bluuebunny/crossref_metadata_2025 huggingface dataset:
Epidemiology and Risk Factors of Cutaneous Leishmaniasis in the West Bank, Palestine: A Cross-Sectional Study
Authors: AbuZaaroor Elaf , AlShakhra Kamal , Alawneh Moath
Published: November 2024

Background

Leishmaniasis Is a vector-borne disease caused by obligate intracellular protozoan flagellate parasite, that is transmitted by the bite of infected female phlebotomine sandflies. Cutaneous Leishmaniasis (CL) is endemic in the Middle East, it’s a major public health concern in Palestine, the current control strategies for Leishmaniasis depend on reservoir and vector control, active case detection and treatment of their disease and the use of insecticides.

Objectives

This study aims to describe the epidemiology, clinical features, and risk factors of CL in the West Bank, Palestine, from 2020 to 2023.

Methods

A retrospective study included all cases of CL that had been reported to the Leishmaniasis Surveillance System in the Department of preventive medicine at the Palestinian Ministry of Health during the period from 2020 to 2023. A total of 322 cases were reported and met the case definition. demographic details, lesion characteristics, and environmental risk factors., Independent t-test and ANOVA were used to obtain the differences between the groups according to lesion duration, number of lesion.

Findings

A total of 322 cases of Cutaneous Leishmaniasis were diagnosed in preventive medicine departments in West bank during the period 2020 till 2023, the ages of patients ranges between less than one year to 82 years old, most cases were young, with mean age of 24 years old, the male to female ratio was 3:2, most patients were illiterate,.

The number of skin lesions was significantly higher in males, farmers and most patients have face lesions mainly nodules. while the duration of the skin lesions was significantly higher in older patients.

Conclusions

CL is endemic in the West Bank. Public health strategies should emphasize early detection, community awareness, and targeted vector control measures.

Funding

No funding was provided for this research.
Brisk: Exact resource-efficient dictionary fork-mers
Authors: Smith Caleb , Martayan Igor , Limasset Antoine , Dufresne Yoann
Published: November 2024

The rapid advancements in DNA sequencing technology have led to an unprecedented increase in the generation of genomic datasets, with modern sequencers now capable of producing up to ten terabases per run. However, the effective indexing and analysis of this vast amount of data pose significant challenges to the scientific community. K-mer indexing has proven crucial in managing extensive datasets across a wide range of applications, including alignment, compression, dataset comparison, error correction, assembly, and quantification. As a result, developing efficient and scalablek-mer indexing methods has become an increasingly important area of research. Despite the progress made, current state-of-the-art indexing structures are predominantly static, necessitating resource-intensive index reconstruction when integrating new data. Recently, the need for dynamic indexing structures has been recognized. However, many proposed solutions are only pseudo-dynamic, requiring substantial updates to justify the costs of adding new datasets. In practice, applications often rely on standard hash tables to associate data with theirk-mers, leading to highk-mer encoding rates exceeding 64 bits perk-mer. In this work, we introduce Brisk, a drop-in replacement for mostk-mer dictionary applications. This novel hashmap-like data structure provides high throughput while significantly reducing memory usage compared to existing dynamic associative indexes, particularly for largek-mer sizes. Brisk achieves this by leveraging hierarchical minimizer indexing and memory-efficient super-k-mer representation. We also introduce novel techniques for efficiently probingk-mers within a set of super-k-mers and managing duplicated minimizers. We believe that the methodologies developed in this work represent a significant advancement in the creation of efficient and scalablek-mer dictionaries, greatly facilitating their routine use in genomic data analysis.
Systematic exploration of domain assortments in NOD-like receptors uncovers two types of NACHT domains inSordarialesfungi
Authors: Bonometti Lucas , Charriat Florian , Hensen Noah , Miñana-Posada Silvia , Johannesson Hanna , Gladieux Pierre
Published: November 2024

Background

Fungi have NOD-Like receptors (NLRs), analogous to the innate immune receptors found in animals, plants and bacteria. Fungal NLRs are characterized by a great variability of domain organizations, but the identity of the nucleotide-binding domains, the genomic localization, and the factors associated with variation in the composition of repertoires of fungal NLRs are not yet fully understood. To better understand the variability of fungal NLR repertoires and the underlying determinants, we conducted a thorough analysis of genome data from the ascomycete orderSordariales.

Results

Using similarity searches based on hidden Markov models profiles for canonical N-terminal, nucleotide-binding, or C-terminal domains, we characterized 4613 NLRs in 82Sordarialestaxa. By examining the Helical Third section of the nucleotide-binding domains, we substantially improved their annotation. We demonstrated that fungi have NACHT domains of both NAIP-like and TLP1-like types, similar to animals. We found that the number of NLR genes was highly variable amongSordarialesfamilies, and independent of the stringency of defense mechanisms against genomic repeat elements. NLRs were organized in clusters in the majority of taxa, and the strong correlation between the number of NLRs and the number of NLR clusters suggested that organizing in clusters may contribute to repertoire diversification.

