bluuebunny/crossref_metadata_2025 huggingface dataset:
Returning Research Results That Indicate Risk of Alzheimer Disease Dementia to Healthy Participants in Longitudinal Studies (WeSHARE)
Authors: Hartz Sarah M. , Goswami Spondita , Oliver Amy , Evans Alissa , Jackson Sacha , Linnenbringer Erin , Moulder Krista , Morris John C. , Mozersky Jessica
Published: July 2024

Introduction

Returning research results that indicate risk of Alzheimer disease (AD) - a disease for which no meaningful treatments or cure exist - to cognitively normal participants is controversial. AD is thought to begin many years before clinical signs and symptoms begin. During this time, individuals are cognitively normal, but have biomarkers that indicate pathophysiological changes in the brain. With this study, we aim to evaluate impact of returning research results on cognitively normal participants recruited from a longitudinal observational cohort on aging at the Knight Alzheimer Disease Research Center (Knight ADRC) at Washington University in St. Louis.

Methods and analysis

Our study uses a 2-year, delayed-start randomized clinical trial design. Participants are randomized to receive their research results either in 2-4 weeks or 1 year after informed consent. We plan to approach approximately 260 participants who have research results from previous genetic and biomarker testing at the Knight ADRC. The primary cognitive outcomes are 1-year change in subjective cognitive score (Clinical Dementia Rating (CDR®) sum of boxes), objective cognitive score (psychometric composite score), and the primary psychosocial outcome is Impact of Event-Revised score 1 year after return of research results.

Ethics and dissemination

This study has been approved by the WUSM Institutional Review Board (IRB) and the Human Research Protection Office (HRPO). Results from these trials are shared through conferences and publications.

Trial registration number

NCT04699786.

Strengths and limitations of this study

This study empirically evaluates how returning research AD biomarkers impacts participants both psychologically and cognitively using a randomized delayed-start clinical trial

Multiple research AD biomarkers are synthesized into a single estimate for AD dementia risk

A delayed-start design is necessary because it is unethical to withhold research results from participants but may limit the generalizability of the results because all participants will be receiving their research results
Inference of ecological networks and possibilistic dynamics based on Boolean networks from observations and prior knowledge
Authors: Paulevé Loïc , Gaucherel Cédric
Published: July 2024

Being able to infer the interactions between a set of species from observations of the system is of paramount importance to obtain explaining and predictive models in ecology. We tackled this challenge by employing qualitative modeling frameworks and logic methods for the synthesis of mathematical models that can integrate both observations and expert knowledge on the system. After devising a formal link between ecological networks and the causal structure of Boolean networks, we applied a generic model synthesis engine to infer Boolean models that are able to reproduce the observed dynamics of a protist community. Our inference method supports optimization criteria to derive most parsimonious and most precise models. It is also able to integrate prior knowledge on the ecological network, adding constraints on impossible interactions, which is necessary to obtain realistic predictions. Such constraints may however prove to be too strict, in which case our method is able to conclude on the absence of a model compatible with both the observations and the input hypotheses. We demonstrated our methodology on experimental data of a protist system, and showed its ability to recover essential and sufficient ecological interactions to explain the observed dynamics.
Designer DNA nanocages modulate anti-oxidative and anti-inflammatory responses in tumor associated macrophages
Authors: Vaswani Payal , Bhatia Dhiraj
Published: July 2024

Cancer is a complex disease, with multiple treatment modalities, but no definitive cure. The tumor microenvironment contributes to the complexity of the disease by forming a niche of multiple cell types supporting each other to carry out various cellular functions. Tumor associated macrophages are one such kind of cells which support the tumor microenvironment via immunosuppression. DNA tetrahedron (TD), a widely explored DNA nanocage, has shown a lot of potential in therapeutics. However, the role of TD still remains quite unexplored in immunology. Here, we first establish the anti-oxidative and anti-inflammatory role of TD. We then proceed with using TD as a therapeutic agent in tumor associated macrophages by modulating the response of PD-L1. The findings of this work create a base for TD in biological applications such as cancer immunotherapy.

