bluuebunny/crossref_metadata_2025_split huggingface dataset:
Audiomotor prediction errors drive speech adaptation even in the absence of overt movement
Authors: Parrell Benjamin , Naber Chris , Kim Olivia A. , Nizolek Caroline A. , McDougle Samuel D. 
Published: August 2024

AbstractObserved outcomes of our movements sometimes differ from our expectations. These sensory prediction errors recalibrate the brain’s internal models for motor control, reflected in alterations to subsequent movements that counteract these errors (motor adaptation). While leading theories suggest that all forms of motor adaptation are driven by learning from sensory prediction errors, dominant models of speech adaptation argue that adaptation results from integrating time-advanced copies of corrective feedback commands into feedforward motor programs. Here, we tested these competing theories of speech adaptation by inducing planned, but not executed, speech. Human speakers (male and female) were prompted to speak a word and, on a subset of trials, were rapidly cued to withhold the prompted speech. On standard trials, speakers were exposed to real-time playback of their own speech with an auditory perturbation of the first formant to induce single-trial speech adaptation. Speakers experienced a similar sensory error on movement cancelation trials, hearing a perturbation applied to a recording of their speech from a previous trial at the time they would have spoken. Speakers adapted to auditory prediction errors in both contexts, altering the spectral content of spoken vowels to counteract formant perturbations even when no actual movement coincided with the perturbed feedback. These results build upon recent findings in reaching, and suggest that prediction errors, rather than corrective motor commands, drive adaptation in speech.
Deep graph convolutional neural network for one-dimensional hepatic vascular haemodynamic prediction
Authors: Zhang Weiqng , Shi Shuaifeng , Qi Quan 
Published: August 2024

AbstractHepatic vascular hemodynamics is an important reference indicator in the diagnosis and treatment of hepatic diseases. However, Method based on Computational Fluid Dynamics(CFD) are difficult to promote in clinical applications due to their computational complexity. To this end, this study proposed a deep graph neural network model to simulate the one-dimensional hemodynamic results of hepatic vessels. By connecting residuals between edges and nodes, this framework effectively enhances network prediction accuracy and efficiently avoids over-smoothing phenomena. The graph structure constructed from the centerline and boundary conditions of the hepatic vasculature can serve as the network input, yielding velocity and pressure information corresponding to the centerline. Experimental results indicate that our proposed method achieves higher accuracy on a hepatic vasculature dataset with significant individual variations and can be extended to applications involving other blood vessels. Following training, errors in both the velocity and pressure fields are maintained below 1.5%. The trained network model can be easily deployed on low-performance devices and, compared to CFD-based methods, can output velocity and pressure along the hepatic vessel centerline at a speed three orders of magnitude faster.Author summaryWhen using deep learning methods for hemodynamic analysis, simple point cloud data cannot express the real geometric structure of the blood vessels, and it is necessary for the network to have additional geometric information extraction capability. In this paper, we use graph structure to express the structure of hepatic blood vessels, and deep graph neural network to predict the corresponding hemodynamic parameters. The graph structure can effectively express the geometric information of hepatic blood vessels and the topology of branch blood vessels, which can effectively improve the prediction accuracy with strong geometric generalisation ability. The results show that the method achieves the highest prediction accuracy in the one-dimensional hepatic vessel blood flow simulation dataset, and the experimental results on the human aorta also show that our method can be effectively applied to the blood flow simulation of other vascular organs.
Borrelia burgdorferiSecretes c-di-AMP as an Extracellular Pathogen-Associated Molecular Pattern to Elicit Type I Interferon Responses in Mammalian Hosts
Authors: Priya Raj , Ye Meiping , Raghunanadanan Sajith , Liu Qiang , Li Wei , Yu Qigui , Lou Yongliang , Sintim Herman O. , Yang X. Frank 
Published: August 2024