Conclusions

Our work highlights the similarity of fungal and animal NLRs in terms of nucleotide-binding domain types, and between fungal and plant NLRs in terms of genomic organization in clusters. Our findings will aid in the comparative analysis of the patterns and processes of diversification of NLR repertoires in various lineages of fungi and between the different kingdoms and domains of life.
Structural and functional insights into activation and regulation of the dynein-dynactin-NuMA complex
Authors: Aslan Merve , d’Amico Ennio A. , Cho Nathan H. , Taheri Aryan , Zhao Yuanchang , Zhong Xinyue , Blaauw Madeline , Carter Andrew P. , Dumont Sophie , Yildiz Ahmet
Published: November 2024

During cell division, NuMA orchestrates the focusing of microtubule minus-ends in spindle poles and cortical force generation on astral microtubules by interacting with dynein motors, microtubules, and other cellular factors. Here we used in vitro reconstitution, cryo-electron microscopy, and live cell imaging to understand the mechanism and regulation of NuMA. We determined the structure of the processive dynein/dynactin/NuMA complex (DDN) and showed that the NuMA N-terminus drives dynein motility in vitro and facilitates dynein-mediated transport in live cells. The C-terminus of NuMA directly binds to and suppresses the dynamics of the microtubule minus-end. Full-length NuMA is autoinhibited, but mitotically phosphorylated NuMA activates dynein in vitro and interphase cells. Together with dynein, activated full-length NuMA focuses microtubule minus-ends into aster-like structures. The binding of the cortical protein LGN to the NuMA C-terminus results in preferential binding of NuMA to the microtubule plus-end. These results provide critical insights into the activation of NuMA and dynein for their functions in the spindle body and the cell cortex.
Barriers to surveillance and control of re-emergence of the Chagas disease vectorTriatoma infestansin Arequipa, Peru
Authors: Tamayo Laura D. , Paz-Soldán Valerie A. , Condori Pino Carlos E. , Malaga Chavez Fernando S. , Levy Michael Z. , Gonçalves Raquel
Published: November 2024

Vector control is usually designed as a top-down system with minimum capacity to respond to specificities of epidemiological settings at fine scale or to adjust to routine stressors. Here, we investigated barriers in Chagas disease vector surveillance and control systems in Arequipa, Peru. We conducted in-depth interviews and focus groups with key stakeholders (n=32) at different levels of the health system and community, using process maps to illustrate the workflow for passive and active surveillance. We identified barriers at each step of the process, including systemic, operational, financial, and policy limitations. For passive surveillance, barriers in community participation to report infestations were linked to challenges in capturing the vector and bringing it to a health facility or community health worker. Amongst systemic barriers were related to the use of a data system that did not meet the needs for recording and managing data on vector control activities. At the policy level, the establishment of quotas on the number of houses staff needed to inspect ignores important determinants for infestation and lacks an appropriate sampling design. We discuss the impact of the reported barriers to effective conduction of surveillance and control activities and the initiatives and strategies that have been designed and assessed to bridge these gaps in order to collaboratively design a more resilient health system.
External validation of plasma CSF1 as a preoperative prognostic marker in patients with resectable intrahepatic cholangiocarcinoma
Authors: Akiki Antonio , Jacobsson Hanna , Nouairia Ghada , Cornillet Martin , Björkström Niklas K. , Sparrelid Ernesto , Taflin Helena , Jansson Hannes
Published: November 2024

Background & Aims

Long-term prognosis after resection for intrahepatic cholangiocarcinoma (iCCA) remains poor and the preoperative risk assessment is difficult. A previous single-center study indicated two immune system-related proteins in plasma, colony stimulating factor 1 (CSF1) and TNF-related apoptosis-inducing ligand (TRAIL), as preoperative prognostic factors in iCCA. This study aimed to externally validate CSF1 and TRAIL as prognostic markers for patients with resectable iCCA.

Methods

Preoperative plasma CSF1 and TRAIL concentrations (pg/mL) were determined from prospectively collected biobank samples using multiplex immunoanalysis (Proximity Extension Assay), from patients operated for iCCA at two tertiary referral centers, Karolinska (2010-2020) and Sahlgrenska (2019-2023) university hospitals. The primary outcome was overall survival (OS), analyzed by Kaplan-Meier method and Cox regression. Secondary outcome was disease-free survival (DFS).

Results

Sixty-one patients with resection for iCCA were included. CSF1 above median was associated with lymph node metastasis (P=0.03). CSF1 was associated with both OS (hazard ratio [HR] 1.03, 95% confidence interval [CI] 1.01-1.05) and DFS (HR 1.02, 95% CI 1.00-1.04). The median OS was eight months for patients with CSF1 values in the upper quartile (≥158 pg/mL), compared to an overall median OS of 47 months. While TRAIL was not significantly associated with OS (P=0.22), values in the lower quartile (≤256 pg/mL) were associated with short DFS (P<0.01). Multivariable analyses confirmed the independent prognostic significance of CSF1. The C-index of CSF1 for OS was 0.70, with excellent calibration for three- and five-year OS.

Conclusion

Plasma CSF1 was validated as a novel independent, well-calibrated preoperative predictor of poor survival in resectable iCCA, which could assist the preoperative risk assessment. Low plasma TRAIL was associated with early recurrence.

