bluuebunny/crossref_metadata_2025_split huggingface dataset:
Metaplastic-EEG: Continuous Training on Brain-Signals
Authors: Aguilar Isabelle , Bersani--Veroni Thomas , Herbozo Contreras Luis Fernando , Nikpour Armin , Querlioz Damien , Kavehei Omid 
Published: May 2024

AbstractDeep learning approaches promise viable solutions for detecting epileptic seizures in a reliable, generalisable and potentially real-time. To apply such techniques in clinical settings, where they can be used with long-term recordings or applied to a continuous stream of incoming datasets, these algorithms should adopt a continual learning ability that allows the agent to acquire and adapt from additional knowledge streamed over its lifespan. Unfortunately, traditional sequential learning can initiate catastrophic forgetting, in which the model loses previously learned information while accumulating new knowledge. Metaplasticity has emerged as a potential technique to provide longer-term stability pertaining to the learning performance for multiple datastream sets, thus enabling a meta-learning capability in artificial learning machines and algorithms. In this paper, we use these biologic-inspired metaplasticity techniques to develop stable learning cycles when we expose it to multiple sets of EEG (electroencephalogram) data for seizure detection. In this feasibility study, adding metaplastic synapses enhances detection accuracy relative to traditional baseline learning. Considering the meta-learning approach demonstrated in this paper, metaplastic binarized neural networks (BNNs) demonstrate improvement (6-7%) in seizure detection performance metrics, with reported accuracies and ROC-AUC values over 70%. Metaplasticity in practice with machine learning holds the potential to provide an adaptable, patient-specific epileptic seizure tracking method for real-world dynamics.
Directly Measuring Atherogenic Lipoprotein Kinetics in Zebrafish with the Photoconvertible LipoTimer Reporter
Authors: Moll Tabea O.C. , Klemek Mackenzie L. , Farber Steven A. 
Published: May 2024

SummaryLipoprotein kinetics are a crucial factor in understanding lipoprotein metabolism since a prolonged time in circulation can contribute to the atherogenic character of apolipoprotein-B (ApoB)-containing lipoproteins (B-lps). Here, we report a method to directly measure lipoprotein kinetics in live developing animals. We developed a zebrafish geneticly encoded reporter, LipoTimer, in which endogenous ApoBb.1 is fused to the photoconvertible fluorophore Dendra2 which shift its emission profile from green to red upon UV exposure. By quantifying the red population of ApoB-Dendra2 over time, we found that B-lp turnover in wild-type larvae becomes faster as development proceeds. Mutants with impaired B-lp uptake or lipolysis present with increased B-lp levels and half-life. In contrast, mutants with impaired B-lp triglyceride loading display slightly fewer and smaller-B-lps, which have a significantly shorter B-lp half-life. Further, we showed that chronic high-cholesterol feeding is associated with a longer B-lp half-life in wild-type juveniles but does not lead to changes in B-lp half-life in lipolysis deficientapoC2mutants. These data support the hypothesis that B-lp lipolysis is suppressed by the flood of intestinal-derived B-lps that follow a high-fat meal.
Control of lumen geometry and topology by the interplay between pressure and cell proliferation rate in pancreatic organoids
Authors: Lee Byung Ho , Fuji Kana , Petzold Heike , Seymour Phil , Yennek Siham , Schewin Coline , Lewis Allison , Riveline Daniel , Hiraiwa Tetsuya , Sano Masaki , Grapin-Botton Anne 
Published: May 2024

AbstractMany internal organs in multicellular organisms comprise epithelia which enclose fluid-filled cavities. These are referred to as lumens and their formation is regulated by a wide range of processes, including epithelial polarization, secretion, exocytosis and actomyosin contractility [1, 2]. While these mechanisms have shed light on lumen growth, what controls lumen morphology remains enigmatic. Here we use pancreas organoids to explore how lumens acquire either a spherical shape or a branched topology [3]. Combining computational simulations based on a phase field model with experimental measurements we reveal that lumen morphology arises from the balance between the cell cycle duration and lumen pressure, with more complex lumen at low pressure and fast proliferation rates. Moreover, the manipulation of proliferation and lumen pressurein silicoandin vitrois sufficient to alter and reverse the morphological trajectories of the lumens. Increasing epithelial permeability of spherical lumens lead to lower lumen pressure and converts their morphology to complex lumen shapes, highlighting its crucial role. In summary, the study underscores the importance of balancing cell proliferation, lumen pressure, and epithelial permeability in determining lumen morphology, providing insights relevant to other organs, for tissue engineering and cystic disease understanding and treatment [4].
Visual detection of seizures in mice using supervised machine learning
Authors: Sabnis Gautam , Hession Leinani , Mahoney J. Matthew , Mobley Arie , Santos Marina , Kumar Vivek 
Published: May 2024