ABSTRACTBorrelia burgdorferi(B. burgdorferi), an extracellular spirochetal pathogen, elicits a type-I interferon (IFN-I) response that contributes to the pathology of Lyme disease, including the development and severity of Lyme arthritis. However, the specific Pathogen-Associated Molecular Patterns (PAMPs) ofB. burgdorferiresponsible for triggering the IFN-I response are not well understood. Previous studies have identified an unknown, nuclease-resistant component inB. burgdorfericulture supernatants that significantly stimulates the IFN-I response, but its identity remains unknown. In this study, we reveal thatB. burgdorferisecretes cyclic-di-adenosine monophosphate (c-di-AMP) as a key extracellular PAMP, inducing the host IFN-I response in macrophages. Using genetically manipulatedB. burgdorferistrains, we demonstrate a requirement of c-di-AMP for stimulating IFN-I response by macrophagesex vivo. Additionally, infecting mice withB. burgdorferialongside exogenous c-di-AMP resulted in a markedly increased IFN-I response in mouse tissues. Furthermore, inactivation or inhibition of the host STING signaling pathway significantly reduced the IFN-I response, indicating that c-di-AMP-induced IFN-I production is STING-dependent. Our findings identify c-di-AMP as a crucial PAMP secreted byB. burgdorferito elicit the host IFN-I response via activation of STING signaling pathway, suggesting that targeting c-di-AMP production could represent a novel therapeutic strategy against Lyme arthritis.SUMMARYBorrelia burgdorferi, the bacteria that causes Lyme disease, induces a robust host immune response, including the production of type-I interferon (IFN-I). While this response helps combat the infection, it also contributes to complications such as Lyme arthritis. Our research aimed to identify the specific bacterial component that triggers the IFN-I response. We discovered thatBorrelia burgdorferireleases a second messenger molecule, cyclic-di-adenosine monophosphate (c-di-AMP), which is recognized by host immune cells and subsequently triggers IFN-I production. This finding is significant as it advances our understanding of Lyme disease pathogenesis and offers a new strategy to tackle Lyme disease by targeting the production of c-di-AMP, in which we may be able to reduce the severity of the disease and mitigate long-term tissue damage.One sentence summaryBorrelia burgdorferic-di-AMP induces Type I IFN response
Orexin population activity precisely reflects net body movement across behavioral and metabolic states
Authors: Tesmer Alexander L. , Viskaitis Paulius , Donegan Dane , Bracey Eva F. , Grujic Nikola , Patriarchi Tommaso , Peleg-Raibstein Daria , Burdakov Denis 
Published: August 2024

AbstractTracking net body movement in real time may enable the brain to estimate ongoing demands and thus better orchestrate muscle tone, energy balance, and arousal. To identify neural populations specializing in tracking net body movement, here we compared self-initiated movement-related activity across genetically-defined subcortical neurons in the mouse brain, including dopaminergic, glutamatergic, noradrenergic, and key peptidergic neurons. We show that hypothalamic orexin/hypocretin-producing neurons (HONs) are exceptionally precise movement-trackers, encoding net body movement across multiple classified behaviors with a high degree of precision, independent of head acceleration. This tracking was so precise, that video analysis of the mouse body movement reliably served as a low-cost biometric for HON population activity. The movement tracking was independent of internal nutritional states, and occurred in a communication bandwidth distinct from HON encoding of blood glucose. At key projection targets, orexin/hypocretin peptide outputs correlated with self-initiated movement in a projection-specific manner, indicating functional heterogeneity in HON outputs. Finally, we found that body movement was not encoded to the same extent in other key neural populations related to arousal or energy. These findings indicate that subcortical orchestrators of arousal and metabolism are finely tuned to encode net body movement, constituting a bridge multiplexing ongoing motor activity with internal energy resources.
VIPER-TACs leverage viral E3 ligases for disease-specific targeted protein degradation
Authors: Mangano Kyle , Guenette Robert G. , Hill Spencer , Li Shiqian , Yang Seung Wook , Ashton Kate S. , Potts Patrick Ryan 
Published: August 2024