Impact and implications

Patients with intrahepatic cholangiocarcinoma (iCCA) suffer a high risk of recurrence within the first years after curative intent surgery, limiting long-term survival. To identify patients where liver surgery has a low potential for cure, prognostic markers are warranted. In the present study, preoperative plasma CSF1, an immune system-related protein, was validated as a novel, well-calibrated predictor for long-term survival after hepatic resection. Plasma CSF1 could assist the preoperative risk assessment in iCCA.
Machine Learning-Driven Correction of Handgrip Strength: A Novel Biomarker for Neurological and Health Outcomes in the UK Biobank
Authors: Nazarzadeh Kimia , Eickhoff Simon B. , Antonopoulos Georgios , Hensel Lukas , Tscherpel Caroline , Komeyer Vera , Raimondo Federico , Müller Veronika , Grefkes Christian , Patil Kaustubh R.
Published: November 2024

Background

Handgrip strength (HGS) is a significant biomarker for overall health, offering a simple, cost-effective method for assessing muscle function. Lower HGS is linked to higher mortality, functional decline, cognitive impairments, and chronic diseases. Considering the influence of anthropometrics and demographics on HGS, this study aims to develop a corrected HGS score using machine learning (ML) models to enhance its utility in understanding brain health and disease.

Methods

Using UK Biobank data, sex-specific ML models were developed to predict HGS based on three anthropometric variables and age. A novel biomarker, ΔHGS, was introduced as the difference between true HGS (i.e., directly measured HGS) and bias-free predicted HGS. The neural basis of true HGS and ΔHGSwas investigated by correlating them to regional gray matter volume (GMV). Statistical analyses were performed to test their sensitivity to longitudinal changes in stroke and major depressive disorder (MDD) patients compared to matched healthy controls (HC).

Results

HGS could be accurately predicted using anthropometric and demographic features, with linear support vector machine (SVM) demonstrating high accuracy. Compared to true HGS, ΔHGSshowed high reassessment reliability and stronger, widespread associations with GMV, especially in motor-related regions. Longitudinal analysis revealed that neither HGS nor ΔHGSeffectively differentiated patients from matched HC at post time-point.

Conclusion

The proposed ΔHGSscore exhibited stronger correlations with GMV compared to true HGS, suggesting it better represents the relationship between muscle strength and brain structure. While not effective in differentiating patients from HC at post time-point, the increase in ΔHGSfrom pre to post time-points in patient cohorts may indicate improved utility for monitoring disease progression, treatment efficacy, or rehabilitation effects, warranting further longitudinal validation.
Adoption of Community Adolescent Treatment Support for HIV Care Retention in Greater Accra Region, Ghana
Authors: Green-Harris Margor A. , Nyasulu Thembikile , Ching Jordanne Futu , Kogi Robert , Asampong Emmanuel , Dako-Gyeke Phyllis
Published: November 2024

Despite the introduction of efficacious antiretroviral therapy, HIV and AIDS continue to pose a threat to global public health. Community adolescent treatment support programs have shown promising signs of improving adherence retention to care which in turn improves HIV-related health outcomes in this population. However, little is known about the adoption of this program among adolescents in Ghana. This study sought to assess the adoption of community adolescent treatment support among adolescents living with HIV in Tema General Hospital and LEKMA Hospital in the Greater Accra Region, Ghana.

A qualitative phenomenological design was carried out at the Tema General Hospital and LEKMA Hospital. Adolescents living with HIV aged 18 to 24 years old who were actively participating in the Community Adolescents Treatment Support (CATS) services were recruited in this study. In addition, healthcare workers involved in the CATS strategy since its inception were recruited. A total of sixteen (16) key informant and in-depth interviews were conducted. The data was transcribed verbatim and imported to NVivo 14.0 software for thematic analysis.

It was found that CATS serves as a crucial support system, strengthening peer connections and providing flexible medication pickup. Improved medication adherence, better retention in care, and positive viral load outcomes were evident among participants. However, communication issues and participants consistency pose challenges. Support group meetings werehighly valued by participants. Mobile health services were widely accepted for maintaining connectivity and support. Home visit services faced reluctance due to privacy concerns, and the wider community was perceived as unwelcoming. While challenges persist, including recruitment difficulties and financial support, there is a strong commitment to improving the program’s effectiveness and scalability. Communication strategies, increasing funding support, and intensifying community education and sensitization efforts should be strengthened to reduce stigma and foster broader community inclusivity.
Diffusion Signals of Glial Activation Correlate with Fitness Scores in Parkinson’s Subcortical Gray Matter
Authors: Newman Benjamin T. , Foreman Ryan , Donahue Erin , Jakowec Michael , Petkus Andrew J. , Holschneider Daniel P. , O’Neil Joseph , Schiehser Dawn M. , Petzinger Giselle , Van Horn John Darrell
Published: November 2024