Graphical Abstract

Immunomodulatory effects of DNA nanocages on tumour associated macrophages
Capturing gait parameters during asymmetric overground walking using ultra-wideband radars: A preliminary study
Authors: Hadjipanayi Charalambos , Yin Maowen , Constandinou Timothy G.
Published: July 2024

This study investigates the deployability of commercially available impulse-radio ultra-wideband radar (UWB) sensors, in accurately detecting and analysing gait patterns during asymmetric overground locomotion. An adjustable knee brace was fitted on the right knee of 10 able-bodied participants, in five different confinement angles, during a 6-meter walking task to simulate asymmetric walking patterns. A computationally efficient signal processing framework extracts seven spatiotemporal gait parameters from six UWB radar signals, based on their joint Range-Doppler-Time representation. Gait asymmetry was quantified using primarily the symmetry ratio metric of step times. Validated against the gold standard motion capture system, radar-based gait parameters were estimated with 88.2-98.8% accuracy for all settings. By capturing step time symmetry ratios with 95.6±2.8% accuracy, the radar system can effectively distinguish between different gait impairment levels.
Regulation of proteostasis by sleep through autophagy inDrosophilamodels of Alzheimer’s Disease
Authors: Ortiz-Vega Natalie , Lobato Amanda G. , Canic Tijana , Zhu Yi , Lazopulo Stanislav , Syed Sheyum , Zhai R. Grace
Published: July 2024

Sleep and circadian rhythm dysfunctions are common clinical features of Alzheimer’s Disease (AD). Increasing evidence suggests that in addition to being a symptom, sleep disturbances can also drive the progression of neurodegeneration. Protein aggregation is a pathological hallmark of AD, however the molecular pathways behind how sleep affects protein homeostasis remain elusive. Here we demonstrate that sleep modulation influences proteostasis and the progression of neurodegeneration inDrosophilamodels of Tauopathy. We show that sleep deprivation enhanced Tau aggregational toxicity resulting in exacerbated synaptic degeneration. In contrast, sleep induction using gaboxadol led to reduced hyperphosphorylated Tau accumulation in neurons as a result of modulated autophagic flux and enhanced clearance of ubiquitinated Tau, suggesting altered protein processing and clearance that resulted in improved synaptic integrity and function. These findings highlight the complex relationship between sleep and autophagy, in regulating protein homeostasis, and the neuroprotective potential of sleep-enhancing therapeutics to slow the progression or delay the onset of neurodegeneration.
Replacing non-biomedical concepts improves embedding of biomedical concepts
Authors: Niyonkuru Enock , Soto Gomez Mauricio , Casiraghi Elena , Antogiovanni Stephan , Blau Hannah , Reese Justin T , Valentini Giorgio , Robinson Peter N
Published: July 2024

Objectives

Concept embeddings are low-dimensional vector representations of concepts such as MeSH:D009203 (Myocardial Infarction), whose similarity in the embedded vector space reflects their semantic similarity. Here, we test the hypothesis that non-biomedical concept synonym replacement can improve the quality of biomedical concepts embeddings.

Materials and methods

We developed an approach that leverages WordNet to replace sets of synonyms with the most common representative of the synonym set.

Results

We tested our approach on 1055 concept sets and found that, on average, the mean intracluster distance was reduced by 8% in the vector-space. Assuming that homophily of related concepts in the vector space is desirable, our approach tends to improve the quality of embeddings.

