bluuebunny/crossref_metadata_2025 huggingface dataset:
Machine learning links T cell function and spatial localization to neoadjuvant immunotherapy and clinical outcome in pancreatic cancer
Authors: Blise Katie E. , Sivagnanam Shamilene , Betts Courtney B. , Betre Konjit , Kirchberger Nell , Tate Benjamin , Furth Emma E. , Dias Costa Andressa , Nowak Jonathan A. , Wolpin Brian M. , Vonderheide Robert H. , Goecks Jeremy , Coussens Lisa M. , Byrne Katelyn T.
Published: October 2023

Tumor molecular datasets are becoming increasingly complex, making it nearly impossible for humans alone to effectively analyze them. Here, we demonstrate the power of using machine learning to analyze a single-cell, spatial, and highly multiplexed proteomic dataset from human pancreatic cancer and reveal underlying biological mechanisms that may contribute to clinical outcome. A novel multiplex immunohistochemistry antibody panel was used to audit T cell functionality and spatial localization in resected tumors from treatment-naive patients with localized pancreatic ductal adenocarcinoma (PDAC) compared to a second cohort of patients treated with neoadjuvant agonistic CD40 (αCD40) monoclonal antibody therapy. In total, nearly 2.5 million cells from 306 tissue regions collected from 29 patients across both treatment cohorts were assayed, and more than 1,000 tumor microenvironment (TME) features were quantified. We then trained machine learning models to accurately predict αCD40 treatment status and disease-free survival (DFS) following αCD40 therapy based upon TME features. Through downstream interpretation of the machine learning models’ predictions, we found αCD40 therapy to reduce canonical aspects of T cell exhaustion within the TME, as compared to treatment-naive TMEs. Using automated clustering approaches, we found improved DFS following αCD40 therapy to correlate with the increased presence of CD44+CD4+Th1 cells located specifically within cellular spatial neighborhoods characterized by increased T cell proliferation, antigen-experience, and cytotoxicity in immune aggregates. Overall, our results demonstrate the utility of machine learning in molecular cancer immunology applications, highlight the impact of αCD40 therapy on T cells within the TME, and identify potential candidate biomarkers of DFS for αCD40-treated patients with PDAC.
From disturbances to nonlinear fitness and back
Authors: Tuljapurkar Shripad , Jaggi Harman , Gascoigne Samuel J. L. , Zuo Wenyun , Kajin Maja , Salguero-Gómez Roberto
Published: October 2023

A fundamental goal of Ecology is to predict how natural populations respond to disturbances. Accordingly, the last decades have witnessed key theoretical developments in stochastic demography and transient dynamics. However, both areas, have to date been largely disconnected. Here, we introduce an expression for the second derivatives of population growth rate with respect to demographic rates (e.g. survival-dependent state transitions and reproduction) with direct links to transient dynamics. We use this connection to develop a new mathematical framework showing how transient responses to pulse disturbances lead to a quantitative description of press disturbances. Second-derivatives of population growth rate with respect to said demographic rates are valuable as they quantify the degree of nonlinear selection acting on demographic rates and how environments shape the long-term performance of populations. Whilst valuable, previous methods to quantify second-order derivatives have heavily relied on vector calculus-potentially obscuring important demographic processes connected to second-order derivatives. Here we offer an intuitive method using perturbation theory and our approach is valid for any discrete-time, st(age)-based structured population model. Importantly, our new method implicates an intimate relationship between the nonlinear selection pressures acting on demographic rates with the emergent transient dynamics of populations over time. We showcase these relationships through mathematical proofs, connecting to Cohen’s cumulative distance, and identifying a strong relationship between generation time across 439 unique plant and animal species (2690 population models). As such, this new method represents a valuable tool for population ecologists, comparative demographers, and conservation biologists to understand and protect structured populations in a changing world.
A systematic screen for co-option of transposable elements across the fungal kingdom
Authors: Oggenfuss Ursula , Badet Thomas , Croll Daniel
Published: October 2023

How novel protein functions are acquired is a central question in molecular biology. Key paths to novelty include gene duplications, recombination or horizontal acquisition. Transposable elements (TEs) are increasingly recognized as a major source of novel domain-encoding sequences. However, the impact of TE coding sequences on the evolution of the proteome remains understudied. Here, we analyzed 1,237 genomes spanning the phylogenetic breadth of the fungal kingdom. We scanned proteomes for evidence of co-occurrence of TE-derived domains along with other conventional protein functional domains. We detected more than 13,000 predicted proteins containing potentially TE-derived domain, of which 825 were identified in more than five genomes, indicating that many host-TE fusions may have persisted over long evolutionary time scales. We used the phylogenetic context to identify the origin and retention of individual TE-derived domains. The most common TE-derived domains are helicases derived fromAcadem,KolobokorHelitron.We found putative TE co-options at a higher rate in genomes of the Saccharomycotina, providing an unexpected source of protein novelty in these generally TE depleted genomes. We investigated in detail a candidate host-TE fusion with a heterochromatic transcriptional silencing function that may play a role in TE and gene regulation in ascomycetes. The affected gene underwent multiple full or partial losses within the phylum. Overall, our work establishes a kingdom-wide view of how domains likely derived from TEs contribute to the evolution of protein functions.
Integrated Proteomics Identifies Troponin I Isoform Switch as a Regulator of a Sarcomere-Metabolism Axis During Cardiac Regeneration
Authors: Aballo Timothy J. , Bae Jiyoung , Paltzer Wyatt G. , Chapman Emily A. , Salamon Rebecca J. , Mann Morgan M. , Ge Ying , Mahmoud Ahmed I.
Published: October 2023