The cholinergic basal forebrain and subcortical gray matter have previously been implicated in Parkinson’s disease (PD) but the relationship between the symptomology of PD, including cognitive impairment, and specific patterns of damage remains unclear. Additionally understanding the impact of fitness, including motor skill fitness, on brain structure remains a gap in knowledge. In this study, we examine a longitudinal cohort of PD patients using advanced microstructural analysis derived from diffusion MRI, alongside volumetric, and connectivity components. These imaging metrics are compared to comprehensive cognitive and motor skill fitness metrics. Though the volumetric components well characterize change across the longitudinal timescale, the microstructural analysis was related to a number of composite cognitive scores including attention, executive function, cognition, language, as well as the level of motor skill fitness. We further assess the connectivity of the cholinergic basal forebrain, particularly the nucleus basalis of Meynert in area 4 (CH4), and find that connectivity between CH4 and the thalamus is associated with latent motor skill fitness. The pattern of microstructural results suggests that increased cellularity, potentially from astrocytic glial cells, may support reduced cognitive decline in individuals with PD as well as higher motor skill fitness.
Acute respiratory distress syndrome and acute kidney injury in critically ill patients: a scoping review protocol about the lung-kidney crosstalk
Authors: Mattedi Francisco Z. , Ribeiro Heitor S. , Busatto Geraldo F. , Carvalho Carlos R. R. , Burdmann Emmanuel A.
Published: November 2024

Introduction

Acute respiratory distress syndrome (ARDS) is a risk factor for several adverse clinical outcomes, including mortality. Acute kidney injury (AKI) is one of the most common extrapulmonary complications in ARDS. Despite the high incidence of AKI in patients with ARDS, the lung-kidney crosstalk is not yet fully understood.

Objective

This scoping review aims to describe the association between ARDS and AKI in critically ill patients.

Methods

We will follow the Joanna Briggs Institute methodology and Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews. Based on theParticipants,Concept, andContext framework, we will include studies that investigated critically ill patients with ARDS (Participants), describe AKI-related outcomes (Concept), and were conducted in hospitals (Context). A comprehensive literature search will be performed using the MEDLINE, Embase, and LILACS databases without date or language restrictions from database inception until January 2024. Observational studies with retrospective, prospective, and case-control designs will be considered. Two independent reviewers will screen titles and abstracts and perform full-text reviews. Data extraction will be performed by the main reviewer and checked by a second one. Data on the diagnosis of ARDS and follow-up time for AKI-related outcomes will be extracted from the selected evidence. The quantitative results will be synthesized and presented in tables and figures along with a narrative summary.

Ethics and dissemination

There is no ethical approval requirement for this scoping review. On completion, the review will be published in a peer-reviewed academic journal and presented at a health conference.
Fixed-Dose Combination Use and Drug Adherence, Healthcare Utilization, and Costs
Authors: Zhang Donglan , Lee Jun Soo , Therrien Nicole L. , Pollack Lisa M. , Jackson Sandra L. , Dong Xiaobei , Rajan Anand , Hong Kai , Moran Andrew E. , Luo Feijun
Published: November 2024

BACKGROUND

Combination-pill therapy using fixed-dose combination (FDC) antihypertensives has the potential to improve hypertension control and management. However, combination-pill therapy remains low. This study aims to assess 1) the association between combination-pill therapy and subsequent medication adherence, healthcare utilization, and costs and 2) the potential to mitigate racial and ethnic disparities in medication adherence, among Medicaid beneficiaries.

METHODS

A retrospective cohort analysis was conducted using the 2017-2021 MerativeTMMarketScan® Medicaid claims database. The study sample included adults aged 18-64 years with hypertension, continuously enrolled one year before and after a random index date of prescribed antihypertensives. Combination-pill therapy was compared with multi-pill therapy. The propensity-score overlap weighting method was used to balance characteristics between individuals using combination- and multi-pill therapy. Logistic models were used for medication adherence, linear models for medication possession ratios (MPRs), negative binomial models for healthcare utilization, and generalized linear models for healthcare costs.

RESULTS

Compared with multi-pill therapy, combination-pill therapy was associated with improved medication adherence (3.17 in MPR, 95% CI: 2.79 - 3.55), fewer hypertension-related emergency department visits (220 per 1,000 individuals, 95% CI: -235 – -204), fewer hospitalizations (153 per 1,000 individuals, 95% CI: -160 – -146), and lower medical costs ($2,862 per person, 95% CI: -$3,035 – -$2,689). However, disparities in medication adherence between non-Hispanic White and non-Hispanic Black adults existed for both FDC and multi-pill therapy.

CONCLUSIONS

Combination-pill therapy could improve hypertension management and save costs for the Medicaid program and beneficiaries. These findings may inform policies on FDC antihypertensive coverage and programs.

Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. Use of trade names and commercial sources is for identification only and does not imply endorsement by the U.S. Department of Health and Human Services.
Chromatin Structures from Integrated AI and Polymer Physics Model
Authors: Schultz Eric R , Kyhl Soren , Willett Rebecca , de Pablo Juan J
Published: November 2024

The physical organization of the genome in three-dimensional space regulates many biological processes, including gene expression and cell differentiation. Three-dimensional characterization of genome structure is critical to understanding these biological processes. Direct experimental measurements of genome structure are challenging; computational models of chromatin structure are therefore necessary. We develop an approach that combines a particle-based chromatin polymer model, molecular simulation, and machine learning to efficiently and accurately estimate chromatin structure fromindirectmeasures of genome structure. More specifically, we introduce a new approach where the interaction parameters of the polymer model are extracted from experimental Hi-C data using a graph neural network (GNN). We train the GNN on simulated data from the underlying polymer model, avoiding the need for large quantities of experimental data. The resulting approach accurately estimates chromatin structures across all chromosomes and across several experimental cell lines despite being trained almost exclusively on simulated data. The proposed approach can be viewed as a general framework for combining physical modeling with machine learning, and it could be extended to integrate additional biological data modalities. Ultimately, we achieve accurate and high-throughput estimations of chromatin structure from Hi-C data, which will be necessary as experimental methodologies, such as single-cell Hi-C, improve.
Identification of neuronatin as a SERCA2b regulin-like protein and assessment of its aggregation propensity via coarse grained simulations
Authors: Mariem Omar Ben , Coppi Lara , De Fabiani Emma , Eberini Ivano , Crestani Maurizio
Published: November 2024

Neuronatin (NNAT) is small transmembrane protein involved in a wide range of physiological processes, such as white adipose tissue browning and neuronal plasticity, as well as pathological ones, such as Lafora disease caused by the formation of NNAT aggregates. However, its 3D structure is unknown, and its mechanism of action is still unclear. In this study the two most well-known NNAT isoforms (α and β) were modelled and the interaction with the SERCA2b calcium pump was assessed using computational methods. First, molecular docking identified the same binding region as the one described for phospholamban, a thoroughly described SERCA inhibitor. Then, analyses of the flux of water molecules during molecular dynamics simulations highlighted significant similarities between the behavior of SERCA2b when in complex with phospholamban, and when in complex with either NNAT isoform. These results suggest that NNAT could be considered a “regulin-like” protein. Additional all-atom and coarse-grained simulations of multiple copies of NNAT highlighted a significant aggregation potential of both NNAT isoforms, supporting experimental data.

Statement of significance

This study presents the first structural model of neuronatin (NNAT) isoforms α and β. Through molecular docking and molecular dynamics simulations, we propose a NNAT interaction mechanism with the SERCA2b calcium pump similar to that of phospholamban, a known regulin and SERCA inhibitor. Our analyses also suggested a strong aggregation potential of NNAT based on all-atom and coarse-grained simulations, in line with experimental data on its involvement in Lafora disease. These insights suggest NNAT can be considered a “regulin-like” protein, advancing our understanding of its molecular function and contributing to new perspectives in targeting NNAT-related pathologies, as well as reinforcing the role of coarse-grained simulations as a valid tool to assess protein aggregation potential.
NF-κB inhibition in dendritic cells pre-treated with sulforaphane-conjugates induces immunotolerance
Authors: Leiva-Castro Camila , Múnera-Rodríguez Ana M. , Martínez-Bailén Macarena , Carmona Ana T. , López-Enríquez Soledad , Palomares Francisca
Published: November 2024

Sulforaphane (SFN) has notable health benefits but faces challenges due to poor solubility and delivery. This study explores SFN glycoconjugates’ effects on LPS-induced inflammation in human dendritic cells (DCs), aiming to enhance therapeutic potential against inflammatory diseases. Monovalent SFN-glycoconjugates with mannose (SFNMan) and fucose (SFNFuc) were developed and tested for their anti-inflammatory and immune-modulatory properties in DCs from healthy donors under chronic LPS exposure.

Our results revealed that carbohydrate-functionalized SFN improves solubility and effectiveness in suppressing inflammation by targeting the p65 NF-κB pathway, without affecting MAPK signaling. SFN-glycoconjugates induce a tolerogenic immune response, characterized by increased IL-10 production and enhanced regulatory T- and B-cell proliferation. Notably, these effects surpass those of p65 NF-κB inhibition alone, highlighting a distinct and potent regulatory mechanism independent of MAPK pathways.

These findings demonstrate the promise of SFN-glycoconjugates as innovative therapeutic agents for inflammatory diseases, offering enhanced anti-inflammatory and immunomodulatory effects through improved delivery and targeted molecular pathways.
Aggressive conflict impacts path integration in homing desert ants
Authors: Bollig Antonio , Freire Marília , Bücking Konrad , Kühnapfel Jana , Knaden Markus
Published: November 2024

The desert antCataglyphis fortisinhabits the salt pans of Tunisia, which are characterized by a lack of precipitation, extreme heat, and the complete absence of landmarks perceivable to humans. The individually foraging ants use path integration to find their way back to their nest (Müller and Wehner 1988, Wehner and Müller 2006, Müller and Wehner 2007, Wehner 2008). Additionally, the ants make use of other sensory cues, mainly visual and olfactory landmarks (Wehner and Raber 1979, Wehner et al. 1996, Steck et al. 2009, Buehlmann et al. 2011, Buehlmann et al. 2012, Wehner 2020), to form a robust toolkit for navigation. Since cooperation during foraging is negligible forC. fortis, the impact of intraspecific contact on its navigation has not yet been investigated. Our data suggests thatC. fortisconsiders intraspecific contact, or social cues, to further augment navigation. We show that contact with foreign conspecifics reduces trust in path integration thus broadening search patterns to optimize homing success. Furthermore, we explore the question of how ants navigate their surroundings without having aggressive encounters with neighboring nests and propose a navigational mechanism that might help ants avoid aggressive encounters with individuals of foreign colonies.
MuMu: a sample multiplexing protocol for droplet-based simultaneous single nuclei RNA- and ATAC-seq systems
Authors: Li Zhen , Haydar Tarik F.
Published: November 2024

