bluuebunny/crossref_metadata_2025 huggingface dataset:
Human sensorimotor cortex reactivates recent visuomotor experience during awake rest
Authors: Ogawa Kenji , Yang Yuxiang , Yang Huixiang , Imai Fumihito , Imamizu Hiroshi
Published: May 2024

Previous studies have suggested that awake rest after training is helpful in improving motor performance and memory consolidation in visuomotor learning. Re-emergence of task-related activation patterns during awake rest has been reported, which play a role in memory consolidation or perceptual learning. This study aimed to test whether such reactivation occurs after visuomotor learning in the primary sensorimotor cortex. During fMRI scanning, 42 normal participants learned visuomotor tracking, while a rotational perturbation was introduced between a cursor position and a joystick angle. This visuomotor learning block was interleaved with the control block, during which the participants passively viewed a replay of previously performed cursor movements of their own. Half of the participants used their right hand, and the other half used their left hand to control the joystick. The resting-state scans were measured before and after the visuomotor learning sessions. A multivariate pattern classifier was trained to classify task and control blocks and then tested with resting scans before and after learning. Results revealed a significant increase in the number of volumes classified as the task in the post-learning rest compared with the pre-learning, indicating a re-emergence of task-related activities. Representational similarity analysis also showed a more similar pattern of activity with the task during the post-learning rest period. Furthermore, this effect is specific to the primary sensorimotor cortex contralateral to the hand used and significantly correlated with motor improvement after rest. Our finding revealed the reactivation of task-related patterns in the primary sensorimotor cortex for offline visuomotor learning.

Significance Statement

Previous research suggests that awake rest after learning promotes memory consolidation, which is subserved by the re-emergence of task-specific activity patterns. We aimed to determine whether such reactivation occurs in the primary sensorimotor cortex following visuomotor learning for offline memory consolidation. Our results showed a significant increase in task-classified brain volumes during the post-learning rest period compared to the pre-learning period, indicating a re-emergence of task-related activity. Furthermore, this effect was specific to the primary sensorimotor cortex contralateral to the hand used for the task and significantly correlated with the motor performance following the rest period. These findings provide evidence for the reactivation of task-related patterns during offline visuomotor learning, which may underlie memory consolidation processes.
Terrestrial ecosystems enhance root zones in response to intensified drought
Authors: Xi Qiaojuan , Gao Hongkai , Wang-Erlandsson Lan , Dong Jianzhi , Fenicia Fabrizio , Savenije Hubert H. G. , Hrachowitz Markus
Published: May 2024

Adaptation of ecosystems’ root zones to climate change critically affects drought resilience and vegetation productivity. However, a global quantitative assessment of this mechanism is missing. Therefore, we analyzed observation-based data and found that the global average root zone water storage capacity (SR) increased by 11%, from 182 to 201 mm in 1982-2020. This increase amounts to 1657 billion m3over the past four decades, affecting hydrological and ecological processes worldwide.SRincreased in 9 out of 12 land cover types, while three relatively dry types experienced decreasing trends, potentially suggesting the crossing of ecosystem tipping points. Our results underscore the importance of considering root zone dynamics while analysing floods, droughts and carbon sequestration under climate change.
Signatures in domesticated beet genomes pointing at genes under selection in a sucrose-storing root crop
Authors: Dhiman Amar Singh , Taliadoros Demetris , Stukenbrock Eva H. , McGrath J. Mitchell , Emrani Nazgol , Jung Christian
Published: May 2024

