bluuebunny/crossref_metadata_2025_split huggingface dataset:
Single neuron contributions to the auditory brainstem EEG
Authors: Kuokkanen Paula T. , Kraemer Ira , Koeppl Christine , Carr Catherine E. , Kempter Richard 
Published: May 2024

AbstractThe auditory brainstem response (ABR) is an acoustically evoked EEG potential that is an important diagnostic tool for hearing loss, especially in newborns. The ABR originates from the response sequence of auditory nerve and brainstem nuclei, and a click-evoked ABR typically shows three positive peaks (‘waves’) within the first six milliseconds. However, an assignment of the waves of the ABR to specific sources is difficult, and a quantification of contributions to the ABR waves is not available. Here, we exploit the large size and physical separation of the barn owl first-order cochlear nucleus magnocellularis (NM) to estimate single-cell contributions to the ABR. We simultaneously recorded NM neurons’ spikes and the EEG, and found that ≥ 5, 000 spontaneous single-cell spikes are necessary to isolate a significant spike-triggered average response at the EEG electrode. An average single-neuron contribution to the ABR was predicted by convolving the spike-triggered average with the cell’s peri-stimulus time histogram. Amplitudes of predicted contributions of single NM cells typically reached 32.9 ± 1.1 nV (mean ± SE, range: 2.5 − 162.7 nV), or 0.07 ± 0.02% (median ± SE; range from 0.01% to 1%) of the ABR amplitude. The time of the predicted peak coincided best with the peak of the ABR wave II, independent of the click sound level. Our results suggest that individual neurons’ contributions to an EEG can vary widely, and that wave II of the ABR is shaped by NM units.Significance statementThe auditory brainstem response (ABR) is a scalp potential used for the diagnosis of hearing loss, both clinically and in research. We investigated the contribution of single action potentials from auditory brainstem neurons to the ABR and provide direct evidence that action potentials recorded in a first order auditory nucleus, and their EEG contribution, coincide with wave II of the ABR. The study also shows that the contribution of single cells varies strongly across the population.
Excitation/Inhibition imbalance increases the proneness to experience the sound-induced flash illusion by impairing multisensory causal inference in the schizophrenia spectrum
Authors: Paredes Renato , Ferri Francesca , Romei Vincenzo , Seriès Peggy 
Published: May 2024

AbstractBackground and HypothesisThe spectrum of schizophrenia is characterised by an altered sense of self with known impairments in tactile sensitivity, proprioception, body-self boundaries, and self-recognition. These are thought to be produced by failures in multisensory integration mechanisms, commonly observed as enlarged temporal binding windows during audiovisual illusion tasks. To our knowledge, there is an absence of computational explanations for multisensory integration deficits in patients with schizophrenia and individuals with high schizotypy, particularly at the neurobiological level.Study DesignWe implemented a multisensory causal inference network to reproduce the responses of individuals who scored low in schizotypy in a simulated double flash illusion task. Next, we explored the effects of Excitation/Inhibition imbalance, feedback weights, and synaptic density on the visual illusory responses of the network.Study ResultsUsing quantitative fitting to empirical data, we found that an increase in recurrent excitation or cross-modal connectivity in the network enlarges the temporal binding window and increases the overall proneness to experience the illusion, matching the responses of individuals scoring high in schizotypy. Moreover, we found that an increase in the E/I balance by either neural mechanism increases the probability of inferring a common cause from the stimuli.ConclusionsWe propose an E/I imbalance account of reduced temporal discrimination in the SCZ spectrum and discuss possible links with Bayesian theories of schizophrenia. We highlight the importance of adopting a multisensory causal inference perspective to address body-related symptomatology of schizophrenia.
Feasibility and acceptability for LION, a fully remote, randomized clinical trial within the VA for light therapy to improve sleep in Veterans with and without TBI: An MTBI2sponsored protocol
Authors: Elliott Jonathan E. , Brewer Jessica S. , Keil Allison T. , Ligman Brittany R. , Bryant-Ekstrand Mohini D. , McBride Alisha A. , Powers Katherine , Sicard Savanah J. , Twamley Elizabeth W. , O’Neil Maya E. , Hildebrand Andrea D. , Nguyen Thuan , Morasco Benjamin J. , Gill Jessica M. , Dengler Bradley A. , Lim Miranda M. 
Published: May 2024