Adult mammalian cardiomyocytes have limited proliferative potential, and after myocardial infarction (MI), injured cardiac tissue is replaced with fibrotic scar rather than with functioning myocardium. In contrast, the neonatal mouse heart possesses a regenerative capacity governed by cardiomyocyte proliferation; however, a metabolic switch from glycolysis to fatty acid oxidation during postnatal development results in loss of this regenerative capacity. Interestingly, a sarcomere isoform switch also takes place during postnatal development where slow skeletal troponin I (ssTnI) is replaced with cardiac troponin I (cTnI). In this study, we first employ integrated quantitative bottom-up and top-down proteomics to comprehensively define the proteomic and sarcomeric landscape during postnatal heart maturation. Utilizing a cardiomyocyte-specific ssTnI transgenic mouse model, we found that ssTnI overexpression increased cardiomyocyte proliferation and the cardiac regenerative capacity of the postnatal heart following MI compared to control mice by histological analysis. Our global proteomic analysis of ssTnI transgenic mice following MI reveals that ssTnI overexpression induces a significant shift in the cardiac proteomic landscape. This shift is characterized by an upregulation of key proteins involved in glycolytic metabolism. Collectively, our data suggest that the postnatal TnI isoform switch may play a role in the metabolic shift from glycolysis to fatty acid oxidation during postnatal maturation. This underscores the significance of a sarcomere-metabolism axis during cardiomyocyte proliferation and heart regeneration.
Bio-efficacy of field aged novel class of long-lasting insecticidal nets, against pyrethroid-resistant malaria vectors in Tanzania: A series of experimental hut trials
Authors: Martin Jackline L. , Messenger Louisa A. , Rowland Mark , Mosha Franklin W , Bernard Edmund , Kisamo Monica , Limbe Shaban , Hape Patric , Thickstun Charles , Steven Crene , Moshi Oliva , Shirima Boniface , Matowo Nancy S. , Mosha Jacklin F , Dee Dominic P , Churcher Thomas S , Kulkarni Manisha A. , Manjurano Alphaxard , Protopopoff Natacha
Published: October 2023

New classes of long-lasting insecticidal nets (LLINs) incorporating two insecticides, or an insecticide and a synergist, are recommended by the World Health Organization (WHO) to prevent malaria transmitted by mosquito vectors resistant to pyrethroid and other common insecticide classes. This study was nested in a large-scale cluster-randomized controlled trial conducted in Tanzania. A series of experimental hut trials (EHTs) aimed to evaluate the bio-efficacy of trial LLINs on the mosquito indicators most pertinent to malaria transmission over 3 years of use in the community. The aim was to evaluate nets subjected to a broader range of household factors than WHO standardized washing.

The following field collected LLINs were assessed: 1/OlysetTMPlus (combining piperonyl butoxide synergist and permethrin), 2/Interceptor®G2 (chlorfenapyr and alpha-cypermethrin), 3/Royal Guard®(pyriproxyfen and alpha-cypermethrin), 4/Interceptor®(alpha-cypermethrin only), 5/a new Interceptor®, and 6/an untreated net. Thirty nets of each type were withdrawn from the community at 12, 24 and 36 months after distribution and used for the EHTs. Pre-specified outcomes were 72-hour mortality for Interceptor®G2, 24-hour mortality for OlysetTMPlus, and fertility based on egg development stage for Royal Guard®.

Overall; Interceptor®G2 LLINs induced higher 72-hour mortality compared to standard LLINs of the same age up to 12 months (44% vs 21%), OR: 3.5, 95% CI: 1.9 – 6.6, p-value < 0.001 and 24-hour mortality was only significantly higher in OlysetTMPlus when new (OR: 13.6, 95%CI: 4.4 – 41.3, p-value < 0.001) compared to standard LLINs but not at 12 months (17% vs 13%; OR: 2.1, 95% CI: 1.0 – 4.3; p-value = 0.112). A small non-significant effect of pyriproxyfen onAnophelesfertility was observed for Royal Guard®up to 12 months (75% vs 98%, OR: 1.1, 95% CI: 0.0 – 24.9, p-value = 0.951). There was no evidence of a difference in the main outcomes for any of the new class of LLINs at 24 and 36 months compared to standard LLINs.