1AbstractSeizures are caused by abnormally synchronous brain activity that can result in changes in muscle tone, such as twitching, stiffness, limpness, or rhythmic jerking. These behavioral manifestations are clear on visual inspection and the most widely used seizure scoring systems in preclinical models, such as the Racine scale in rodents, use these behavioral patterns in semiquantitative seizure intensity scores. However, visual inspection is time-consuming, low-throughput, and partially subjective, and there is a need for rigorously quantitative approaches that are scalable. In this study, we used supervised machine learning approaches to develop automated classifiers to predict seizure severity directly from noninvasive video data. Using the PTZ-induced seizure model in mice, we trained video-only classifiers to predict ictal events, combined these events to predict an univariate seizure intensity for a recording session, as well as time-varying seizure intensity scores. Our results show, for the first time, that seizure events and overall intensity can be rigorously quantified directly from overhead video of mice in a standard open field using supervised approaches. These results enable high-throughput, noninvasive, and standardized seizure scoring for downstream applications such as neurogenetics and therapeutic discovery.
The subcortical correlates of self-reported sleep quality
Authors: Monti Martin M. 
Published: May 2024

AbstractStudy objectivesTo assess the association between self-reported measures of sleep quality and cortical and subcortical local morphometry.MethodsSleep quality, operationalized with the Pittsburgh Sleep Quality Index (PSQI), and neuroanatomical data from the full release of the young adult Human Connectome Project dataset were analyzed (N=1,112; 46% female; mean age: 28.8 years old). Local cortical and subcortical morphometry was measured with subject-specific segmentations resulting in voxelwise gray matter difference (i.e., voxel based morephometry) measurements for cortex and local shape measurements for subcortical regions. Associations between the total score of PSQI, two statistical groupings of its subcomponents (obtained with a principal component analysis), and their interaction with demographic (i.e., sex, age, handedness, years of education) and biometric (i.e., BMI) variables were assessed using a general linear model and a nonparametric permutation approach.ResultsSleep quality-related variance was significantly associated with subcortical morphometry, particularly in the bilateral caudate, putamen, and left pallidum, where smaller shape measures correlated with worse sleep quality. Notably, these associations were independent of demographic and biometric factors. In contrast, cortical morphometry, along with additional subcortical sites, showed no direct associations with sleep quality but demonstrated interactions with demographic and biometric variables.ConclusionsThis study reveals a specific link between self-reported sleep quality and subcortical morphometry, particularly within the striatum and pallidum, reinforcing the role of these regions in sleep regulation. These findings underscore the importance of considering subcortical morphology in sleep research and highlight potential neuromodulatory targets for sleep-related interventions.Statement of SignificanceThis study provides evidence for the role of subcortical structures in sleep regulation, demonstrating that poorer self-reported sleep quality is associated with reduced shape measures in the bilateral caudate, putamen, and left pallidum. These associations were independent of demographic and biometric factors, distinguishing subcortical morphometry as a unique correlate of sleep quality. In contrast, cortical morphology exhibited no direct relationship with sleep quality but showed interactions with factors such as sex, BMI, and age, highlighting the complexity of brain-sleep relationships. These findings contribute to a growing body of literature emphasizing the basal ganglia’s role in non-motor functions, including sleep regulation, and suggest potential neuromodulatory targets for sleep-related interventions, such as transcranial focused ultrasound or deep brain stimulation.
Gastrin-releasing peptide signaling in the nucleus accumbens medial shell regulates neuronal excitability and motivation
Authors: Aisenberg Erin E. , Li Thomas L. , Wang Hongli , Sahagun Atehsa A. , Tu Emilie M. , Bateup Helen S. 
Published: May 2024