ABSTRACTSleep-wake disturbances frequently present in Veterans with mild traumatic brain injury (mTBI). These TBI-related sleep impairments confer significant burden and commonly exacerbate other functional impairments. Therapies to improve sleep following mTBI are limited and studies in Veterans are even more scarce. In our previous pilot work, morning bright light therapy (MBLT) was found to be a feasible behavioral sleep intervention in Veterans with a history of mTBI; however, this was single-arm, open-label, and non-randomized, and therefore was not intended to establish efficacy. The present study, LION (light vs ion therapy) extends this preliminary work as a fully powered, sham-controlled, participant-masked randomized controlled trial (NCT03968874), implemented as fully remote within the VA (target n=120 complete). Randomization at 2:1 allocation ratio to: 1) active: MBLT (n=80), and 2) sham: deactivated negative ion generator (n=40); each with identical engagement parameters (60-min duration; within 2-hrs of waking; daily over 28-day duration). Participant masking via deception balanced expectancy assumptions across arms. Outcome measures were assessed following a 14-day baseline (pre-intervention), following 28-days of device engagement (post-intervention), and 28-days after the post-intervention assessment (follow-up). Primary outcomes were sleep measures, including continuous wrist-based actigraphy, self-report, and daily sleep dairy entries. Secondary/exploratory outcomes included cognition, mood, quality of life, circadian rhythm via dim light melatonin onset, and biofluid-based biomarkers. Participant drop out occurred in <10% of those enrolled, incomplete/missing data was present in <15% of key outcome variables, and overall fidelity adherence to the intervention was >85%, collectively establishing feasibility and acceptability for MBLT in Veterans with mTBI.
Prostad: The development and evaluation of a prostate cancer rapid diagnostic pathway, a protocol
Authors: Jones Katie , Rees Sarah , Farrington Steven , Chandran Arya , Moosa Sohail , MacKrell Janet , Shanbhag Savita , Ng Yeung , Sewell Berni , Jones Mari , Erdem Esra , Fitzsimmons Deborah , Rich Nick , Rance Jaynie , Gemine Rachel 
Published: May 2024

AbstractBackgroundDelay to cancer diagnosis is associated with poorer outcomes. In response to delays to cancer diagnosis in the UK, a number of Rapid Diagnosis Centres (RDCs), Multi-Disciplinary Centres (MDCs) and other pathway reforms have been piloted and implemented in recent years. Prostate cancer is the most commonly diagnosed cancer for men or those assigned male at birth in the UK. In Wales, the recommended time to diagnosis is within 62 days from point of suspicion. For patients served by Hywel Dda University Health Board, current waiting times on the prostate cancer diagnostic pathway are prolonged, falling well outside the 28-day decision to treat and 62-day referral to treatment targets. A revised prostate cancer diagnostic pathway called Prostad (Wesh for “prostate”) has been developed and is currently being implemented with the aim of reducing time to diagnosis (or discharge) for patients referred for investigation. This protocol describes Prostad and the planned evaluation approach.MethodsThis is a mixed-method evaluation. It is shaped by patient and public involvement throughout and incorporates realist interviews with multiple stakeholders (including NHS staff and patients), process mapping, economic evaluation, and monitoring of the intervention against its aims using routinely collected data.DiscussionTo the authors’ knowledge, this is the first project of its kind to combine service aims evaluation, cost-effectiveness analysis and realist evaluation approaches, and as such promises findings applicable to organisations and individuals with regard to various aims and priorities. Continued patient and public involvement throughout the study constitutes one of its strengths.
An intra-family conserved high-order RNA structure within the M ORF is important for arterivirus subgenomic RNA accumulation and infectious virus production
Authors: Shang Pengcheng , Li Yanhua , Chen Chi , Brierley Ian , Firth Andrew E. , Fang Ying 
Published: May 2024