The genusBetaencompasses important crops such as sugar, table, fodder, and leaf beets. All cultivated beets are believed to have originated from the wild sea beet,B.vulgarissubsp.maritima. Sugar beet, a recent crop dating back nearly 200 years, was selectively bred for enhanced root yield in combination with high sucrose content. We assembled aBetadiversity panel comprising wild and cultivated beet accessions. Whole-genome sequencing identified 10.3 million SNP markers. Four distinct genetic clusters were identified: table beet, sugar beet, Mediterranean sea beet, and Atlantic sea beet. A phylogenetic analysis revealed that cultivated beet accessions were genetically closer to Mediterranean than to Atlantic sea beet and that cultivated beets producing storage roots share a common ancestor. Cultivated beets exhibited genome regions with reduced nucleotide diversity compared to Mediterranean sea beets, indicating selection signatures. These regions contained putative candidate genes with potential roles in root development, suppression of lateral root formation, flowering time, and sucrose metabolism. A yet unknown sucrose transporter on chromosome 6 showed reduced nucleotide diversity exclusively in sugar beet accessions compared to otherBetatypes with low sucrose content, suggesting its role in sucrose storage. Within a region of high nucleotide diversity between accessions with contrasting root phenotypes, we found two genes encoding auxin response factors, which play a crucial role in root development. We reason these genes to be significant root thickening regulators in root crops.
Periodic ER-plasma membrane junctions support long-range Ca2+signal integration in dendrites
Authors: Benedetti Lorena , Fan Ruolin , Weigel Aubrey V. , Moore Andrew S. , Houlihan Patrick R. , Kittisopikul Mark , Park Grace , Petruncio Alyson , Hubbard Philip M. , Pang Song , Xu C. Shan , Hess Harald F. , Saalfeld Stephan , Rangaraju Vidhya , Clapham David E. , De Camilli Pietro , Ryan Timothy A. , Lippincott-Schwartz Jennifer
Published: May 2024

Neuronal dendrites must relay synaptic inputs over long distances, but the mechanisms by which activity-evoked intracellular signals propagate over macroscopic distances remain unclear. Here, we discovered a system of periodically arranged endoplasmic reticulum-plasma membrane (ER-PM) junctions tiling the plasma membrane of dendrites at ∼1 μm intervals, interlinked by a meshwork of ER tubules patterned in a ladder-like array. Populated with Junctophilin-linked plasma membrane voltage-gated Ca2+channels and ER Ca2+-release channels (ryanodine receptors), ER-PM junctions are hubs for ER-PM crosstalk, fine-tuning of Ca2+homeostasis, and local activation of the Ca2+/calmodulin-dependent protein kinase II. Local spine stimulation activates the Ca2+modulatory machinery facilitating voltage-independent signal transmission and ryanodine receptor-dependent Ca2+release at ER-PM junctions over 20 μm away. Thus, interconnected ER-PM junctions support signal propagation and Ca2+release from the spine-adjacent ER. The capacity of this subcellular architecture to modify both local and distant membrane-proximal biochemistry potentially contributes to dendritic computations.

Highlights

Periodic ER-PM junctions tile neuronal dendritic plasma membrane in rodent and fly.

ER-PM junctions are populated by ER tethering and Ca2+release and influx machinery.

ER-PM junctions act as sites for local activation of CaMKII.

Local spine activation drives Ca2+release from RyRs at ER-PM junctions over 20 μm.
The External Microbiome Communicates with the Developing Zebrafish (Danio rerio) Embryo Through the Chorion and Influences Developmental Trajectory
Authors: Green Emily M. , Harishchandra Akila , Lickwar Colin R. , Rawls John F. , Di Giulio Richard T. , Jayasundara Nishad
Published: May 2024

