Yuma , Murata Koshi , Hirokawa Junya , Sakurai Yoshio , Manabe Hiroyuki 
Published: May 2023

SummaryFlavor plays a critical role in the pleasure of food. Flavor research has mainly focused on human subjects and revealed that many brain regions are involved in flavor perception. However, animal models for elucidating the mechanisms of neural circuits are lacking. Herein, we demonstrate the use of a novel behavioral task in which mice are capable of flavor discrimination. When the olfactory pathways of the mice were blocked, they could not perform the task. However, behavioral accuracy was not affected when the gustatory pathway was blocked by benzocaine. These results indicate that the mice performed this discrimination task mainly based on the intraoral flavor. We conclude that this novel task can contribute to research on the neural mechanisms of flavor perception.
Deep Learning models for retinal cell classification
Authors: Kostałkowski Maciej , Kordecka Katarzyna , Płaczkiewicz Jagoda , Posłuszny Anna , Foik Andrzej 
Published: May 2023

AbstractData analysis is equally important as an experimental part of the scientist’s work. Therefore any reliable automatization would accelerate research. Histology is a good example, where scientists work with different cell types. The difficulty level can be severe while trying to distinguish cell types from one another. In this paper, we focus on the retina. The retina consists of eight basic cell types, creating a layered structure. Some types of cells overlap within the layer, and some differ significantly in size. Fast and thorough manual analysis of the cross-section is impossible. Even though Deep Learning models are applied in multiple domains, we observe little effort to automatize retinal analysis. Therefore, this research aims to create a model for classifying retinal cell types based on morphology in a cross-section of retinal cell images.In this study, we propose a classification Deep Learning model for retinal cell classification. We implemented two models, each tested in three different approaches: Small dataset, Extended dataset, and One cell type vs. All cell types. Although the problem presented to the trained model was simplified, a significant data imbalance was created from multiclass to binary classification, influencing the models’ performance. Both, Sequential and Transfer Learning models performed best with the Extended dataset. The Sequential model generated the best overall results. The obtained results allow us to place prepared models within the benchmark of published models.This paper proposes the first Deep Learning tool classifying retinal cell types based on a dataset prepared from publicly available images collated from multiple sources and images obtained in our laboratory. The multiclass approach with an extended dataset showed the best results. With more effort, the model could become an excellent analytical tool.
MDM2 acts as a timer reporting the length of mitosis
Authors: Fulcher Luke J. , Sobajima Tomoaki , Batley Caleb , Gibbs-Seymour Ian , Barr Francis A. 
Published: May 2023

AbstractDelays in mitosis trigger p53-dependent arrest in G1 of the following cell cycle, enabling cells to respond to changes that would otherwise promote chromosome instability and aneuploidy1–10. We find that MDM2, the p53 ubiquitin ligase, is a key component of the timer mechanism triggering G1 arrest in response to prolonged mitosis. This timer function arises because MDM2 has a short half-life and ongoing protein synthesis is therefore necessary to maintain its steady-state concentration. Due to the attenuation of protein synthesis in mitosis, the amount of MDM2 gradually falls during mitosis, but normally remains above a critical threshold for p53 regulation at the onset of G1. When mitosis is extended by prolonged spindle assembly checkpoint activation, the amount of MDM2 drops below this threshold, stabilising p53. Subsequent p53-dependent p21 accumulation in the following G1 then channels cells into a prolonged cell cycle arrest, whereas abrogation of the response in p53-deficient cells allows them to bypass this crucial defence mechanism.
Goat Discrimination of Emotional Valence in the Human Voice
Authors: Mason Marianne A. , Semple Stuart , Marshall Harry H. , McElligott Alan G. 
Published: May 2023

ABSTRACTReading another animal’s emotional state can enable receivers to anticipate their behavioural motivations, which is important in guiding interactions with that individual. For species living closely alongside humans, the emotional cues that people express can be almost as informative as those of conspecifics. Goats can discriminate differences in emotional valence present in another goat’s calls, and we investigated whether this ability extends to human speech. We presented goats with a habituation-dishabituation-rehabituation paradigm, where they experienced multiple playbacks of a familiar or unfamiliar human voice conveying a single emotional valence (e.g., angry; habituation phase), before the valence of the voice changed (e.g., happy; dishabituation phase) and then reversed again in-line with the habituation phase (e.g., angry; rehabituation phase). Over the habituation phase, goat behavioural responses decreased, showing evidence of having habituated to the playback stimuli presented. Following a change in emotional valence (dishabituation phase), although goats were overall less likely to respond, those that did looked for longer, suggesting they had perceived the shift in emotional content conveyed in human voice playbacks. We found no changes in physiological arousal (heart rate or heart rate variability) with shifts in playback valence. Goats, as a domesticated species, may have developed a sensitivity to our cues over their long association with humans, but the differences in individual behaviour towards the playback paradigm could highlight a role for learning and individual experience in particular on interspecific emotional communication.