ABSTRACTSynthesis of subgenomic RNAs is a strategy commonly used by polycistronic positive sense single-stranded RNA viruses to express 3′-proximal genes. Members of the order ofNidovirales, including coronaviruses and arteriviruses, use a unique discontinuous transcription strategy to synthesize subgenomic RNAs. In this study,in silicosynonymous site conservation analysis and RNA structure folding predicted the existence of intra-family conserved high-order RNA structure within the M ORF of arteriviral genomes, which was further determined to be important for the transcription/accumulation of subgenomic RNAs and production of infectious viral particles. Mutations disrupting the stability of the RNA structures significantly decreased the accumulation of multiple subgenomic RNAs. In contrast, the impact of mutagenesis on full-length genomic RNA accumulation was limited. The degree to which wild-type levels of subgenomic RNA accumulation were maintained was found to correlate with the efficiency of infectious virus production. Moreover, the thermo-stability of stems within the high-order RNA structure is also well correlated with viral replication capacity and the maintenance of subgenomic RNA accumulation. This study is the first to report an intra-Arteriviridaeconserved high-order RNA structure that is located in a protein-coding region and functions as an importantcis-acting element to control the accumulation/transcription of arteriviral subgenomic RNAs. This work suggests a complex regulation mechanism between genome replication and discontinuous transcription in nidoviruses.IMPORTANCEArteriviruses are a group of RNA viruses that infect different animal species. They can cause diseases associated with respiratory/reproductive syndromes, abortion, or haemorrhagic fever. Among arteriviruses, porcine reproductive and respiratory syndrome virus (PRRSV) and equine arteritis virus (EAV) are economically important veterinary pathogens. The challenge in control of arterivirus infection reflects our limited knowledge of viral biology. In this study, we conducted a comprehensive bioinformatical analysis of arteriviral genomes and discovered intra-family conserved regions in the M ORF with a high-order RNA structure. The thermo-stability of the RNA structure influences sgRNA transcription/accumulation and correlates with the level of infectious virus production. Our studies provide a new insight on arterivirus replication mechanism, which may have implications in developing disease control and prevention strategies.
Catalytically inactive subgroup VIII receptor-like cytoplasmic kinases regulate the immune-triggered oxidative burst inArabidopsis thaliana
Authors: Dias Márcia Gonçalves , Dharmasena Thakshila , Gonzalez-Ferrer Carmen , Maika Jan Eric , Gallo Maria Camila Rodriguez , Miguel Virginia Natali , Dou Ruoqi , Bredow Melissa , Siegel Kristen R , Uhrig Richard Glen , Simon Rüdiger , Monaghan Jacqueline 
Published: May 2024

AbstractProtein kinases are key components of multiple cell signaling pathways. Several protein kinases of the receptor-like cytoplasmic kinase (RLCK) family have demonstrated roles in immune and developmental signaling across various plant species, making them a family of interest in the study of phosphorylation-based signal relay. Here, we present our investigation of a subfamily of RLCKs inArabidopsis thaliana. Specifically, we focus on subgroup VIII RLCKs: MAZ and its paralog CARK6, as well as CARK7 and its paralog CARK9. We found that both MAZ and CARK7 associate with the calcium-dependent protein kinase CPK28in planta,and furthermore that CPK28 phosphorylates both MAZ and CARK7 on multiple residues in areas that are known to be critical for protein kinase activation. Genetic analysis suggests redundant roles for MAZ and CARK6 as negative regulators of the immune-triggered oxidative burst. We find evidence that supports homo– and hetero-dimerization between CARK7 and MAZ, which may be a general feature of this protein family. Multiple biochemical experiments suggest that neither MAZ nor CARK7 demonstrate catalytic protein kinase activityin vitro.Interestingly, we find that a mutant variant of MAZ incapable of protein kinase activity is able to complementmaz-1mutants, suggesting noncatalytic roles of MAZin planta. Overall, our study identifies subgroup VIII RLCKs as new players in Arabidopsis immune signaling and highlights the importance of noncatalytic functions of protein kinases.
Cerebellar tonic inhibition orchestrates the maturation of information processing and motor coordination
Authors: Kwon Jea , Kim Sunpil , Woo Junsung , De Schutter Erik , Hong Sungho , Lee C. Justin 
Published: May 2024