Interceptor®G2 LLINs showed superior bio-efficacy compared to standard LLINs for only up to 12 months and the effect of OlysetTMPlus was observed when new for all species and 12 months forAn. gambiaes.l. only. The pyriproxyfen component of Royal Guard®had a short and limited effect on fertility
Evidence for a role of synchrony but not common fate in the perception of biological group movements
Authors: Cracco Emiel , Papeo Liuba , Wiersema Jan R.
Published: October 2023

Extensive research has shown that observers are able to efficiently extract summary information from groups of people. However, little is known about the cues that determine whether multiple people are represented as a social group or as independent individuals. Initial research on this topic has primarily focused on the role of static cues. Here, we instead investigate the role of dynamic cues. In two experiments with male and female human participants, we use EEG frequency tagging to investigate the influence of two fundamental Gestalt principles - synchrony and common fate - on the grouping of biological movements. In Experiment 1, we find that brain responses coupled to four point-light figures walking together are enhanced when they move in sync vs. out of sync, but only when they are presented upright. In contrast, we found no effect of movement direction (i.e., common fate). In Experiment 2, we rule out that synchrony takes precedence over common fate by replicating the null effect of movement direction while keeping synchrony. These results put forward synchrony as an important driver of social grouping, consistent with the fact that it is an important feature of social interaction and an indicator of social cohesion. In contrast, the influence of common fate on social grouping is less clear and will require further research.
A continental-scale analysis reveals the latitudinal gradient of stomatal density across amphistomatous species: Evolutionary history vs. present-day environment
Authors: Liu Congcong , Huang Kexiang , Zhao Yifei , Li Ying , He Nianpeng
Published: October 2023

Amphistomy is a potential method for increasing photosynthetic rate; however, latitudinal gradients of stomatal density across amphistomatous species and their drivers remain unknown. Here, the adaxial stomatal density (SDad) and abaxial stomatal density (SDab) of 486 amphistomatous species-site combinations, belonging to 32 plant families, were collected from China, and their total stomatal density (SDtotal) and stomatal ratio (SR) were calculated. Overall, these four stomatal traits did not show significant phylogenetic signals. There were no significant differences in SDaband SDtotalbetween woody and herbaceous species, but SDadand SR were higher in woody species than in herbaceous species. Besides, a significantly positive relationship between SDaband SDadwas observed. We also found that stomatal density (including SDab, SDad, and SDtotal) decreased with latitude while SR increased with latitude, and temperature seasonality was the most important environmental factor driving it. Besides, evolutionary history (represented by both phylogeny and species) explained about 10–22 fold more of the variation in stomatal traits than the present-day environment (65.2%–71.1% vs. 2.9%–6.8%). Our study extended our knowledge of trait-environment relationships and highlighted the importance of evolutionary history in driving stomatal trait variability.
Coordinated changes in a cortical circuit sculpt effects of novelty on neural dynamics
Authors: Ito Shinya , Piet Alex , Bennett Corbett , Durand Séverine , Belski Hannah , Garrett Marina , Olsen Shawn R. , Arkhipov Anton
Published: October 2023

Recent studies have found dramatic cell-type specific responses to stimulus novelty, highlighting the importance of analyzing the cortical circuitry at the cell-type specific level of granularity to understand brain function. Although initial work classified and characterized activity for each cell type, the specific alterations in cortical circuitry—particularly when multiple novelty effects interact—remain unclear. To address this gap, we employed a large-scale public dataset of electrophysiological recordings in the visual cortex of awake, behaving mice using Neuropixels probes and designed population network models to investigate the observed changes in neural dynamics in response to a combination of distinct forms of novelty. The model parameters were rigorously constrained by publicly available structural datasets, including multi-patch synaptic physiology and electron microscopy data. Our systematic optimization approach identified tens of thousands of model parameter sets that replicate the observed neural activity. Analysis of these solutions revealed generally weaker connections under novel stimuli, as well as a shift in the balance e between SST and VIP populations. Along with this, PV and SST populations experienced overall more excitatory influences compared to excitatory and VIP populations. Our results also highlight the role of VIP neurons in multiple aspects of visual stimulus processing and altering gain and saturation dynamics under novel conditions. In sum, our findings provide a systematic characterization of how the cortical circuit adapts to stimulus novelty by combining multiple rich public datasets.
Whole brain mapping of orexin receptor mRNA expression visualized by branchedin situhybridization chain reaction
Authors: Tsuneoka Yousuke , Funato Hiromasa
Published: October 2023

Orexins, which are produced within neurons of the lateral hypothalamic area, play a pivotal role in the regulation of various behaviors, including sleep/wakefulness, reward behavior, and energy metabolism, via orexin receptor type 1 (OX1R) and type 2 (OX2R). Despite the advanced understanding of orexinergic regulation of behavior at the circuit level, the precise distribution of orexin receptors in the brain remains unknown. Here, we develop a new branchedin situhybridization chain reaction (bHCR) technique to visualize multiple target mRNAs in a semiquantitative manner, combined with immunohistochemistry, which provided comprehensive distribution of orexin receptor mRNA and neuron subtypes expressing orexin receptors in mouse brains. Only a limited number of cells expressing bothOx1randOx2rwere observed in specific brain regions, such as the dorsal raphe nucleus and ventromedial hypothalamic nucleus. In many brain regions,Ox1r-expressing cells andOx2r-expressing cells belong to different cell types, such as glutamatergic and GABAergic neurons. Moreover, our findings demonstrated considerable heterogeneity inOx1r- orOx2r-expressing populations of serotonergic, dopaminergic, noradrenergic, cholinergic, and histaminergic neurons. The majority of orexin neurons did not express orexin receptors. This study provides valuable insights into the mechanism underlying the physiological and behavioral regulation mediated by the orexin system, as well as the development of therapeutic agents targeting orexin receptors.