ABSTRACTIn targeted protein degradation (TPD) a protein of interest is degraded by chemically induced proximity to an E3 ubiquitin ligase. One limitation of using TPD therapeutically is that most E3 ligases have broad tissue expression, which can contribute to toxicity via target degradation in healthy cells. Many pathogenic and oncogenic viruses encode E3 ligases (vE3s), which de facto have strictly limited expression to diseased cells. Here, we provide proof-of-concept forViral E3Pan-EssentialRemovingTargetingChimeras (VIPER-TACs) that are bi-functional molecules that utilize viral E3 ubiquitin ligases to selectively degrade pan-essential proteins and eliminate diseased cells. We find that the human papillomavirus (HPV) ligase E6 can degrade the SARS1 pan-essential target protein in a model of HPV-positive cervical cancer to selectively kill E6 expressing cancer cells. Thus, VIPER-TACs have the capacity to dramatically increase the therapeutic window, alleviate toxicity concerns, and ultimately expand the potential target space for TPD.
Circadian geneBmal1in the lateral habenula regulates alcohol drinking behavior in a sex specific manner
Authors: Goldfarb Cassandra , Hasenhundl Vanessa , Menasce Arianne , Amir Shimon , Schöttner Konrad 
Published: August 2024

ABSTRACTThe circadian clock regulates most aspects of mammalian physiology and behaviour, including alcohol drinking behaviour. Disrupted circadian clock function via deletion of clock genes along the mesolimbic dopamine (DA) pathway has been linked to altered patterns of alcohol drinking behaviour. The lateral habenula (LHb), an epithalamic structure that house a semi-autonomous circadian clock, is a negative regulator of the mesolimbic DA system and of alcohol consumption. To study the role of the LHb circadian clock in alcohol consumption, we knocked out the core clock gene,Bmal1specifically in the LHb and examined the impact on various alcohol drinking paradigms and affective behaviours in male and female mice. Our findings demonstrate thatBmal1deletion in the LHb leads to sex-specific alterations in alcohol consumption. Male knockout mice exhibited increased voluntary alcohol intake, enhanced consumption of a bitter alcohol solution, and elevated alcohol binge drinking compared to controls. Conversely, female knockouts showed a marginal decrease in voluntary intake, significantly reduced consumption of an aversive alcohol solution, and lower post abstinence, relapse-like drinking. These results indicate thatBmal1in the LHb exerts a repressive effect on alcohol intake in males, while it facilitates intake under certain aversive conditions in females. Interestingly,Bmal1deletion did not significantly affect anxiety-like or depressive-like behaviours, suggesting that the habenular clock’s role in alcohol consumption is independent of affective state. These findings markBmal1in the LHb as a novel sexually dimorphic regulator of alcohol consumption in mice. Potential mechanisms involving the circadian modulation of DA and serotonin signaling pathways by the LHb clock is discussed.
Overcoming fixation and permeabilization challenges in flow cytometry by optical barcoding and multi-pass acquisition
Authors: Fahlberg Marissa D. , Forward Sarah , Assita Emane Rose , Mazzola Michael , Kiem Anna , Handley Maris , Yun Seok-Hyun , Kwok Sheldon J.J. 
Published: August 2024

AbstractThe fixation and permeabilization of cells are essential for labeling intracellular biomarkers in flow cytometry. However, these chemical treatments often alter fragile targets, such as cell surface and fluorescent proteins, and can destroy chemically-sensitive fluorescent labels. This reduces measurement accuracy and introduces compromises into sample workflows, leading to losses in data quality. Here, we demonstrate a novel multi-pass flow cytometry approach to address this long-standing problem. Our technique utilizes individual cell barcoding with laser particles, enabling sequential analysis of the same cells with single-cell resolution maintained. Chemically-fragile protein markers and their fluorochrome conjugates are measured prior to destructive sample processing and adjoined to subsequent measurements of intracellular markers after fixation and permeabilization. We demonstrate the effectiveness of our technique in accurately measuring intracellular fluorescent proteins and methanol-sensitive antigens and fluorophores, along with various surface and intracellular markers. This approach significantly enhances assay flexibility, enabling accurate and comprehensive cell analysis without the constraints of conventional one-time measurement flow cytometry. This innovation paves new avenues in flow cytometry for a wide range of applications in immuno-oncology, stem cell research, and cell biology.
Age-Dependent Cortical Overconnectivity in Shank3 Mice is Reversed by Anesthesia
Authors: Elena Montagni , Ambrosone Manuel , Martello Alessandra , Curti Lorenzo , Baroncelli Laura , Guido Mannaioni , Pavone Francesco Saverio , Masi Alessio , Allegra Mascaro Anna Letizia 
Published: August 2024