SummaryNeuropeptides are the largest class of neuromodulators. It has been shown that subpopulations of dopamine neurons express mRNA for the neuropeptide Gastrin-releasing peptide (GRP); however, its functional relevance in dopaminergic circuits is unknown. Here, we find that the GRP receptor (GRPR) is present in the nucleus accumbens medial shell (NAc MSh), which is targeted by GRP-expressing midbrain dopamine neurons as well as glutamatergic inputs from the hippocampus and amygdala. We show that the NAc MSh GRPR-positive cells are a subpopulation of D2 receptor-expressing neurons, comprising both classical indirect pathway striatal projection neurons (iSPNs) and eccentric SPNs (eSPNs), which have high intrinsic excitability, and can be activated by GRPin vivo. NAc-specific deletion ofGrprincreases motivation in a progressive ratio test, demonstrating that GRPR regulates motivated behaviors. These experiments establish GRP/GRPR signaling as a potent modulator of mesolimbic circuits and advance our understanding of neuropeptide actions in the brain.
Preference heterogeneity for HIV pre-exposure prophylaxis care among gay, bisexual, and other men who have sex with men in the United States: a large discrete choice experiment
Authors: Patel Viraj V. , Andrade Eli , Zimba Rebecca , Mirzayi Chloe , Zhang Chenshu , Kharfen Michael , Edelstein Zoe , Freeman Anthony , Doshi Rupali , Nash Denis , Grov Christian 
Published: May 2024

AbstractBackgroundPrEP uptake among Black and Latino gay, bisexual, and other men who have sex with men (GBM) remains low in the United States. The design and implementation of PrEP delivery programs that incorporate the preferences of Black and Latino GBM may overcome barriers to uptake. We aimed to identify preferences for PrEP care among high-priority GBM in the U.S. with a large discrete choice experiment.MethodsWe conducted two discreet choice experiments (DCE) to elicit care preferences for (1) Starting PrEP and (2) Continuing PrEP care among GBM clinically indicated for PrEP. The DCE web-based survey was nested in a longitudinal cohort study of GBM in the U.S., implemented with video and audio directions among 16-49 year-old participants, not using PrEP, and verified to be HIV-negative. All participants were presented with 16 choice sets, with choices determined by BLGBM and PrEP implementation stakeholders. We calculated overall utility scores and relative importance and used latent class analyses (LCA) to identify classes within the Starting and Continuing PrEP DCE. Multivariable analysis was performed to identify factors associated with class membership.FindingsAmong 1514 participants, mean age was 32 years; 46·5% identified as Latino, 21·4% Black, and 25·2 White; 37·5% had an income less than USD $20,000. Two latent classes were identified for Starting PrEP:Class 1(n=431 [28·5%]) was driven by preference for more traditional in-person care, andClass 2(n=1083 [71·5%]) preferred flexible care options and on-demand PrEP. In a multivariable model, having a sexual health doctor (adjusted OR 0·7, CI 0·5, 0·9), having a primary care provider (OR 0·7,CI 0·5, 0·9, p= 0·023), and concerns over PrEP side effects (OR 1·1, CI 1·0,1·2, p= 0·003) were all associated with class membership.InterpretationThe different preferences identified for PrEP care indicate the need for diverse care and formulation choices to improve PrEP uptake and persistence. Addressing these preferences and understanding the factors that shape them can inform the implementation of programs that increase PrEP uptake.
Evaluation of a Multiplexed Immunoassay for Assessing Long-Term Humoral Immunity to Monkeypox virus infection and Orthopoxvirus Vaccination
Authors: Hicks Bethany , Jones Scott , Callaby Helen , Bailey Daniel , Gordon Claire , Rampling Tommy , Houlihan Catherine , Linley Ezra , Tonge Simon , Oeser Clarissa , Jones Rachael , Pond Marcus , Mehta Ravi , Wright Deborah , Hallis Bassam , Rowe Cathy , Otter Ashley 
Published: May 2024