Significance statement

The neuropeptide orexin regulates sleep and other behaviors through its receptors, OX1R and OX2R, which are targets for the development of therapeutic agents for sleep and related disorders. However, the cellular distribution of orexin receptors in the brain is only partially known. We applied a newly developed branchedin situhybridization chain reaction (bHCR) technique and conducted a whole-brain mapping of orexin receptor mRNA expression in the brain with neuron subtype markers. Few cells expressed both OX1R and OX2R, and OX1R and OX2R were expressed in the different neuronal subtypes in many brain regions. This study fills an important gap in understanding and modulating the orexin system.
The biological role of local and global fMRI BOLD signal variability in human brain organization
Authors: Baracchini Giulia , Zhou Yigu , Castanheira Jason da Silva , Hansen Justine Y. , Rieck Jenny , Turner Gary R. , Grady Cheryl L. , Misic Bratislav , Nomi Jason , Uddin Lucina Q. , Spreng R. Nathan
Published: October 2023

Variability drives the organization and behavior of complex systems, including the human brain. Understanding the variability of brain signals is thus necessary to broaden our window into brain function and behavior. Few empirical investigations of macroscale brain signal variability have yet been undertaken, given the difficulty in separating biological sources of variance from artefactual noise. Here, we characterize the temporal variability of the most predominant macroscale brain signal, the fMRI BOLD signal, and systematically investigate its statistical, topographical and neurobiological properties. We contrast fMRI acquisition protocols, and integrate across histology, microstructure, transcriptomics, neurotransmitter receptor and metabolic data, fMRI static connectivity, and empirical and simulated magnetoencephalography data. We show that BOLD signal variability represents a spatially heterogeneous, central property of multi-scale multi-modal brain organization, distinct from noise. Our work establishes the biological relevance of BOLD signal variability and provides a lens on brain stochasticity across spatial and temporal scales.
Screening Peptide Drug Candidates to Neutralize Whole Viral Agents : A Case study with SARS-CoV-2 Virus
Authors: Özçelik Cemile Elif , Araz Cemre Zekiye , Yılmaz Özgür , Gülyüz Sevgi , Özkul Aykut , Şeker Urartu Özgür Şafak
Published: October 2023

Covid19 pandemic revealed the reality for the need of therapeutic and pharmaceutical molecule development in a short time with different approaches. Although the enhancement of immunological memory by vaccination was the quicker and robust strategy, still medication is required for immediate treatment for a patient. For this purpose, one of the approaches is developing new therapeutic molecule development like peptide-based drugs. Also, peptides can be used developing other molecules like nanobodies. Here, M13 phage display library was used for selecting SARS-CoV-2 interacting peptides for developing a neutralizing molecule for further use. Biopanning was applied with four iterative cycles to select phages displaying different 12-amino acid-long peptides. Then, the M13 phage genomic region where peptide sequences expressed were analyzed and sequences were obtained. Randomly selected peptide sequences were synthesized by solid-state peptide synthesis method. These peptides were analyzed by quartz crystal microbalance method in terms or peptide interaction capacity with specifically wild-type S protein. Next, QCM data was further validated by enzyme-linked immunosorbent assay (ELISA) in order to check peptides according to their neutralizing capacity rather than binding to S1 protein. The results showed that, phage display served an opportunity for selecting peptides which can be used and developed further as pharmaceutical molecules. More specifically, scpep3, scpep8 and scpep10 had both binding and neutralizing capacity for S1 protein as a candidate for therapeutic molecule.
Comparing ancestry calibration approaches for a trans-ancestry colorectal cancer polygenic risk score
Authors: Rosenthal Elisabeth A. , Hsu Li , Thomas Minta , Peters Ulrike , Kachulis Christopher , Patterson Karynne , Jarvik Gail P.
Published: October 2023

Background

Colorectal cancer (CRC) is a complex disease with monogenic, polygenic and environmental risk factors. Polygenic risk scores (PRS) are being developed to identify high polygenic risk individuals. Due to differences in genetic background, PRS distributions vary by ancestry, necessitating calibration.

Methods

We compared four calibration methods using the All of Us Research Program Whole Genome Sequence data for a CRC PRS previously developed in participants of European and East Asian ancestry. The methods contrasted results from linear models with A) the entire data set or an ancestrally diverse training set AND B) covariates including principal components of ancestry or admixture. Calibration with the training set adjusted the variance in addition to the mean.

Results

All methods performed similarly within ancestry with OR (95% C.I.) per s.d. change in PRS: African 1.5 (1.02, 2.08), Admixed American 2.2 (1.27, 3.85), European 1.6 (1.43, 1.89), and Middle Eastern 1.1 (0.71, 1.63). Using admixture and an ancestrally diverse training set provided distributions closest to standard Normal with accurate upper tail frequencies.

Conclusion

Although the PRS is predictive of CRC risk for most ancestries, its performance varies by ancestry.Post-hoccalibration preserves the risk prediction within ancestries. Training a calibration model on ancestrally diverse participants to adjust both the mean and variance of the PRS, using admixture as covariates, created standard Normal z-scores. These z-scores can be used to identify patients at high polygenic risk, and can be incorporated into comprehensive risk scores including other known risk factors, allowing for more precise risk estimates.
READi-Dem: ML-powered, web-interface tool for Robust, Efficient, Affordable Diagnosis of Dementia
Authors: Klar Verena , Thompson Elinor , Atay Melvin Selim , Owoade Peter , Toniolo Sofia , Dehsarvi Amir , Rathee Sanjay
Published: October 2023

Background

Dementia screening tools typically involve face-to-face cognitive testing. Indeed, this introduces an increasing burden on the clinical staff, particularly in low-resource settings. The objective of our study is to develop an integrated online platform for efficient dementia screening, using a brief and cost-effective assessment.