The microbiome has a significant influence on host physiological processes including energy metabolism and neurobiology. However, current knowledge is largely limited to post-embryonic development, highlighting a notable gap in host-microbe communication during embryonic development, particularly in oviparous organisms. This is because the developing embryo is protected from the external environment by the chorion and typically considered to be sterile. We hypothesized the external microbiome influences embryonic development in oviparous organisms despite lack of physical contact with microbes, shaping host physiology beyond embryogenesis. To test this interaction, we utilized zebrafish (Danio rerio) reared germ-free or conventionalized with microbes at different times during embryonic development (6 and 24 hours post fertilization) to examine changes in transcriptomics, proteomics, and physiology at 32 hours post-fertilization. In contrast to the prevailing notion, we reveal a significant role of the external aquatic microbial community in regulating embryonic transcript and protein abundance associated with critical developmental processes including energy metabolism and neurodevelopment. Furthermore, we demonstrate the external microbial community drives differential expression of genes involved in cytochrome P450 directed xenobiotic metabolism and associated bioenergetic and behavioral responses following exposure to a CYP1A activator during embryogenesis. These findings reveal embryonic development is an integration of host genetic blueprints and external microbial cues, enhancing knowledge of fundamental developmental processes influenced by embryo-microbe interactions that shape developmental susceptibility to environmental stressors.

Significance Statement

Host-microbiome interactions play a crucial role in shaping vertebrate physiology. However, the impact of these interactions during embryonic development remains poorly understood which has limited our evaluation of environmental drivers of developmental disorders and disease. Here, we provide evidence that the external microbiome indirectly communicates with the developing zebrafish (Danio rerio) embryo through the chorion, influencing physiological processes including bioenergetics, neurodevelopment, and xenobiotic responses. These findings signify a critical role of the external microbiome during the early stages of embryonic development and may inform research addressing the effects of the maternal microbiome on human embryonic and fetal development, particularly in the context of developmental origins of disease and prenatal chemical exposures.
Genomic and functional analysis ofrmplocus variants inKlebsiella pneumoniae
Authors: Lam Margaret M.C. , Salisbury Stephen M. , Treat Logan P. , Wick Ryan R. , Judd Louise M. , Wyres Kelly L. , Brisse Sylvain , Walker Kimberly A. , Miller Virginia L. , Holt Kathryn E.
Published: May 2024

Abstract

Background

Klebsiella pneumoniaeis an opportunistic pathogen and a leading cause of healthcare-associated infections in hospitals, which are frequently antimicrobial resistant (AMR). Exacerbating the public health threat posed byK. pneumoniae, some strains also harbor additional hypervirulence determinants typically acquired via mobile genetic elements such as the well-characterised large virulence plasmid KpVP-1. ThermpADClocus is considered a key virulence feature ofK. pneumoniaeand is associated with upregulated capsule expression and the hypermucoid phenotype, which can enhance virulence by contributing to serum resistance. Typically such strains have been susceptible to all antimicrobials besides ampicillin, however the recent emergence of AMR hypermucoid strains is concerning.

Methods

Here, we investigate the genetic diversity, evolution, mobilisation and prevalence ofrmpADC, in a dataset of 14000 genomes from isolates of theKlebsiella pneumoniaespecies complex, and describe the RmST virulence typing scheme for trackingrmpADCvariants for the purposes of genomic surveillance. Additionally, we examine the functionality of representatives for variants ofrmpADCintroduced into a mutant strain lacking its nativermpADClocus.

Results

ThermpADClocus was detected in 7% of the dataset, mostly from genomes ofK. pneumoniaeand a very small number ofK. variicolaandK. quasipneumoniae. Sequence variants ofrmpADCgrouped into five distinct lineages (rmp1, rmp2, rmp2A, rmp3andrmp4) that corresponded to unique mobile elements, and were differentially distributed across different populations (i.e. clonal groups) ofK. pneumoniae. All variants were demonstrated to produce enhanced capsule production and hypermucoviscosity.