AbstractIn the summer of 2022, a large outbreak of Monkeypox virus (MPXV) cases occurred globally. By December 2022, a total of 3,582 Mpox cases had been confirmed within the UK. As a result, the Modified Vaccinia Ankara-Bavarian Nordic (“IMVANEX”) vaccine was offered to high-risk groups to protect against the spread of the virus. This outbreak led to the development of multiple serological assays to aid the current understanding of Mpox immunology. This study assessed the performance of a multiplexed solid-phase electrochemiluminescence (Meso Scale Discovery (MSD)) immunoassay for simultaneous detection of antibodies against MPXV A29, A35, B6, E8, and M1 antigens, along with the corresponding Vaccina Virus (VACV) homologues A27, A33, B5, D8, and L1. Sensitivity and specificity were evaluated with paediatric negatives (n=215), pre- and post-IMVANEX vaccinated (n=80) and MPXV (2022 Clade IIb outbreak, n=39) infected serum samples. The overall Orthopoxvirus multiplex assay demonstrated high specificity ranging from 75.68% (CI: 69.01-81.29) - 95.98% (CI:92.54-97.87) and sensitivity from 62.11% (CI:52.06-71.21) - 98.59% (CI:92.44% - 99.93%) depending on the Orthopoxvirus antigen, either used singularly or combined. Additionally, preferential binding was observed between Mpox-infected individuals and MPXV antigens, whilst vaccinated individuals exhibited increased binding to VACV antigens. These results highlight the differential binding patterns between antigen homologues in closely related viruses. Using this assay, we show that the Orthopoxvirus MSD assay is highly sensitive in detecting IgG titres for vaccinated sera ≥24-days post dose one and ≥14-days post dose two for all antigens within the assay except for MPXV A29 and VACV A27. A similar trend was observed with convalescent sera, although differing antigens demonstrate stronger sensitivities. Overall, this assay has the capability to accurately assess antibody titres for multiple relevant MPXV and VACV antigens post infection and post vaccination, demonstrating its utility in understanding immune responses to Orthopox viruses in current and future outbreaks, and assessing the immunogenicity of new generation Orthopox and Mpox-specific vaccinations.
Proteomic profiling of bronchoalveolar lavage fluid uncovers protein clusters linked to survival in idiopathic forms of interstitial lung disease
Authors: Ngo Linh T. , Rekowski Michaella J. , Koestler Devin C. , Yorozuya Takafumi , Saito Atsushi , Azeem Imaan , Harrison Alexis , Demoruelle M. Kristen , Boomer Jonathan , England Bryant R. , Wolters Paul , Molyneaux Philip L. , Castro Mario , Lee Joyce S. , Solomon Joshua J. , Koronuma Koji , Washburn Michael P. , Matson Scott M. 
Published: May 2024

AbstractBackgroundIdiopathic interstitial pneumonias (IIPs) such as idiopathic pulmonary fibrosis (IPF) and interstitial pneumonia with autoimmune features (IPAF), present diagnostic and therapeutic challenges due to their heterogeneous nature. This study aimed to identify intrinsic molecular signatures within the lung microenvironment of these IIPs through proteomic analysis of bronchoalveolar lavage fluid (BALF).MethodsPatients with IIP (n=23) underwent comprehensive clinical evaluation including pre-treatment bronchoscopy and were compared to controls without lung disease (n=5). Proteomic profiling of BALF was conducted using label-free quantitative methods. Unsupervised cluster analyses identified protein expression profiles which were then analyzed to predict survival outcomes and investigate associated pathways.ResultsProteomic profiling successfully differentiated IIP from controls.k-means clustering, based on protein expression revealed three distinct IIP clusters, which were not associated with age, smoking history, or baseline pulmonary function. These clusters had unique survival trajectories and provided more accurate survival predictions than the Gender Age Physiology (GAP) index (C-index 0.794 vs. 0.709). The cluster with the worst prognosis featured decreased inflammatory signaling and complement activation, with pathway analysis highlighting altered immune response pathways related to immunoglobulin production and B cell-mediated immunity.ConclusionsThe unsupervised clustering of BALF proteomics provided a novel stratification of IIP patients, with potential implications for prognostic and therapeutic targeting. The identified molecular phenotypes underscore the diversity within the IIP classification and the potential importance of personalized treatments for these conditions. Future validation in larger, multi-ethnic cohorts is essential to confirm these findings and to explore their utility in clinical decision-making for patients with IIP.
Phosphorylation of VapB antitoxins affects intermolecular interactions to regulate VapC toxin activity inMycobacterium tuberculosis
Authors: Malakar Basanti , Barth Valdir , Puffal Julia , Woychik Nancy , Husson Robert N. 
Published: May 2024