Discussion and Conclusion

This pilot study shows that non-biomedical synonym replacement tends to improve the quality of embeddings of biomedical concepts using the Word2Vec algorithm. We have implemented our approach in a freely available Python package available athttps://github.com/TheJacksonLaboratory/wn2vec.
Poly(allylamine)/tripolyphosphate nanocomplex coacervate as a NLRP3-dependent systemic adjuvant for vaccine development
Authors: Rizzo Gastón P. , Sanches Rodrigo C. , Chavero Camila , Bianchi Daiana S. , Apuzzo Eugenia , Herrera Santiago E. , Agazzi Maximiliano L. , Cortez M. Lorena , Marmisollé Waldemar A. , Keitelman Irene A. , Trevani Analía S. , Oliveira Sergio C. , Azzaroni Omar , Smaldini Paola L. , Docena Guillermo H.
Published: July 2024

Nanotechnology plays a crucial role in vaccine development. It allows the design of functional nanoparticles (NPs) that can act both as antigen carriers and as adjuvants to enhance the immune response. The present study aims to evaluate complex coacervate-like NPs composed of poly(allylamine hydrochloride) (PAH) and tripolyphosphate (TPP) as a safe vehicle and adjuvant for systemic vaccines. We investigated the activation of different antigen-presenting cells (APCs) with NPs and their adjuvanticity in Balbc/c and different KO mice that were intraperitoneally immunized with NP-OVA.

We found that NPs increased the expression of CD86 and MHCII and promoted the production and secretion of interleukin-1β (IL-1β) and IL-18 through the inflammasome NLRP3 when macrophages and dendritic cells were co-incubated with LPS and NPs. We evidenced an unconventional IL-1β release through the autophagosome pathway. The inhibition of autophagy with 3-methyladenine reduced the LPS/NPs-induced IL-1β secretion. Additionally, our findings showed that the systemic administration of mice with NP-OVA triggered a significant induction of serum OVA-specific IgG and IgG2a, an increased secretion of IFN-γ by spleen cells, and high frequencies of LT CD4+IFN-γ+and LT CD8+IFN-γ+. Our findings show that NPs promoted the inflammasome activation of innate cells with Th1-dependent adjuvant properties, making them valuable for formulating novel preventive or therapeutic vaccines for infectious and non-infectious diseases.

Graphical Abstract
tauX: A Gene Expression Ratio Strategy to Improve Machine Learning Applications in Precision Medicine
Authors: Pfeil Jacob , Ma Liqian , Lo Hin Ching , Turan Tolga , McLaughlin R. Tyler , Shi Xu , Villarruel Severiano , Wilson Stephen , Zhao Xi , Samayoa Josue , Halliwill Kyle
Published: July 2024

Machine learning algorithms identify patterns that would otherwise be difficult to observe in high-dimensional molecular and clinical data. For this reason, machine learning has the potential to have a profound impact on clinical decision making and drug target discovery. Nevertheless, there remain considerable technical challenges in adapting these tools for clinical use. These challenges include clinical feature engineering, model selection, and defining optimal strategies for model training. For cancer care, RNA sequencing of patient tumor biopsies has already proven to be a powerful molecular assay to characterize tumor-intrinsic and -extrinsic phenotypes influencing therapeutic response. To improve the predictive performance of RNA-sequencing data, we developed the tauX machine learning framework to refine gene expression features and improve the performance of machine learning algorithms. The tauX framework uses aggregated ratios of positively and negatively associated predictive genes to simplify the prediction task. We showed a significant improvement in predictive performance using a large database of synthetic gene expression profiles. We also show how the tauX framework can be used to elucidate the mechanisms of response and resistance to checkpoint blockade therapy using data from the Stand Up to Cancer (SU2C) Lung Response Cohort and The Cancer Genome Atlas (TCGA). The tauX strategy achieved superior predictive performance compared to models built upon established feature engineering strategies or widely used cancer gene expression signatures. The tauX framework is available as a freely deployable docker container (https://hub.docker.com/r/pfeiljx/taux).
Fecal metaproteomics enables functional characterization of remission in patients with inflammatory bowel disease
Authors: Wolf Maximilian , Lange Julian , Benndorf Dirk , Welz Lina , Nikolaus Susanna , Sievers Laura , Tran Florian , Schallert Kay , Hellwig Patrick , Schreiber Stefan , Gunzer Matthias , Rosenstiel Philip , Reichl Udo , Aden Konrad , Heyer Robert
Published: July 2024

Background

The gut microbiome is an important contributor to the development and the course of inflammatory bowel disease (IBD). While changes in the gut microbiome composition were observed in response to IBD therapy using biologics, studies elucidating human and microbial proteins and pathways in dependence on therapy success are sparse.