ABSTRACTGrowing evidence points to brain network dysfunction as a central neurobiological basis for autism spectrum disorders (ASDs). As a result, studies on Functional Connectivity (FC) have become pivotal for understanding the large-scale network alterations associated with ASD. Despite ASD being a neurodevelopmental disorder, and FC being significantly influenced by the brain state, existing FC studies in mouse models predominantly focus on adult subjects under anesthesia. The differential impact of anesthesia and age on cortical functional networks in ASD subjects remains unexplored. To fill this gap, we conducted a longitudinal evaluation of FC across three brain states and three ages in the Shank3b mouse model of autism. We utilized wide-field calcium imaging to monitor cortical activity in Shank3b+/-and Shank3b+/+mice fromlate development (P45) through adulthood (P90), and isoflurane anesthesia to manipulate the brain state. Our findings reveal that network hyperconnectivity, emerging from the barrel-field cortices during the juvenile stage, progressively expands to encompass the entire dorsal cortex in adult Shank3b+/-mice. Notably, the severity of FC imbalance is highly dependent on the brain state: network alterations are more pronounced in the awake state and shift towards hypoconnectivity under anesthesia. These results underscore the crucial role of anesthesia in detecting autism-related FC alterations and identify a significant network of early cortical dysfunction associated with autism. This network represents a potential target for non-invasive translational treatments.
Eomes directs the formation of spatially and functionally diverse extra-embryonic hematovascular tissues
Authors: Theeuwes Bart , Harland Luke TG , Bisia Alexandra , Costello Ita , Ton Mai-Linh , Lohoff Tim , Clark Stephen J , Argelaguet Ricard , Wilson Nicola K , Reik Wolf , Bikoff Elizabeth , Robertson Elizabeth J , Gottgens Berthold 
Published: August 2024

SummaryDuring mouse gastrulation, extraembryonic mesoderm (ExEM) contributes to the extraembryonic yolk sac (YS) and allantois, both of which are essential for successful gestation. Although the genetic networks coordinating intra-embryonic mesodermal subtype specification are well-studied, the mechanisms driving ExEM diversification are poorly understood. Here, we reveal that embryoid bodyin vitrodifferentiation generates two distinct lineages of mesodermal cells matching YS and allantois respectively. Combiningin vitromodels within vivochimeric embryo analysis, we discover that Eomesodermin (Eomes) regulates the formation of a subset of YS-fated ExEM but is dispensable for allantois formation. Furthermore, simultaneous disruption of Eomes and T impedes the specification of any YS or allantois mesoderm, indicating compensatory roles for T during allantois formation when Eomes is disrupted. Our study highlights previously unrecognized functional and mechanistic diversity in ExEM diversification and endothelial development and introduces a tractable EB model to dissect the signaling pathways and transcriptional networks driving the formation of key extraembryonic tissues.
The relationship between sleep and cognitive performance on tests of pattern separation
Authors: Roenningen Aina , Gill Devan , Kent Brianne A 
Published: August 2024

AbstractStudy objectivesSleep disturbances are considered both a risk factor and symptom of dementia. The present research aimed to identify cognitive tests that are sensitive to sleep-dependent cognition, focusing on cognitive tests designed to evaluate the earliest cognitive changes in dementia.MethodsIn Experiment 1, we recruited younger (n=89) and older (n=40) adults and remotely monitored their sleep patterns for 7 consecutive days using actigraphy and sleep diaries. On day 7, participants completed a battery of cognitive tests, which included the Prodromal Alzheimer’s and MCI battery from the Cambridge Neuropsychological Test Automated Battery (CANTAB) and the Mnemonic Similarity Task (MST). In Experiment 2, we examined the effects of a night of total sleep deprivation on cognitive performance in young adults. We observed a sleep deprived group (n=16) overnight in the lab. The rested control group (n=32) slept normally at home.ResultsIn Experiment 1, there was a significant relationship between performance on MST and total sleep time in the older adults. There were no relationships between cognitive performance and sleep quantity or quality in the younger adults. In the older adults, Montreal Cognitive Assessment (MoCA) scores were correlated with performance on the CANTAB and MST. In Experiment 2, the young adults who underwent 24-hour sleep deprivation performed worse than the rested participants on the MST task.ConclusionPerformance on cognitive tests designed to assess pattern separation are sensitive to sleep patterns, particularly in older adults and should be evaluated for potential use as clinical trial outcome measures for sleep-promoting treatments.Statement of SignificanceThere is growing emphasis on the importance of sleep as a potential therapeutic target for neurodegenerative diseases (e.g., Alzheimer’s disease). Finding cognitive measures sensitive to sleep are needed for use as outcome measures in clinical trials evaluating the effectiveness of sleep-promoting interventions. Our research addresses this need by investigating the relationship between sleep patterns and performance on a variety of cognitive tests. Our results suggest that cognitive tests designed to assess pattern separation are uniquely sensitive to sleep quality and quantity, particularly in older adults.
Contingency awareness shapes neural responses in fear conditioning
Authors: Pavlov Yuri G. , Menger Nick S. , Keil Andreas , Kotchoubey Boris 
Published: August 2024