AbstractTonic inhibition in cerebellar granule cells (GC) is crucial in information coding fidelity for motor coordination. It emerges in activity-dependent and -independent manners, and their interplay evolves with age. However, specific molecular and cellular mechanisms and how their change affects network-level computation and motor behavior remain unclear. Here we show that, while net tonic inhibitory current remains unchanged, the main source of tonic GABA switches from synaptic spillover (neuronal activity-dependent) to astrocytic Best1 (activity-independent) throughout adolescence (4-8 weeks) in mice. Computational modeling based on experimental data demonstrated that this switch down-regulates the internally generated network activity mediating mutual inhibition between GC clusters receiving different inputs, thereby enhancing their independence. Consistent with simulations, 3D-posture analysis revealed an age-dependent increase in independent limb movements during spontaneous motion, which was impaired in Best1 knockout mice. Our findings highlight the late-stage development of complex motor coordination driven by the emergence of astrocyte-mediated tonic inhibition.
Spatial selective auditory attention is preserved in older age but is degraded by peripheral hearing loss
Authors: Caso Andrea , Griffiths Timothy D , Holmes Emma 
Published: May 2024

AbstractInterest in how ageing affects attention is long-standing, although interactions between sensory and attentional processing in older age have not been systematically studied. Here, we examined interactions between peripheral hearing and selective attention in a spatialised cocktail party listening paradigm, in which three talkers spoke different sentences simultaneously and participants were asked to report the sentence spoken by a talker at a particular location. By comparing a sample of older (N = 61; age = 55– 80 years) and younger (N = 58; age = 18–35 years) adults, we show that, as a group, older adults benefit as much as younger adults from preparatory spatial attention. Although, for older adults, this benefit significantly reduces with greater age-related hearing loss. These results demonstrate that older adults without hearing loss retain the ability to direct spatial selective attention, but this ability deteriorates with age-related hearing loss. Thus, reductions in spatial selective attention likely contribute to difficulties communicating in social settings for older adults with age-related hearing loss. Overall, these findings demonstrate a relationship between mild perceptual decline and attention in older age.
Distinct ventral tegmental area neuronal ensembles are indispensable for reward-driven approach and stress-driven avoidance behaviors
Authors: Koutlas Ioannis , Patrikiou Lefkothea , van der Starre Stef E. , Danko Diaz , Wolterink-Donselaar Inge G. , Luijendijk Mieneke C. M. , Adan Roger A.H. , Meye Frank J. 
Published: May 2024

AbstractAssigning valence to stimuli for adaptive behavior is an essential function, involving the ventral tegmental area (VTA). VTA cell types are often defined through neurotransmitters (NT). However, valence function in VTA does not parse along NT-boundaries as, within each NT-class, certain neurons are excited by reward and others by stressors. Here we identify the co-activated mouse VTA neuronal ensembles for reward and stress, and determine their role in adaptive behaviors. We show that stimuli of opposite valence (opioid vs acute social stress) recruit two segregated intermingled small VTA neuronal ensembles. These two ensembles continue to be preferentially engaged by congruent valence stimuli. Stimulation of VTA stress- or reward ensembles is aversive/reinforcing, respectively. Strikingly, external valence stimuli fully require activity of these small discrete VTA ensembles for conferring approach/avoidance outcomes. Overall, our study identifies distinct small VTA ensembles for positive and negative valence coding and shows their indispensability for adaptive behavior.
Predicting Suicide Risk in Bipolar Disorder patients from Lymphoblastoid Cell Lines genetic signatures
Authors: Sharma Omveer , Nayak Ritu , Mizrahi Liron , Rike Wote Amelo , Choudhary Ashwani , Hussein Yara , Rosh Idan , Tripathi Utkarsh , Shemen Aviram , Squassina Alessio , Alda Martin , Stern Shani 
Published: May 2024

AbstractThis research investigates the genetic signatures associated with a high risk of suicide in Bipolar disorder (BD) patients through RNA sequencing analysis of lymphoblastoid cell lines (LCLs). By identifying differentially expressed genes (DEGs) and their enrichment in pathways and disease associations, we uncover insights into the molecular mechanisms underlying suicidal behavior. LCL gene expression analysis reveals significant enrichment in pathways related to primary immunodeficiency, ion channel, and cardiovascular defects. Notably, genes such asLCK,KCNN2, andGRIA1emerged as pivotal in these pathways, suggesting their potential roles as biomarkers. Machine learning models trained on a subset of the patients and then tested on other patients demonstrate high accuracy in distinguishing low and high-risk of suicide in BD patients. Moreover, the study explores the genetic overlap between suicide-related genes and several psychiatric disorders. This comprehensive approach enhances our understanding of the complex interplay between genetics and suicidal behavior, laying the groundwork for future prevention strategies.
Energy Deficit is a Key Driver of Sleep Homeostasis
Authors: Park Scarlet J. , Murphy Keith R. , Ja William W. 
Published: May 2024