Methods

Fecal samples of a cohort of IBD patients were collected before and after 14 weeks of treatment with three different biologics. Clinical disease activity scores were used to determine the clinical response and remission. Fecal metaproteomes of remitting patients (n=12) and of non-remitting patients (n=12) were compared before treatment and changes within both groups were assessed over sampling time to identify functional changes and potential human and microbial biomarkers.

Results

The abundance of proteins associated with the intestinal barrier, neutrophilic granulocytes, and immunoglobulins significantly decreased in remitting patients. In contrast, an increase of those proteins was observed in non-remitting patients. There were significant changes in pathways of microbial metabolism in samples from patients with remission after therapy. This included, for example, an increased abundance of proteins from butyrate fermentation. Finally, new potential biomarkers for the prediction and monitoring of therapy success could be identified, e.g. human lysosome-associated membrane glycoprotein 1, a cytotoxicity marker, or microbial anthranilate synthase component 2, a part of the tryptophan metabolism.

Conclusions

Distinct changes of proteins related to gut inflammation and gut microbiome metabolism showed whether IBD remission was achieved or not. This suggests that metaproteomics could be a useful tool for monitoring remission in IBD therapies.
Patient information needs for transparent and trustworthy artificial intelligence in healthcare
Authors: Stroud Austin M. , Minteer Sarah A. , Zhu Xuan , Ridgeway Jennifer L. , Miller Jennifer E. , Barry Barbara A.
Published: July 2024

Background

As health systems incorporate artificial intelligence (AI) into various aspects of patient care, there is growing interest in understanding how to ensure transparent and trustworthy implementation. However, little attention has been given to what information patients need about these technologies to promote transparency of their use.

Methods

We conducted three asynchronous online focus groups with 42 patients across the United States discussing perspectives on their information needs for trust and uptake of AI, focusing on its use in cardiovascular care. Data were analyzed using a rapid content analysis approach.

Results

Our results suggest that patients have a set of core information needs, including specific information factors pertaining to the AI model, oversight, and healthcare experience, that are relevant to calibrating trust as well as perspectives concerning information delivery, disclosure, consent, and physician AI use.

Conclusions

Identifying patient information needs is a critical starting point for calibrating trust in healthcare AI systems and designing strategies for information delivery. These findings highlight the importance of patient-centered engagement when considering approaches for transparent healthcare AI.
Cryptic recombination and transposition drive structural variation to shape genomic plasticity and life history traits in a host generalist fungal plant pathogen
Authors: Derbyshire Mark C , Newman Toby E , Khentry Yuphin , Michael Pippa J , Bennett Sarita Jane , Rijal Lamichhane Ashmita , Graham-Taylor Carolyn , Chander Subhash , Camplone Claudia , Vicini Simone , Esquivel-Garcia Laura , Coutu Cathy , Hegedus Dwayne , Clarkson John , Lindbeck Kurt , Kamphuis Lars G
Published: July 2024

Background

An understanding of plant pathogen evolution is important for sustainable management of crop diseases. Plant pathogen populations must maintain adequate heritable phenotypic variability to survive. Polymorphisms >= 50 bp, known as structural variants (SVs), could contribute strongly to this variability by disrupting gene activities. SV acquisition is largely driven by mobile genetic elements called transposons, though a less appreciated source of SVs is erroneous meiotic double-strand break repair. The relative impacts of transposons and recombination on SV diversity and the overall contribution of SVs to phenotypic variability is elusive, especially in host generalists.