Conclusion

These results provide an overview of the diversity and evolution of a prominentK. pneumoniaevirulence factor and support the idea that screening forrmpADCinK. pneumoniaeisolates and genomes is valuable to monitor the emergence and spread of hypermucoidK. pneumoniae, including AMR strains.
Exploring evolution to uncover insights into protein mutational stability
Authors: Hermans Pauline , Tsishyn Matsvei , Schwersensky Martin , Rooman Marianne , Pucci Fabrizio
Published: May 2024

Determining the impact of mutations on the thermodynamic stability of proteins is essential for a wide range of applications such as rational protein design and genetic variant interpretation. Since protein stability is a major driver of evolution, evolutionary data are often used to guide stability predictions. Many state-of-the-art stability predictors extract evolutionary information from multiple sequence alignments (MSA) of proteins homologous to a query protein, and leverage it to predict the effects of mutations on protein stability. To evaluate the power and the limitations of such methods, we used the massive amount of stability data recently obtained by deep mutational scanning to study how best to construct MSAs and optimally extract evolutionary information from them. We tested different evolutionary models and found that, unexpectedly, independent-site models achieve similar accuracy to more complex epistatic models. A detailed analysis of the latter models suggests that their inference often results in noisy couplings, which do not appear to add predictive power over the independent-site contribution, at least in the context of stability prediction. Interestingly, by combining any of the evolutionary features with a simple structural feature, the relative solvent accessibility of the mutated residue, we achieved similar prediction accuracy to supervised, machine learning-based, protein stability change predictors. Our results provide new insights into the relationship between protein evolution and stability, and show how evolutionary information can be exploited to improve the performance of mutational stability prediction.
Guidance for triangulating data and estimates of HIV prevalence among pregnant women and coverage of PMTCT using the Spectrum AIDS Impact Module
Authors: Walters Magdalene K. , Korenromp Eline L. , Yakusik Anna , Wanyeki Ian , Kaboré André , Poimouribou Arthur , Ki Célestine , Dao Coumbo , Bambara Paul , Derme Salam , Ouedraogo Théophile , Tang Kai Hon , Boily Marie-Claude , Mahy Mary , Imai-Eaton Jeffrey W.
Published: May 2024

Background

Most countries use the Spectrum AIDS Impact Module (Spectrum-AIM), antenatal care routine HIV testing, and antiretroviral treatment data to estimate HIV prevalence among pregnant women. Non-representative programme data may lead to inaccurate estimates HIV prevalence and treatment coverage for pregnant women.

Setting

154 locations in 126 countries.

Methods

Using 2023 UNAIDS HIV estimates, we calculated three ratios: (1) HIV prevalence among pregnant women to all women 15-49y (prevalence), (2) ART coverage before pregnancy to women 15-49y ART coverage (ART pre-pregnancy), and (3) ART coverage at delivery to women 15-49y ART coverage (PMTCT coverage). We developed an algorithm to identify and adjust inconsistent results within regional ranges in Spectrum-AIM, illustrated using Burkina Faso’s estimates.

Results

In 2022, the mean regional ratio of prevalence among pregnant women to all women ranged from 0.68 to 0.95. ART coverage pre-pregnancy ranged by region from 0.40 to 1.22 times ART coverage among all women. Mean regional PMTCT coverage ratios ranged from 0.85 to 1.51. The prevalence ratio in Burkina Faso was 1.59, above the typical range 0.62-1.04 in western and central Africa. Antenatal clinics reported more PMTCT recipients than estimated HIV-positive pregnant women from 2015 to 2019. We adjusted inputted PMTCT programme data to enable consistency of HIV prevalence among pregnant women from programmatic routine HIV testing at antenatal clinics with values typical for Western and central Africa.

Conclusion

These ratios offer Spectrum-AIM users a tool to gauge the consistency of their HIV prevalence and treatment coverage estimates among pregnant women with other countries in the region.
Neuropsychological and social predictors of participation in a deep brain stimulation study of Parkinson’s disease and dystonia
Authors: Hahn Amelia , Lazar Ann A. , Cernera Stephanie , Little Simon , Wang Sarah S. , Starr Philip A. , Racine Caroline A.
Published: May 2024

Objectives

Participation is essential to DBS research, yet circumstances that affect diverse participation remain unclear. Here we evaluate factors impacting participation in an adaptive DBS study of Parkinson’s disease (PD) and dystonia.