Sample multiplexing is a common approach to reduce experimental cost and technical batch effect. Here, we present a protocol that for the first time allows the pooling of single nuclei from multiple biological samples prior to performing simultaneous single nuclei RNA-seq and ATAC-seq, which we termMultiplexedMultiome (MuMu). We describe steps for assembling the custom Tn5 transposome, performing the transposition reaction, nuclei pooling, sequencing library preparation, and sequencing data pre-processing. This protocol will greatly reduce the cost of sn-Multiome.

Graphical abstract
Emulating randomized controlled trials of long-acting insulins and cardiovascular events using real-world data for patients with type 2 diabetes
Authors: Wang Wanning , Reynier Pauline , Webster-Clark Michael , Yu Oriana HY , Brunetti Vanessa , Filion Kristian B.
Published: November 2024

Aims

Randomized controlled trials (RCTs) have high internal validity but often have limited generalizability. To our knowledge, there are no studies examining potential differences between RCTs and real-world data in patient characteristics and risk of major adverse cardiovascular events (MACE) among patients with type 2 diabetes mellitus (T2DM) treated with long-acting insulin analogues.

Methods

We emulated the DEVOTE trial of insulin degludec vs glargine among patients with T2DM using data from the United Kingdom’s Clinical Practice Research Datalink. DEVOTE eligible and ineligible subpopulations were created. Cox proportional hazards models with inverse probability of treatment weighting were used to estimate hazard ratios (HRs) and corresponding confidence intervals (CIs) for MACE comparing new users of insulin degludec to new users of insulin glargine overall and in the eligible/ineligible subpopulations.

Results

There were 10,430 patients in the overall population, 5,280 in the DEVOTE eligible population, and 5,150 in the DEVOTE ineligible population. The overall (HR: 1.36, 95% CI: 0.83, 1.86) and DEVOTE eligible populations (HR: 1.07, 95% CI: 0.63, 1.58) were compatible with findings from the DEVOTE trial (HR: 0.91, 95% CI: 0.78, 1.06) for the risk of MACE. Due to a low number of events the DEVOTE ineligible population had deviations in point estimates and wider CIs (HR: 2.19, 95% CI: 0.30, 3.83).

Conclusion

The risk of MACE among patients with T2DM newly prescribed insulin degludec compared to insulin glargine was consistent between the overall population and the DEVOTE eligible subpopulation, while the DEVOTE ineligible population had discrepant point estimates.

Twitter Summary

Our study emulated the DEVOTE trial using RWD. Half of the RWD population would be eligible for the trial. RWD and RCTs had compatible effect estimate for risk of major cardiovascular outcomes.
Epigenetic Age Monitoring in Professional Soccer Players for Tracking Recovery and the Effects of Strenuous Exercise
Authors: Brooke Robert T , Kocher Thomas , Zauner Roland , Gordevicius Juozas , Milčiūtė Milda , Nowakowski Marc , Haser Christian , Blobel Thomas , Sieland Johanna , Langhoff Daniel , Banzer Winfried , Horvath Steve , Pfab Florian
Published: November 2024

Elite sports have become increasingly professionalized and personalized, with soccer players facing a high number of games per season. This trend presents significant challenges in optimizing training for peak performance and requires rigorous monitoring of athletes to prevent overload and reduce injury risks. The emerging field of epigenetic clocks offers promising new pathways for developing useful biomarkers that enhance training management. This study investigates the effects of intense physical activity on epigenetic age markers in professional soccer players. We analyzed DNA methylation data from saliva samples collected before and after physical activity. Vigorous physical activity was found to rejuvenate epigenetic clocks, with significant decreases in DNAmGrimAge2 and DNAmFitAge observed immediately after games. Among player subgroups, midfielders exhibited the most substantial epigenetic rejuvenation effect following games. Additionally, the study suggests a potential link between DNA methylation patterns and injury occurrence. Overall, our study suggests that DNA methylation based biomarkers may have applications in monitoring athlete performance and managing physical stress.
Blood methylation biomarkers are associated with diabetic kidney disease progression in type 1 diabetes
Authors: Syreeni Anna , Dahlström Emma H. , Smyth Laura J. , Hill Claire , Mutter Stefan , Gupta Yogesh , Harjutsalo Valma , Chen Zhuo , Natarajan Rama , Krolewski Andrzej S. , Hirschhorn Joel N. , Florez Jose C. ,   GENIE consortium, Maxwell Alexander P. , Groop Per-Henrik , McKnight Amy Jayne , Sandholm Niina
Published: November 2024

Background

DNA methylation differences are associated with kidney function and diabetic kidney disease (DKD), but prospective studies are scarce. Therefore, we aimed to study DNA methylation in a prospective setting in the Finnish Diabetic Nephropathy Study type 1 diabetes (T1D) cohort.