Methods

We used the Longitudinal Ageing Study in India dataset (LASI-DAD, n=2528) to predict dementia diagnosis based on the Clinical Dementia Rating (CDR). Using feature selection algorithms and principal component analysis (PCA), we identified key predictive features. We compared the performance of six machine learning (ML) classifiers that were trained on the 42 selected features (full model) and the two components identified by PCA (minimal model). The best-performing model was selected for our web platform.

Results

Selected features mapped onto two distinct, interpretable domains: a cognitive domain and an informant domain. The first two principal components cumulatively explained 90.2% of the variance and included questions from the Mini-Mental State Exam (MMSE) and the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). Classifiers trained on the minimal model performed on par with the full model, with Support Vector Machine performing best (93.4%). The model did not reliably predict Parkinson’s disease (67% accuracy) or stroke (53.1% accuracy), suggesting dementia specificity. The respective questions from MMSE and IQCODE (27 items) were incorporated into our online platform.

Conclusion

We built an online platform enabling end-to-end screening for dementia from assessment to prediction, based on patient and caregiver reports. Web App code is available at GitHub:https://github.com/sanjaysinghrathi/READi-Dem& Web App link is available at Web Page:https://researchmind.co.uk/readi-dem. For the convenience of researchers, a video summarizing our work is also accessible on theWeb App PageandYouTube Link.
Clostridioides difficileMreE (PBP2) variants facilitate clinical disease during cephalosporin exposures
Authors: Worley Jay Noboru , Benedetto Nicholas D. , Delaney Mary , Paiva Ana Oliveira , Chapot-Chartier Marie-Pierre , Peltier Johann , Bry Lynn
Published: October 2023

Cephalosporins are the most common triggers of healthcare-associatedClostridioides difficileinfections (CDI). Here, we confirm gene-level drivers of cephalosporin resistance and their roles in promoting disease. Genomic-epidemiologic analyses of 306C. difficileisolates from a hospital surveillance program monitoring asymptomatic carriers and CDI patients identified prevalent third-generation cephalosporin resistance to ceftriaxone at >256 ug/mL in 26% of isolates. Resistance was associated with patient cephalosporin exposures 8-10 days beforeC. difficiledetection. Genomic analyses identified variants in themreEpenicillin binding protein 2 (PBP2) associated with resistance to multiple beta-lactam classes. Transfer of variants into susceptible strain CD630 elevated resistance to first and third-generation cephalosporins. Transfer into the mouse-infective strain ATCC 43255 enabled disease when mice were exposed to 500ug/mL cefoperazone, a dose that inhibited the isogenic susceptible strain. Our findings establish roles of cephalosporins andmreE-cephalosporin-resistant variants in CDI and provide testable genetic loci for detecting resistance in patient strains.
Device-measured vigorous intermittent lifestyle physical activity and major cardiovascular events
Authors: Stamatakis Emmanuel , Ahmadi Matthew N. , Biswas Raaj Kishore , del Pozo Cruz Borja , Thøgersen-Ntoumani Cecilie , Murphy Marie H , Sabag Angelo , Lear Scott A. , Gill Jason MR , Chow Clara K , Hamer Mark
Published: October 2023

Importance

Vigorous physical activity is a time-efficient and potent preventive intervention for major adverse cardiovascular events (MACE), although longer traditional exercise sessions are unappealing or inaccessible to most adults.

Objective

We examined the dose-response associations of device-measured vigorous intermittent lifestyle physical activity (VILPA, brief sporadic bouts of higher intensity occurring during daily living) with MACE and its sub-types in women and men. We also undertook analogous analyses in a sample of exercisers.

Design, Setting, and Participants

Prospective cohort analysis of 13,018 women and 9,350 men non-exercisers from the UK Biobank accelerometry sub-study; the contextual analyses involved 34,364 female/24,284 male exercisers from the same sub-study.

Exposures

Wrist accelerometer assessed daily VILPA duration of bouts lasting up to 1 and up to 2 minutes.

Outcomes and Measures

Overall and sex-specific dose-response associations of daily VILPA with MACE and its subtypes (incident myocardial infarction, heart failure and stroke).

Results

Among female/male non-exercisers there were 331/488 all-MACE events (129/250 myocardial infarction, 96/119 heart failure,106/119 stroke events) over a mean 7.9-year follow-up. Daily VILPA duration exhibited a near-linear dose-response association with all MACE, myocardial infarction, and heart failure in women but not in men. Compared to women with no VILPA, the median daily VILPA duration of 3.4 minutes per day was associated with HRs of 0.55 (0.41, 0.75) for all MACE; and 0.33 (0.18, 0.59) for heart failure. Women’s minimum doses (the dose associated with 50% of the optimal risk reduction) of 1.2-1.6 minutes of VILPA per day were associated with HRs of 0.70 (0.58, 0.86) for all-MACE, 0.67 (0.50, 0.91) for myocardial infarction and 0.60 (0.45, 0.81) for heart failure, respectively. The equivalent analyses in exercisers in the UK Biobank showed comparable beneficial associations of vigorous intensity activity with all MACE, myocardial infarction and heart failure in both sex groups.