Results

We use 25 high quality genomes to create a graphical pan-genome of the globally distributed host-generalist crop pathogenSclerotinia sclerotiorum. Outcrossing and recombination rates in this self-fertile species have been debated. Using bisulfite sequencing, and short read data from 190 strains, we show thatS. sclerotiorumhas many hallmarks of eukaryotic meiosis, including recombination hot and cold spots, centromeric and genic recombination suppression, and rapid linkage disequilibrium decay. Using a new statistic that captures average pairwise structural variation, we show that recombination and transposons make distinct contributions to SV diversity. Furthermore, despite only 5 % of genes being dispensable, SVs often had a stronger impact than other variants across 14 life history traits measured in 103 distinct strains.

Conclusion

Transposons and recombination make distinct contributions to SV diversity inS. sclerotiorum. Despite limited gene content diversity, SVs may strongly impact phenotypic variability. This sheds light on the genomic forces shaping adaptive flexibility in host generalists.
GTestimate: Improving relative gene expression estimation in scRNA-seq using the Good-Turing estimator
Authors: Fahrenberger Martin , Esk Christopher , von Haeseler Arndt
Published: July 2024

Background

Single-cell RNA-seq suffers from unwanted technical variation between cells, caused by its complex experiments and shallow sequencing depths. Many conventional normalization methods try to remove this variation by calculating the relative gene expression per cell. However, their choice of the Maximum Likelihood estimator is not ideal for this application.

Results

We presentGTestimate, a new normalization method based on the Good-Turing estimator, which improves upon conventional normalization methods by accounting for unobserved genes. To validateGTestimatewe developed a novel cell targeted PCR-amplification approach (cta-seq), which enables ultra-deep sequencing of single cells. Based on this data we show that the Good-Turing estimator improves relative gene expression estimation and cell-cell distance estimation. Finally, we useGTestimate’s compatibility with Seurat workflows to explore three common example data-sets and show how it can improve downstream results.

Conclusion

By choosing a more suitable estimator for the relative gene expression per cell, we were able to improve scRNA-seq normalization, with potentially large implications for downstream results.GTestimateis available as an easy-to-use R-package and compatible with a variety of workflows, which should enable widespread adoption.
Bulk and Single-cell Transcriptomic Brain Data Identify Overlapping Processes and Cell-types with Human AUD and Mammalian Models of Alcohol Use
Authors: Huggett Spencer B. , Selveraj Sharmila , McGeary John E. , Ikeda Ami , Yuan Emerald , Loeffel Lauren B. , Palmer Rohan H.C.
Published: July 2024

This study explores the neurobiological underpinnings of alcohol use disorder (AUD) by integrating bulk and single-cell transcriptomic data from humans, primates, and mice across three brain regions associated with addiction (i.e., prefrontal cortex (PFC), nucleus accumbens (NAc), and central amygdala (CeA)). We compared AUD RNA expression and cell-type abundance from 92 human brain to data from 53 primates and 90 mice engaged in diverse alcohol use paradigms. The findings revealed significant and reproducible correlations between human AUD and mammalian models of alcohol use that vary by tissue, species, and behavioral paradigm. The strongest correlations occurred between primate and mouse models of binge drinking (i.e., high drinking in the dark). Certain primate models demonstrated that the brain RNA correlations with human alcohol use disorder (AUD) were approximately 40% as strong as the correlations observed within human samples themselves. By integrating single-cell transcriptomic data, this study observed decreased oligodendrocyte proportions in the PFC and NAc of human AUD with similar trends in animal models. Gene co-expression network analyses revealed conserved systems associated with human AUD and animal models of heavy/binge alcohol consumption. Gene co-expression networks were enriched for pathways related to inflammation, myelination, and synaptic plasticity and the genes within them accounted for ∼20% of the heritability in human alcohol consumption. Identified hub genes were associated with relevant traits (e.g., impulsivity, motivation) in humans and mice. This study sheds light on conserved biological entities underlying AUD and chronic alcohol use, providing insights into the cellular, genetic, and neuromolecular basis across species.
Putting the Asymmetric Response Concept to the test: modeling multiple stressor exposure and release in a stream food web
Authors: Kuppels Annabel , Bayat Helena S. , Gillmann Svenja M. , Schäfer Ralf B. , Vos Matthijs
Published: July 2024