AbstractContingency awareness refers to an observer’s ability to identify the association between a conditioned (CS) and an unconditioned stimulus (US). A widely held belief in human fear conditioning is that this form of associative learning may occur independently of contingency awareness. To test this hypothesis, in this preregistered study (https://osf.io/vywq7), we recorded electroencephalography (EEG) during a task, where participants were presented with compounds of words (from two semantic categories) and tactile stimulation, followed by either a neutral sound (US-) or a loud noise (US+). Based on interviews, participants were divided into an aware (N=50) and an unaware (N=31) group. Only the aware group showed signs of learning, as expressed in larger stimulus-preceding negativity developing before US+ and a stronger theta response to vibrations predicting US+. The aware group also showed stronger alpha and beta suppression around the vibrations and a weaker theta response to US+, possibly indicating heightened attention to the cue and the violation/confirmation of expectation. Personality tests showed that elevated anxiety, neuroticism, higher intolerance of uncertainty, or harm avoidance are not predictive to the acquisition of contingency awareness. Our findings support the notion that fear conditioning, as reflected in cortical measures, cannot occur without contingency awareness.
Development of a preclinical screening platform for clinically relevant therapy of Dravet syndrome
Authors: Mensah Jeffrey A. , Thomson Kyle E. , Huff Jennifer L. , Freeman Tia , Reilly Christopher A. , Rower Joseph E. , Metcalf Cameron S. , Wilcox Karen S. 
Published: August 2024

AbstractBackgroundPatients with drug-resistant epilepsy, including Dravet syndrome (DS), are frequently prescribed multiple antiseizure medications (ASMs). Nevertheless, people with DS often have inadequate seizure control, and there is an ongoing unmet clinical need to identify novel therapeutics. As a proof-of-principle study to further validate and characterize theScn1aA1783V/WTmouse model and identify a drug screening paradigm with face, construct, and predictive value, we assessed the efficacy of subchronic administration of stiripentol add-on to clobazam and valproic acid at clinically relevant doses using theScn1aA1783V/WTmouse model.MethodsWe evaluated the efficacy of STP add-on to CLB and VPA using hyperthermia-induced and video-EEG monitoring of spontaneous seizure tests following a 14-day treatment. VPA was delivered via osmotic minipump, while STP and CLB were administered via food pellets delivered through automatic feeders. Bioanalytical assays were performed to evaluate drug concentrations in plasma and brain using liquid chromatography-tandem mass spectrometry.ResultsSTP, CLB, N-desmethylclobazam, and VPA all yielded plasma concentrations within the human therapeutic plasma concentrations range. STP added to CLB and VPA significantly elevated the seizing temperatures in the hyperthermia-induced seizure assay. CLB, VPA, and STP coadministration significantly reduced spontaneous seizure frequency compared to CLB and VPA combined.SignificanceThis research lays the groundwork for exploring effective add-on compounds to CLB and VPA in treating DS. The study further highlights the utility of theScn1aA1783V/WTmice in discovering therapies for DS-associated pharmacoresistant seizures.Key pointsIntegrating pharmacokinetic studies to guide the selection of doses in preclinical studies to achieve target concentrations comparable to the human therapeutic range is crucial in successfully translating animal drug development studies to clinical use.STP add-on to CLB and VPA significantly reduced spontaneous seizure frequency inScn1aA1783V/WTmice.A triple-drug polytherapy approach that mimics the clinical treatment paradigm will be an essential preclinical drug screening strategy for identifying novel investigational compounds for Dravet syndrome.