Conclusions and Relevance

Amongst non-exercisers, small amounts of VILPA were associated with substantially lower risk of myocardial infarction and heart failure in women but not in men. No such sex differences were evident among exercisers. VILPA may be a promising physical activity target for CVD prevention in women not willing or able to exercise.
Comparison of metabolic syndrome prevalence using three different definitions: A population-based study in Peru
Authors: Vera-Ponce Víctor Juan , Zuzunaga-Montoya Fiorella E. , Romero Luisa Erika Milagros Vásquez , Loayza-Castro Joan A. , Valladares-Garrido Mario J.
Published: October 2023

Introduction

Metabolic syndrome (MetS) is important for public health; however, there are different ways to define it.

Objectives

1) to estimate the prevalence of MetS using three different definitions: the criteria of the International Diabetes Federation (IDF), the World Health Organization (WHO), and the National Cholesterol Education Program’s Adult Treatment Panel III (ATPIII), 2) to identify the factors associated with the presence of MetS according to each criterion, and 3) to evaluate the agreement between these three.

Materials and Methods

A secondary and cross-sectional analysis of the database from the Life Stages Food and Nutrition Surveillance Survey (VIANEV) was conducted. For the definition of MetS, the aforementioned definitions were used. A multivariable Poisson regression analysis with robust variance and agreement was evaluated through the Kappa index.

Results

According to ATPIII, IDF, and WHO, the prevalence of MetS was 42.60%, 46.78%, and 49.49%, respectively. The agreement between IDF with WHO and ATPIII criteria was 0.42 and 0.45, while for ATPIII and WHO it was 0.44. In general, the associated factors were identified as sex, marital status, age, region of residence, level of physical activity, smoking habit, and body mass index (BMI). However, the association of these varied according to the definition used.

Conclusion

The prevalence of MetS varies significantly according to the criteria used. This was higher when the WHO definition was used compared to the others. Additionally, the associated factors varied according to the definition used, although a consistency was observed across all definitions with BMI.
Interaction Between the Prefrontal and Visual Cortices Supports Subjective Fear
Authors: Taschereau-Dumouchel Vincent , Côté Marjorie , Manuel Shawn , Valevicius Darius , Cushing Cody A. , Cortese Aurelio , Kawato Mitsuo , Lau Hakwan
Published: October 2023

It has been reported that threatening and non-threatening visual stimuli can be distinguished based on the multi-voxel patterns of hemodynamic activity in the human ventral visual stream. Do these findings mean that there may be evolutionarily hardwired mechanisms within early perception, for the fast and automatic detection of threat, and maybe even for the generation of the subjective experience of fear? In this human neuroimaging study, we presented participants (Fear group: N=30; No Fear group: N = 30) with 2700 images of animals that could trigger subjective fear or not as a function of individual’s idiosyncratic “fear profiles” (i.e., fear ratings of animals reported by a given participant). We provide evidence that the ventral visual stream may represent affectively neutral visual features that are statistically associated with fear ratings of participants, without representing the subjective experience of fear itself. More specifically, we show that patterns of hemodynamic activity predictive of a specific “fear profile” can be observed in the ventral visual stream whether a participant reports being afraid of the stimuli or not. Further, we found that the multivariate information synchronization between ventral visual areas and prefrontal regions distinguished participants who reported being subjectively afraid of the stimuli from those who did not. Together, these findings support the view that the subjective experience of fear may depend on the relevant visual information triggering implicit metacognitive mechanisms in the prefrontal cortex.
Distinct eLPBChATprojections for methamphetamine anxiety and relapse
Authors: Chen Wenwen , Guo Hao , Zhou Ning , Xu Xing , Mai Yuning , He Teng , Wen Jun , Ge Feifei , Qin Shan , Liu Chengyong , Wu Wenzhong , Kim Hee Young , Fan Yu , Guan Xiaowei
Published: October 2023

Choline acetyltransferase-positive neurons in the external lateral parabrachial nucleus (eLPBChAT) send projections to PKCδ-positive (PKCδ+) neurons in lateral portion of central nucleus of amygdala (lCeAPKCδ) and oval portion of bed nucleus of the stria terminalis (ovBNSTPKCδ), forming eLPBChAT–lCeAPKCδand eLPBChAT–ovBNSTPKCδpathways. At least in part, the eLPBChATneurons positively innervate lCeAPKCδand ovBNSTPKCδthrough regulating synaptic elements of presynaptic acetylcholine (Ach) release and postsynaptic nicotinic acetylcholine receptors (nAChRs). Methamphetamine (METH) withdrawal anxiety and METH-primed reinstatement of conditioned place preference (CPP) recruit eLPBChAT–lCeAPKCδpathway and eLPBChAT–ovBNSTPKCδpathway in male METH-exposed mice, respectively.
Imaginary scenes are represented in cortical alpha activity
Authors: Stecher Rico , Kaiser Daniel
Published: October 2023