Communities in stream ecosystems often respond asymmetrically to increase and release of stressors, as indicated by slow and incomplete recovery. The Asymmetric Response Concept (ARC) posits that this is due to a shift in the relative importance of three mechanisms: tolerance, dispersal, and biotic interactions. In complex natural communities, these mechanisms may produce alternative outcomes through poorly understood indirect effects. To understand how the three mechanisms respond to different temporal stressor scenarios, we studied multiple scenarios using a stream food web model. We asked the following questions: Do groups of species decline as expected on the basis of individual tolerance rankings derived from laboratory experiments when they are embedded in a complex dynamic food web? Does the response of ecosystem function match that of communities? To address these questions, we aggregated data on individual tolerances at the level of functional groups and studied how single and multiple stressors affect food web dynamics and nutrient cycling. Multiple stressor scenarios involved different intensities of salt and temperature increase. Functional groups exhibited a different relative tolerance ranking between the laboratory and dynamic food web contexts. Salt as a single stressor had only minor and transient effects at low level but led to the loss of one or more functional groups at high level. In contrast, high temperature, alone or in combination with salt, caused the loss of functional groups at all tested levels. Patterns often differed between the response of communities and ecosystem function. We discuss our findings with respect to the ARC.

Graphical Abstract
Sleep homeostasis in a naturalistic setting
Authors: Ujma Péter P. , Bódizs Róbert
Published: July 2024

Sleep, especially NREM sleep depth is homeostatically regulated, as sleep pressure builds up during wakefulness and diminishes during deep sleep. Previous evidence from this phenomenon, however, mainly stems from experimental studies which may not generalize to an ecologically valid setting. In the current study, we used a dataset of 246 individuals sleeping for at least seven nights each with a mobile EEG headband according to their ordinary daily schedule to investigate the effect of time spent in wakefulness on sleep characteristics. Increased time in wakefulness prior to sleep was associated with decreased sleep onset latency, increased sleep efficiency, a larger percentage of N3 sleep, and higher delta activity. Moreover, increased sleep pressure resulted in an increase in both the slope and the intercept of the sleep EEG spectrum. As predicted, PSD effects were most prominent in the earliest hours of sleep. Our results demonstrate that experimental findings showing increased sleep depth after extended wakefulness generalize to ecologically valid settings, and that time spent awake is an important determinant of sleep characteristics on the subsequent night. Our findings are evidence for the efficacy of sleep restriction, a behavioral technique already widely used in clinical settings, as a simple but powerful method to improve the objective quality of sleep in those with sleep problems.
Gene expression asymmetry in Parkinson’s Disease; variation ofCCTandBEXgene expression levels are correlated with hemisphere specific severity
Authors: Pierce Steven E. , van der Schans Edwin J.C. , Ensink Elizabeth , Coetzee Gerhard A.
Published: July 2024

Parkinson’s Disease (PD) develops unilaterally, which may be related to brain hemispheric differences in gene expression. Here we measured bulk RNA-seq levels in neuronal nuclei obtained from prefrontal cortex postmortem brain samples from males and females with PD and from healthy controls. Left and right hemispheres from each brain were related the side of symptom onset and compared. We employed twoa prioriapproaches; first we identified genes differentially expressed between PD and controls and between left vs right PD brain hemispheres. Second, we examined the presence of, and correlates to, variable asymmetry seen in candidate PD differentially expressed genes. We found large variation among individuals with PD, and PD stratification by gene expression similarity was required for patterns of genetic asymmetry to emerge. For a subset of PD brains, hemispherical variation ofCCTandBEXgene levels correlated with the side of PD symptom onset.
Response of photosynthetic efficiency to short-term fluctuating light and cold in tomato
Authors: Rayaprolu Laavanya , Jayasankar Keshav , Aarts Mark G. M. , Harbinson Jeremy
Published: July 2024