Methods

Twenty participants were implanted with a sensing-enabled DBS device (Medtronic Summit RC+S) that allows neural data streaming in naturalistic settings and encouraged to stream as much as possible for the first five months after surgery. Using standardized baseline data obtained through neuropsychological evaluation, we compared neuropsychological and social variables to streaming hours.

Results

Marital status and irritability significantly impacted streaming hours (estimate=136.7, bootstrapped (b)CIb=45.0 to 249.0,pb=0.016, and estimate=-95.1,CIb=-159.9 to -49.2,pb=0.027, respectively). These variables remained significant after multivariable analysis. Composite scores on verbal memory evaluations predicted the number of hours of data streamed (R2=0.284, estimate=67.7,CIb=20.1 to 119.9,pb=0.019).

Discussion

Verbal memory impairment, irritability, and lack of a caregiver may be associated with decreased participation. Further study of factors that impact research participation is critical to the sustained inclusion of diverse participants.
A multimodal dataset for precision oncology in head and neck cancer
Authors: Dörrich Marion , Balk Matthias , Heusinger Tatjana , Beyer Sandra , Kanso Hassan , Matek Christian , Hartmann Arndt , Iro Heinrich , Eckstein Markus , Gostian Antoniu-Oreste , Kist Andreas M.
Published: May 2024

Head and neck cancer is a common disease and is associated with a poor prognosis. A promising approach to improving patient outcomes is personalized treatment, which uses information from a variety of modalities. However, only little progress has been made due to the lack of large public datasets. We present a multimodal dataset, HANCOCK, that comprises monocentric, real-world data of 763 head and neck cancer patients. Our dataset contains demographical, pathological, and blood data as well as surgery reports and histologic images. We show its potential clinical impact in a multimodal machine-learning setting by proposing adjuvant treatment for previously unidentified risk patients. We found that especially the multimodal model outperformed single-modality models (area under the curve (AUC): 0.85). We believe that HANCOCK will not only open new insights into head and neck cancer pathology but also serve as a major source for researching multimodal machine-learning methodologies in precision oncology.
The Influence of Parkinson’s Disease on Depression Through Structural Equation Modeling
Authors: Moon Jasmine , Winninghoff Jonah , Paracha Mariam
Published: May 2024

Objective

To analyze and compare the magnitudes of nonmotor symptoms in depressed individuals with and without Parkinson’s Disease.

Methods

Downloaded in January 2023, symptoms and characteristics of depressed individuals with and without Parkinson’s Disease were extracted from the longitudinal study Fox Insight. The directed acyclic graph theory was used to represent causal relationships and to determine the associations between nonmotor symptoms, depression, and Parkinson’s Disease. The 2-PL and the Rasch models were used to better fit the data and identify the items consistent with the assumptions.

Results

Dropped interests and activitieswas the item that was of greatest impact and most characteristic for depressed individuals both with and without PD.Double visionwas the item of least difficulty while an additional item of significant impact wasPreferred to stay at home. Education attainment had little to no impact on depression severity in individuals with and without PD.

Conclusions

Dropped interests and activitieswas most severe within both populations. Relatedly, an increased average number of leisure hours was associated with greater depression severity. Overall, as an individual’s depression worsens, there is an overall upward trend in the severity of their nonmotor symptoms. We recommend additional analyses on the strength of relationships between these neurologic disorders and nonmotor symptoms.
Antimalarial Drug Resistance inPlasmodium falciparumfrom Tak Province, Thailand (1998-2001): A TaqMan Array Card Study
Authors: Thaloengsok Sasikanya , Chaisatit Chaiyaporn , Saingam Piyaporn , Lertsethtakarn Paphavee , Spring Michele , Sabaithip Sriwichai , Pholwat Suporn , Guler Jennifer L , Houpt Eric , Vesely Brian
Published: May 2024