Methods

We analysed baseline blood sample-derived DNA methylation (Illumina’s EPIC array) of 403 individuals with normal albumin excretion rate (early progression group) and 373 individuals with severe albuminuria (late progression group) and followed-up their DKD progression defined as decrease in eGFR to <60 mL/min/1.73m2(early DKD progression group; median follow-up 13.1 years) or end-stage kidney disease (ESKD) (late DKD progression group; median follow-up 8.4 years). We conducted two epigenome-wide association studies (EWASs) on DKD progression and sought methylation quantitative trait loci (meQTLs) for the lead CpGs to estimate genetic contribution.

Results

Altogether, 14 methylation sites were associated with DKD progression (P<9.4×10−8). Methylation at cg01730944 nearCDKN1Cand at other CpGs associated with early DKD progression were not correlated with baseline eGFR, whereas late progression CpGs were strongly associated. Importantly, 13 of 14 CpGs could be linked to a gene showing differential expression in DKD or chronic kidney disease. Higher methylation at the lead CpG cg17944885, a frequent finding in eGFR EWASs, was associated with ESKD risk (HR [95% CI] = 2.15 [1.79, 2.58]). Additionally, we replicated meQTLs for cg17944885 and identified ten novel meQTL variants for other CpGs. Furthermore, survival models including the significant CpG sites showed increased predictive performance on top of clinical risk factors.

Conclusions

Our EWAS on early DKD progression identified a podocyte-specificCDKN1Clocus. EWAS on late progression proposed novel CpGs for ESKD risk and confirmed previously known sites for kidney function. Since DNA methylation signals could improve disease course prediction, a combination of blood-derived methylation sites could serve as a potential prognostic biomarker.
PADI4 minor haplotype as risk factor for excessive NET formation and associated wound healing disorders in diabetes mellitus
Authors: Ehnert Sabrina , Hemmann Philipp , Ihle Christoph , Linnemann Caren , Mück Jonas , Anastasiou Panagiota-Georgia , Lobmann Ralf , Blumenstock Gunnar , Pscherer Stefan , Fritsche Andreas , Baumgartner Heiko , Histing Tina , Rollmann Mika F. , Nussler Andreas K.
Published: November 2024

Diabetes mellitus (DM) complicates wound healing, partly due to excessive neutrophil extracellular trap (NET) formation, a process regulated by the enzyme peptidyl-arginine deiminase 4 (PADI4). Circulating NET markers can predict the healing outcome of chronic wounds, but may not allow enough time for intervention as the accumulated NETs may have already damaged the tissue. In search for an early detectable risk marker, this study aimed at relating PADI4 haplotype, to PADI4 expression, NET formation and clinical outcomes,i.a.infections, delayed wound and bone healing, in 687 surgical patients (44.7% with DM). Pre-surgical PADI4 expression was 9.4-fold higher in patients with DM, especially those with complicated wound healing. The study linked PADI4 haplotypes to NET formation and clinical outcomes, finding that neutrophils with the PADI4 minor haplotype had higher PADI4 mRNA and protein levels and more rapidly produced a larger amount of NETs than neutrophils with the PADI4 major haplotype. Patients with DM and the PADI4 minor haplotype experienced the highest rates of delayed wound healing and infections. Our findings suggest that the PADI4 haplotype influences neutrophil behavior and clinical outcomes, making it a potential biomarker to screen patients with DM for their risk of developing wound healing complications.

Graphical Abstract
Deteriorated mechanics of left ventricular diastolic filling one year after coronary artery bypass grafting
Authors: Norderfeldt Joakim , Sundqvist Martin G , Maret Eva , Löfström Ulrika , Corbascio Matthias , Hage Camilla , Ekström Mattias , Wallén Håkan , Lyngå Patrik , Persson Bengt , Persson Hans E , Linde Cecilia , Marlevi David , Eriksson Maria J , Ugander Martin
Published: November 2024

Background

Ischemic heart disease impairs left ventricular (LV) diastolic function, but little is known about changes in the mechanical properties of LV relaxation following coronary artery bypass grafting (CABG).

Objectives

This study aimed to explore if and how the mechanics of LV filling change following CABG.

Methods

Patients underwent transthoracic echocardiography before and one year after elective CABG. Mitral inflow E-waves were analyzed using the parameterized diastolic filling (PDF) method, allowing for quantification of mechanical properties of diastolic function.

Results

Among patients (n=96, 10% female, median [interquartile range] age 68 [62–74] years), LV ejection fraction (LVEF) at baseline was 59 [53–63] %. At follow-up, there was an increase in the PDF-derived measures of myocardial stiffness, damping, peak driving and resistive forces, and filling energy, together with increase in left atrial (LA) volume index, and a decrease in LA conduit and contractile strains and tricuspid annular plane systolic excursion (p<0.001 for all). There was no change in heart rate, LV size, LVEF, E/é ratio, or LV filling efficiency. Furthermore, there were no differences in the mechanics of LV filling in patients when grouped according to baseline LVEF, or the number of revascularized coronary arteries.