AbstractToxin-antitoxin modules are present in many bacterial pathogens. The VapBC family is particularly abundant in members of theMycobacterium tuberculosiscomplex, with 50 modules present in theM. tuberculosisgenome. In type IIA modules the VapB antitoxin protein binds to and inhibits the activity of the co-expressed cognate VapC toxin protein. VapB proteins also bind to promoter region sequences and repress expression of thevapB-vapCoperon. Though VapB-VapC interactions can control the amount of free VapC toxin in the bacterial cell, the mechanisms that affect this interaction are poorly understood. Based on our recent finding of Ser/Thr phosphorylation of VapB proteins inM. tuberculosis, we substituted phosphomimetic or phosphoablative amino acids at the phosphorylation sites of two VapB proteins. We found that phosphomimetic substitution of VapB27 and VapB46 resulted in decreased interaction with their respective cognate VapC proteins, whereas phosphoablative substitution did not alter binding. Similarly, we determined that phosphomimetic substitution interfered with VapB binding to promoter region DNA sequences. Both decreased VapB-VapC interaction and decreased VapB repression ofvapB-vapCoperon transcription would result in increased free VapC in theM. tuberculosiscell.M. tuberculosisstrains expressingvapB46-vapC46constructs containing a phosphoablativevapBmutation resulted in lower toxicity compared to a strain expressing nativevapB46, whereas similar or greater toxicity was observed in the strain expressing the phosphomimeticvapBmutation. These results identify a novel mechanism by which VapC toxicity activity can be regulated by VapB phosphorylation, potentially in response to extracytoplasmic as well as intracellular signals.ImportanceIntracellular bacterial toxins are present in many bacterial pathogens and have been linked to bacterial survival in response to stresses encountered during infection. The activity of many toxins is regulated by a co-expressed antitoxin protein that binds to and sequesters the toxin protein. The mechanisms by which an antitoxin may respond to stresses to alter toxin activity are poorly understood. Here we show that antitoxin interactions with its cognate toxin, and with promoter DNA required for antitoxin and toxin expression, can be altered by Ser/Thr phosphorylation of the antitoxin, and thus affect toxin activity. This reversible modification may play an important role in regulating toxin activity within the bacterial cell in response to signals generated during infection.
Structural dynamics of the intrinsically disordered linker region of cardiac troponin T
Authors: Cubuk Jasmine , Greenberg Lina , Greenberg Akiva E. , Emenecker Ryan J. , Stuchell-Brereton Melissa D. , Holehouse Alex S. , Soranno Andrea , Greenberg Michael J. 
Published: May 2024

ABSTRACTThe cardiac troponin complex, composed of troponins I, T, and C, plays a central role in regulating the calcium-dependent interactions between myosin and the thin filament. Mutations in troponin can cause cardiomyopathies; however, it is still a major challenge to connect how changes in sequence affect troponin’s function. Recent high-resolution structures of the thin filament revealed critical insights into the structure-function relationship of troponin, but there remain large, unresolved segments of troponin, including the troponin-T linker region that is a hotspot for cardiomyopathy mutations. This linker region is predicted to be intrinsically disordered, with behaviors that are not well described by traditional structural approaches; however, this proposal has not been experimentally verified. Here, we used a combination of single-molecule Förster resonance energy transfer (FRET), molecular dynamics simulations, and functional reconstitution assays to investigate the troponin-T linker region. We show that in the context of both isolated troponin and the fully regulated troponin complex, the linker behaves as a dynamic, intrinsically disordered region. This region undergoes polyampholyte expansion in the presence of high salt and distinct conformational changes during the assembly of the troponin complex. We also examine the ΔE160 hypertrophic cardiomyopathy mutation in the linker and demonstrate that it does not affect the conformational dynamics of the linker, rather it allosterically affects interactions with other troponin complex subunits, leading to increased molecular contractility. Taken together, our data clearly demonstrate the importance of disorder within the troponin-T linker and provide new insights into the molecular mechanisms driving the pathogenesis of cardiomyopathies.SIGNIFICANCE STATEMENTTroponin plays a central role in regulating heart contraction, and mutations in troponin can cause human cardiomyopathies. There are several functionally-significant regions of troponin that have not been structurally resolved, including the troponin T linker region that contains multiple cardiomyopathy mutations. In these unresolved regions, it is not possible to understand how changes in sequence affect function. We used computational and experimental techniques to demonstrate that this linker is dynamic and intrinsically disordered both in isolation and in the fully regulated thin filament. Moreover, we show how a cardiomyopathy mutation in this region affects function via allosteric disruption of intermolecular interactions. Our results highlight the need to consider how key mutations affect troponin disorder rather than the structure-function relationship.