AbstractSleep and feeding are vital homeostatic behaviors, and disruptions in either can result in substantial metabolic consequences. Distinct neuronal manipulations inDrosophilacan dissociate sleep loss from subsequent homeostatic rebound, offering an optimal platform to examine the precise interplay between these fundamental behaviors. Here, we investigate concomitant changes in sleep and food intake in individual animals, as well as respiratory metabolic expenditure, that accompany behavioral and genetic manipulations that induce sleep loss inDrosophila melanogaster. We find that sleep disruptions resulting in energy deficit through increased metabolic expenditure and manifested as increased food intake were consistently followed by rebound sleep. In contrast, “soft” sleep loss, which does not induce rebound sleep, is not accompanied by increased metabolism and food intake. Our results demonstrate that homeostatic sleep rebound is linked to energy deficit accrued during sleep loss. Collectively, these findings support the notion that sleep functions to conserve energy and highlight the need to examine the effects of metabolic therapeutics on sleep.
Three waves of ovarian follicles in juvenile mice
Authors: Yin Qi , Spradling Allan C. 
Published: May 2024

ABSTRACTWe characterized 3 waves of ovarian follicles in juvenile mice using tissue clearing, lineage tracing and scRNAseq. Wave 1 follicles grow with little delay, and express steroidogenic cell inducers by 2 weeks, as thecal and interstitial gland cells arise. Beginning at 3 weeks, >80% of wave 1 follicles degrade their oocytes, turn over most granulosa cells, and cluster together in the medulla. Thecal cells increase further around holes left by oocytes, and during puberty (5 wk), highly express androgen biosynthetic genes. "Boundary follicles" at the medullar-cortical boundary, comprise the earliest-activated wave 2 follicles. They expressFoxl2as early as E14.5, and generate >70% of the first mature oocytes. Our results indicate the medulla’s broad importance in initial follicular development, and argue that gamete waves, a common animal strategy, serve specific purposes. Wave 1 follicle derivatives bring about high androgen expression during puberty that likely impacts sex-specific neurodevelopment, while boundary and wave 2 follicles support early and lifelong fertility. Consistent with their distinct roles, granulosa cells of antral wave 1 and wave 2 follicles differentially express multiple genes, includingWnt4andIgfbp5.SIGNIFICANCE STATEMENTWe studied the ovaries of juvenile mice 2-6 weeks (wk) of age using transcriptomics and cell lineage to characterize the earliest developing groups of follicles. "Wave 1" follicles begin growing at birth in the ovarian medulla (central region), but most do not produce mature oocytes. Instead they remodel to generate cells synthesizing androgens at puberty, which likely affect sex-specific neurodevelopment. A newly recognized group, "boundary follicles" activate next at the medulla-cortex boundary; their oocytes mature and give rise to most early offspring. The remaining "wave 2" follicles constitute the quiescent ovarian reserve and activate in small groups throughout later life. Our results highlight the importance of specific spatially-localized follicle subgroups and show that they aid reproduction in distinct ways, some of which involve extensive cellular remodeling.
Ex Vivo Cortical Circuits Learn to Predict and Spontaneously Replay Temporal Patterns
Authors: Liu Benjamin , Buonomano Dean V. 
Published: May 2024

ABSTRACTIt has been proposed that prediction and timing are computational primitives of neocortical microcircuits, specifically, that neural mechanisms are in place to allow neocortical circuits to autonomously learn the temporal structure of external stimuli and generate internal predictions. To test this hypothesis, we trained cortical organotypic slices on two specific temporal patterns using dual-optical stimulation. After 24-hours of training, whole-cell recordings revealed network dynamics consistent with training-specific timed prediction. Unexpectedly, there was replay of the learned temporal structure during spontaneous activity. Furthermore, some neurons exhibited timed prediction errors. Mechanistically our results indicate that learning relied in part on asymmetric connectivity between distinct neuronal ensembles with temporally-ordered activation. These findings further suggest that local cortical microcircuits are intrinsically capable of learning temporal information and generating predictions, and that the learning rules underlying temporal learning and spontaneous replay can be intrinsic to local cortical microcircuits and not necessarily dependent on top-down interactions.