Despite declining malaria cases in Thailand, surveillance in endemic areas is crucial. Retrospectively analyzing samples from Tak province, Thailand, we found prevalent drugresistantPlasmodium falciparum, particularly to mefloquine and sulfadoxine/pyrimethamine. Notably, mutations indicating resistance to artemisinin were detected at low frequencies, suggesting evolving resistance. These findings stress the need for continuous surveillance to guide control strategies and prevent outbreaks, even with decreasing cases, to sustain malaria elimination efforts.
Associations between mosaic loss of sex chromosomes and incident hospitalization for atrial fibrillation in the United Kingdom
Authors: Lim Jungeun , Hubbard Aubrey K. , Blechter Batel , Shi Jianxin , Zhou Weiyin , Loftfield Erikka , Machiela Mitchell J. , Wong Jason Y.Y.
Published: May 2024

Background

Mosaic loss of chromosome Y (mLOY) in leukocytes of men reflects genomic instability from aging, smoking, and environmental exposures. A similar mosaic loss of chromosome X (mLOX) occurs among women. However, the associations between mLOY, mLOX, and risk of incident heart diseases are unclear.

Methods

We estimated associations between mLOY, mLOX, and risk of incident heart diseases requiring hospitalization, including atrial fibrillation, myocardial infarction, ischemic heart disease, cardiomyopathy, and heart failure. We analyzed 190,613 men and 224,853 women with genotyping data from the UK Biobank. Among these participants, we analyzed 37,037 men with mLOY and 13,978 women with mLOX detected using Mosaic Chromosomal Alterations caller. Multivariable Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of each incident heart disease in relation to mLOY in men and mLOX in women. Additionally, Mendelian randomization (MR) was conducted to estimate causal associations.

Results

Among men, detectable mLOY was associated with elevated risk of atrial fibrillation (HR=1.06, 95%CI:1.03-1.11). The associations were apparent in both never-smokers (HR=1.07, 95%:1.01-1.14) and ever-smokers (HR=1.05, 95%CI:1.01-1.11) as well as men > and ≤60 years of age. MR analyses supported causal associations between mLOY and atrial fibrillation (HRMR-PRESSO=1.15, 95%CI:1.13-1.18). Among post-menopausal women, we found a suggestive inverse association between detectable mLOX and atrial fibrillation risk (HR=0.90, 95%CI:0.83-0.98). However, associations with mLOY and mLOX were not found for other heart diseases.

Conclusions

Our findings suggest that mLOY and mLOX reflect sex-specific biological processes or exposure profiles related to incident atrial fibrillation requiring hospitalization.

WHAT IS KNOWN?

A previous population study found links between death from atrial fibrillation and heart failure, and mosaic loss of chromosome Y (mLOY) in leukocytes, which is a marker of genomic instability, environmental exposures, and aging. Additionally, mLOY has been associated cross-sectionally with prevalent cardiovascular and metabolic diseases.

A similar but less common mosaic loss of chromosome X (mLOX) occurs among women but is role in disease pathogenesis is less characterized.

The contributions of mLOY and mLOX to risk of hospitalization for incident atrial fibrillation, heart failure syndrome, and other heart diseases are unclear.

WHAT THE STUDY ADDS?

Among men, mLOY was associated with elevated risk of incident atrial fibrillation. Further, we found suggestive evidence linking mLOX to atrial fibrillation risk among women. Taken together, mLOY and mLOX potentially reflects sex-specific factors related to the pathogenesis of atrial fibrillation.
Carotid Intima-media thickness, carotid distensibility and incident heart failure in older men: The British Regional Heart Study
Authors: Akinmolayan Atinuke , Papacosta A Olia , Lennon Lucy T , Ellins Elizabeth A , Halcox Julian PJ , Whincup Peter H , Wannamethee S Goya
Published: May 2024

Objectives

Carotid intima-media thickness (CIMT) and carotid distensibility are markers of arterial change, however little is known of the prognostic value in incident HF. We aimed to assess this prospective association.