Conclusions

One year after CABG, there was consistent deterioration in the mechanics of diastolic filling assessed using comprehensive conventional and mechanistic evaluation. Revascularization with CABG may worsen diastolic function one year after CABG. However, causes and significance of these changes remain to be further investigated.

Abstract Figure

Central illustration.

Deterioration in LV diastolic properties one year after CABG.

Overview of background, study design, methods and main results. Abbreviations: LV – Left Ventricular; CABG – Coronary artery bypass graft surgery; CMR – Cardiovascular magnetic resonance; ECHO – transthoracic echocardiography.
Do Researchers Consider the Inter-relationship Between Time to Assessment and Admission Severity in Acute Stroke?
Authors: Lu Zewen , Gittins Matthew , Kishore Amit K , Smith Craig J , Vail Andy
Published: November 2024

Background

Stroke severity, often quantified by NIHSS at admission, evolves and may influence patients’ time to hospital arrival. The inclusion of timing in stroke severity assessment remains unclear in stroke research. Oversight of time to assessment can affect prognostic model interpretation, acute clinical decision-making, and the design of future clinical trials by considering admission severity in the context of time since symptom onset.

Aims

This study aimed to assess whether and, if so, how stroke researchers account for time from symptom onset to admission severity assessment in their analyses. We sought to compare this with approaches used by perinatal researchers, considering a similar statistical relationship between gestational age and birth weight.

Summary of review

Two reviewers systematically reviewed papers in leading specialty journals published in 2019 using NIHSS at admission and birth weight respectively as an explanatory factor in the statistical analysis. We targeted a minimum of 50 articles from each field to ensure 90% to identify approaches used in 5% or more of studies.

A total of 111 studies were included. Perinatal researchers considered the temporal variable gestational age more often than time to assessment in stroke studies (89% vs. 7%, chi-squared p<0.001). It was consequently included more often (56% vs. 5%, chi-squared p<0.001). Four methods, including stratification, distribution, regression and combined approaches, were found. Time to assessment was only included as a continuous (n=2) or categorical (n=1) factor alongside admission NIHSS in three studies. Methods for covariate selection, essential for the interpretation of statistical models, were rarely specified.

Conclusions

Few researchers explore the inter-relationship between baseline severity and time to assessment in stroke prognostication, in sharp contrast to consideration of timing in perinatal studies. Future research will investigate whether time to assessment or serial NIHSS in the hyper-acute phase could benefit both clinical practice and stroke research.
Extensive antagonistic variants across human genome
Authors: Bian Beilei , Hivert Valentin , Wray Naomi R , McRae Allan F
Published: November 2024

Pleiotropic conflict, where a genetic locus has antagonistic effects on different traits, is a common phenomenon observed in animals and plants. While pleiotropy has been widely reported in humans, there is no systematic study of pleiotropic conflict in humans. Here, we leverage GWAS summary statistics of complex diseases and traits derived from large-scale population cohorts to identify pleiotropic regions with conflicting effects. Through a multi-trait colocalization approach, we identified 219 independent regions containing variants showing pleiotropic conflict, which cover ∼11.4% of linkage disequilibrium blocks in the human genome. Antagonistic variants are observed to be enriched for SNPs with intermediate minor allele frequencies and antagonistic regions show signatures of positive/balancing selection. Our results suggest that antagonistic variants are pervasive in humans and indicate their role in maintaining phenotypic and genetic diversity in humans.
Gaussian Process Emulation for Modeling Dengue Outbreak Dynamics
Authors: Langmüller Anna M. , Chandrasekher Kiran A. , Haller Benjamin C. , Champer Samuel E. , Murdock Courtney C. , Messer Philipp W.
Published: November 2024

Epidemiological models that aim for a high degree of biological realism by simulating every individual in a population are unavoidably complex, with many free parameters, which makes systematic explorations of their dynamics computationally challenging. This study investigates the potential of Gaussian Process emulation to overcome this obstacle. To simulate disease dynamics, we developed an individual-based model of dengue transmission that includes factors such as social structure, seasonality, and variation in human movement. We trained three Gaussian Process surrogate models on three outcomes: outbreak probability, maximum incidence, and epidemic duration. These models enable the rapid prediction of outcomes at any point in the eight-dimensional parameter space of the original model. Our analysis revealed that average infectivity and average human mobility are key drivers of these epidemiological metrics, while the seasonal timing of the first infection can influence the course of the epidemic outbreak. We use a dataset comprising more than 1,000 dengue epidemics observed over 12 years in Colombia to calibrate our Gaussian Process model and evaluate its predictive power. The calibrated Gaussian Process model identifies a subset of municipalities with consistently higher average infectivity estimates, highlighting them as promising areas for targeted public health interventions. Overall, this work underscores the potential of Gaussian Process emulation to enable the use of more complex individual-based models in epidemiology, allowing a higher degree of realism and accuracy that should increase our ability to control important diseases such as dengue.