Imagining natural scenes enables us to engage with a myriad of simulated environments. How do our brains generate such complex mental images? Recent research suggests that cortical alpha activity carries information about individual objects during visual imagery. However, it remains unclear if more complex imagined contents such as natural scenes are similarly represented in alpha activity. Here, we answer this question by decoding the contents of imagined scenes from rhythmic cortical activity patterns. In an EEG experiment, participants imagined natural scenes based on detailed written descriptions, which conveyed four complementary scene properties: openness, naturalness, clutter level and brightness. By conducting classification analyses on EEG power patterns across neural frequencies, we were able to decode both individual imagined scenes as well as their properties from the alpha band, showing that also the contents of complex visual images are represented in alpha rhythms. An additional cross-classification analysis between alpha power patterns during the imagery task and during a perception task, in which participants were presented images of the described scenes, showed that scene representations in the alpha band are shared between imagery and late stages of perception. This suggests that alpha activity mediates the top-down re-activation of scene-related visual contents during imagery.
Age-related spatial ecology of Audouin’s gull during the non-breeding season
Authors: Ponti Raquel , Morera-Pujol Virginia , Sallent Ángel , González-Solís Jacob , Ramos Raül
Published: October 2023

Relationships between individual’s age and the movement ecology and habitat preference of long-lived migratory birds still remain understudied. According to the exploration-refinement hypothesis it is thought that adults would select better and more productive areas for foraging than inexperienced juvenile birds would do. Additionally, age-related differences in migratory patterns and exploited habitats could be explained by the attempt to avoid competition between juveniles and adults. Here, we explored the differences in the migratory patterns, habitat selection and foraging behaviour between juvenile and adult Audouin’s gulls (Ichthyaetus audouinii), a species listed as vulnerable by the IUCN. We captured 9 juveniles and 8 adults in the colony of San Pedro (SE Spain) and equipped them with high-resolution 5-min programmed GPS to track their postnuptial/first migration and non-breeding destinations. First, juveniles tended to migrate longer distances than adults did. Second, the time spent foraging between age groups did not differ. Third, freshwater masses constituted an essential habitat during the non-breeding season for both juveniles and adults. Fourth, we found that adults used a greater variety of habitats than juveniles did, but adults positively select foraging habitats despite the low availability while juveniles do not. Finally, repeatability in habitat use of individuals of the same age was rather low. We provided evidence of age-related differences in migratory patterns and habitat exploitation during the non-breeding period in a migratory seabird which can be explained by the avoidance of competition between adults and juveniles and the greater experience in foraging performance that adults have in comparison with juveniles.
ENDOTHELIAL GENE REGULATORY ELEMENTS ASSOCIATED WITH CARDIOPHARYNGEAL LINEAGE DIFFERENTIATION
Authors: Aurigemma Ilaria , Lanzetta Olga , Cirino Andrea , Allegretti Sara , Lania Gabriella , Ferrentino Rosa , Krishnan Varsha Poondi , Angelini Claudia , Illingworth Elizabeth , Baldini Antonio
Published: October 2023

Endothelial cells (EC) differentiate from multiple sources, including the cardiopharyngeal mesoderm, which gives rise also to cardiac and branchiomeric muscles. Here, we used a cardiogenic mesoderm cell differentiation model that also activates an endothelial transcription program to identify endothelial regulatory elements activated in early cardiogenic mesoderm. Integrating our chromatin remodeling and gene expression data with available single-cell RNA-seq data from mouse embryos, we identified 101 putative regulatory elements of EC genes. We then applied a machine-learning strategy, trained on validated enhancers, to predict the probability of the sequences to function as enhancers. The computational assay determined that 50% of these sequences were likely enhancers, some of which have been previously reported. We also identified a smaller set of regulatory elements of well-known EC genes and validated them using genetic and epigenetic perturbation. Finally, we used the integration of multiple data sources and computational tools to search for transcriptional factor binding motifs. In conclusion, we identified novel EC regulatory sequences with a high likelihood to be enhancers, and we validated a subset of them using computational and cell culture models. Motif analyses revealed that the core EC transcription factors GATA/ETS/FOS is a likely driver of EC differentiation in cardiopharyngeal mesoderm.
High capacity of BrazilianAedes aegyptipopulations to transmit a locally circulating lineage of Chikungunya virus
Authors: de Freitas Amanda Cupertino , Rezende Fernanda Oliveira , de Mendonça Silvana Faria , Baldon Lívia Vieira , Silva Emanuele Guimarães , Ferreira Flávia Viana , de Almeida João Paulo , Amadou Siad Cedric , Marçal Bruno Almeida , Comini Sara Grangeiro , Rocha Marcele Neves , Fritsch Hegger Machado , Giovanetti Marta , Alcantara Luiz Carlos , Moreira Luciano Andrade , Ferreira Alvaro Gil
Published: October 2023

The global incidence of chikungunya has surged in recent decades, with South America, particularly Brazil, experiencing devastating outbreaks. The primary vector for transmitting CHIKV in urban areas is the mosquito speciesAedes aegypti, which is very abundant in Brazil. However, little is known about the impact of locally circulating CHIKV genotypes and specific combinations of mosquito populations on vector competence. In this study, we analyzed and compared the infectivity and transmissibility of a recently isolated CHIKV-ECSA lineage from Brazil among fourAe. aegyptipopulations collected from different regions of the country. When exposed to CHIKV-infected mice for blood feeding, all mosquito populations showed high infection rates and dissemination efficiency. Moreover, using a mouse model to assess transmission rates in a manner that better mirrors natural cycles, we observed that these populations exhibit highly efficient transmission rates of CHIKV-ECSA. Our findings underscore the robust capability of BrazilianAe. aegyptipopulations to transmit the locally circulating CHIKV-ECSA lineage, potentially explaining its higher prevalence compared to the Asian lineage also introduced in Brazil.