Design

Longitudinal analysis of data from the British Regional Heart Study, a prospective cohort study

Participants

1069 men aged 71-92 years, without a diagnosis of heart failure or myocardial infarction (MI) at baseline.

Methods

Between 2010-2012, participants completed a questionnaire, underwent a physical examination, and provided a fasting blood sample. CIMT and carotid artery distension were measured and carotid distensibility was calculated. Cox proportional hazards modelling was used to assess the multivariate-adjusted hazard ratios of incident HF by quartiles of CIMT and distensibility.

Results

Adjusted for age, social class, smoking, physical activity, alcohol status, BMI, use of statins and antihypertensives, prevalent diabetes mellitus and stroke, pulse pressure, and presence of atrial arrhythmias, lower carotid distensibility was associated with increased risk of incident HF (HR 2.55, 95% CI 1.24 to 5.24, p=0.01). The association persisted after further adjustment for CIMT and incident MI (HR 2.53, 95% CI 1.23 to 5.22, p=0.01). Higher CIMT was associated with increased risk of incident HF (HR 2.20, 95% CI 1.14 to 4.23, p=0.02). However, this was attenuated after adjustment for both CIMT and incident MI (HR 1.64, 95% CI 0.84 to 3.21, p=0.1).

Conclusions

Low carotid artery distensibility, but not high carotid intima-media thickness (CIMT), was associated with an increased risk of incident heart failure, independent of the development of myocardial infarction.
Long-term risk of Stroke after Acute Coronary Syndrome. The ABC-10* Study on Heart Disease
Authors: Mahmoud Heba T. , Cordiano Rocco , Merotto David , Dario Mattia Ludovico , Cavuto Fiorella , Berton Giuseppe
Published: May 2024

Background

Previous studies link myocardial infarction to increased stroke risk. This long-term prospective study examines stroke incidence and outcomes in acute coronary syndrome (ACS) patients, identifying risk factors and geographic disparities.

Methods

We enrolled 535 ACS patients admitted to hospitals across three provinces in the Veneto region of Italy. Patients’ residences were classified into three urban and three rural areas in each province. Patients were followed prospectively for 24 years or until death.

Results

All patients, except for three, completed the follow-up, totaling 6151 person-years. During follow-up, 84 patients experienced a stroke, with 85% being ischemic and 15% hemorrhagic, proving fatal in 43 cases. The stroke incidence rate was 14/1000 person-years. Multivariable Cox regression analysis identified older age (HR 1.84; 95% CI 1.30-2.60), atrial fibrillation (AF) (HR 2.64; 95% CI 1.49-4.67), and a higher albumin-to-creatinine ratio (HR 1.38; 95% CI 1.04-1.83) as independent predictors of overall stroke risk, while higher eGFR (HR 0.71; 95% CI 0.53-0.95) was independently associated with a lower risk.

A sub-analysis revealed older age (HR 2.67; 95% CI 1.60-4.45) and AF (HR 2.95; 95% CI 1.38-6.32) as independent predictors of fatal stroke. Unexpectedly, we observed a higher fatal stroke risk in urban areas (HR 1.89; 95% CI 1.03-3.48) and southern provinces (HR 1.71; 95% CI 1.15-2.53).

Conclusion

The ABC study identified several baseline clinical predictors associated with higher stroke risk long after ACS. A geographical association with the risk of fatal stroke was also observed, underscoring the importance of considering both individual clinical predictors and broader geographic factors in stroke prevention policies.
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

Deep 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

Lipoprotein 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

Many 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

1

Seizures 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

Study objectives

To assess the association between self-reported measures of sleep quality and cortical and subcortical local morphometry.

Methods

Sleep 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.

Results

Sleep 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.

Conclusions

This 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 Significance

This 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

Neuropeptides 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

Background

PrEP 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.

Methods

We 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.

Findings

Among 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.

Interpretation

The 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

In 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

Background

Idiopathic 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).

Methods

Patients 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.

Results

Proteomic 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.

Conclusions

The 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.