Author Summary

Chikungunya virus (CHIKV) is an alphavirus transmitted by mosquitoes, gaining attention due to its rapid global spread and public health impact. Initially isolated in Tanzania in 1952, it was confined to Africa, Asia, and the Indian subcontinent. Local transmission of CHIKV in the Americas began in December 2013, leading to a 2014 epidemic. TheAedes aegyptimosquito, prevalent in Brazil, is suspected as the primary vector. Yet, our understanding of how different mosquito populations and virus lineages impact spread is limited. In this Brazilian study, we collected mosquitoes from four regions, exposing them to the local African ECSA lineage of CHIKV. Remarkably, all mosquito populations exhibited high infection rates and efficient virus transmission to vertebrate hosts. This research sheds light on why the ECSA chikungunya lineage is spreading rapidly in Brazil. The BrazilianAe. aegyptimosquitoes appear to possess exceptional capabilities in transmitting African ECSA lineage of CHIKV, potentially contributing to its rapid dissemination within the country and neighboring regions. Comprehending these dynamics is vital for developing strategies to control and mitigate the impact of chikungunya in affected areas.
Infection dynamics in the urinary tract - The importance of non-planktonic phases during early infection and resistance evolution
Authors: Raatz Michael , Drabik Karolina , de Azevedo-Lopes Amanda , Traulsen Arne , Wacław Bartłomiej
Published: October 2023

Treatment of urinary tract infections (UTIs) and the prevention of their recurrence is a pressing global health problem. During the infection establishment, pathogenic bacteria may attach to and invade into the bladder tissue, and thus access non-planktonic phases besides the bladder lumen. Planktonic, attached, and intracellular bacteria face different selection pressures from physiological responses (frequent micturition and immune responses), or antibiotic treatment. Acknowledging this heterogeneity of selection pressures is essential to increase treatment efficacy, reduce resistance evolution and develop new treatments. Here, we present a mathematical model capturing the initial infection phase to unravel the effects of this heterogeneity on the ecological and evolutionary dynamics of UTIs. We explicitly represent planktonic bacteria in the bladder lumen, bacteria attached to epithelial cells of the bladder wall, and bacteria that have invaded these epithelial cells. We find that access to non-planktonic compartments increases the risk of infection establishment substantially. With antibiotic treatment, the trajectories of resistance evolution are shaped by the accessibility of the intracellular compartment and antibiotic permeation into the epithelial cells. Further, we evaluate conditions where probiotic pretreatment can reduce the pathogen load during an infection and increase the efficacy of accompanying antibiotic therapies. We find that faster-growing probiotic strains achieve a stronger increase in antibiotic treatment efficacy, although too strong antibiotic treatment can diminish this effect. Our study shows that accounting for the selection heterogeneity is crucial to understand the eco-evolutionary dynamics of UTIs, and that mathematical modeling can help to steer this complex system into a healthy state.

Competing Interests

The authors declare no competing interests.
Reduction of a-synuclein aggregates by PIKfyve inhibition via TFEB-mediated lysosomal biogenesis in a Parkinson disease model
Authors: Lucas-Del-Pozo Sara , Uras Giuseppe , Fierli Federico , Lentini Veronica , Koletsi Sofia , Chau Kai-Yin , Hughes Derralynn , Schapira Anthony HV
Published: October 2023

Parkinson disease is a neurodegenerative disorder characterised by impairment of motor function, and is associated with a progressive accumulation of insoluble aggregates of misfolded alpha-synuclein. In the present study, we exploited the SH-SY5Y cell model overexpressing a pro-aggregation form of alpha-synuclein to investigate the efficacy of PIKfyve-mediated lysosomal biogenesis, through TFEB, as potential target for Parkinson therapy.

To investigate this, we exploited high-content imaging along with enzymatic assays to follow the progression of lysosomal biogenesis, lysosomal function and alpha-synuclein accumulation. The cellular model exploited in this study recapitulated important elements of the biochemical phenotype observed in Parkinson patient-derived neurons, including synuclein aggregates and impaired glucocerebrosidase (GCase) function. PIKfyve inhibition by YM201636 resulted in a lysosomal-dependant reduction of alpha-synuclein aggregates as early as 24 hours post-treatment. The mechanism of action of YM201636 was shown to be TFEB-mediated, with an increase in TFEB in the nuclei which subsequently resulted in increased lysosomal markers LAMP1 and GCase. PIKfyve inhibtion efficacy was also tested in differentiated SH-SY5Y cells, exhibiting a neuron-like morphology. In these cells, YM201636 also significantly reduced alpha-synuclein aggregates and increased TFEB nuclear presence.

These findings suggest that PIKfyve inhibition could be exploited as therapeutic target for Parkinson disease.