Climate-resilient crops are crucial for meeting global food demand and increasing crop productivity. Photosynthesis, a crucial process, is impacted by environmental changes such as temperature and irradiance. Photosynthesis and stomatal opening often lag behind these changes, resulting in a loss in Light Use Efficiency (LUE). Temperature variations also affect photosynthesis, with a decrease below the optimal threshold resulting in a decrease in photosynthetic efficiency. To enhance photosynthetic LUE, understanding plant responses to environmental changes is essential. This study examines the short-term responses of four tomato genotypes to irradiance fluctuations using chlorophyll fluorescence and the effects of transient cold stress. The results show genotype-to-genotype variation in the maximum quantum efficiency of PSII, the kinetics of the quantum efficiency of PSII’s response to step changes in irradiance, and steady-state values of ΦPSII, which is used as a stand-in for photosynthetic efficiency. The control conditions were measured at 24°C and the cold stress conditions at 14°C. The fact that ΦPSII responds dynamically to step decrease and increase in irradiance and how cold impacts these responses illustrates the way tomato genotypes are impacted by cold stress. It also reveals how the genotypes adapt to cold exposure and recover once the cold stress is reversed.

Highlight

This study investigates the adaptation and recovery of four tomato genotypes to irradiance fluctuations and transient cold stress, highlighting the importance of climate-resilient crops for food demand.
Microglia mediate the early-life programming of adult glucose control
Authors: Valdearcos M , McGrath ER , Brown Mayfield SM , Folick A , Cheang RT , Li L , Bachor TP , Lippert RN , Xu AW , Koliwad SK
Published: July 2024

Mammalian glucose homeostasis is, in part, nutritionally programmed during early neonatal life, a critical window for the formation of synapses between hypothalamic glucoregulatory centers. Although microglia are known to prune synapses throughout the brain, their specific role in refining hypothalamic glucoregulatory circuits remains unknown. Here, we show that microglia in the mediobasal hypothalamus (MBH) of mice actively engage in synaptic pruning during early life. Microglial phagocytic activity is induced following birth, regresses upon weaning from maternal milk, and is exacerbated by feeding dams a high-fat diet while lactating. In particular, we show that microglia refine perineuronal nets (PNNs) within the neonatal MBH. Indeed, transiently depleting microglia before weaning (P6-16), but not afterward (P21-31), remarkably increased PNN abundance in the MBH. Furthermore, mice lacking microglia only from P6-16 had glucose intolerance due to impaired glucose-responsive pancreatic insulin secretion in adulthood, a phenotype not seen if microglial depletion occurred after weaning. Viral retrograde tracing revealed that this impairment is linked to a reduction in the number of neurons in specific hypothalamic glucoregulatory centers that synaptically connect to the pancreatic β-cell compartment. These findings show that microglia facilitate synaptic plasticity in the MBH during early life through a process that includes PNN refinement, to establish hypothalamic circuits that regulate adult glucose homeostasis.
Benchmarking for genotyping and imputation using degraded DNA for forensic applications across diverse populations
Authors: Zavala Elena I. , Rohlfs Rori V. , Moorjani Priya
Published: July 2024

Advancements in sequencing and laboratory technologies have enabled forensic genetic analysis on increasingly low quality and degraded DNA samples. However, existing computational methods applied to genotyping and imputation for generating DNA profiles from degraded DNA have not been tested for forensic applications. Here we simulated sequencing data of varying qualities– coverage, fragment lengths, and deamination patterns–from forty individuals of diverse genetic ancestries. We used this dataset to test the performance of commonly used genotype and imputation methods (SAMtools, GATK, ATLAS, Beagle, and GLIMPSE) on five different SNP panels (MPS- plex, FORCE, two extended kinship panels, and the Human Origins array) that are used for forensic and population genetics applications. For genome mapping and variant calling with degraded DNA, we find use of parameters and methods (such as ATLAS) developed for ancient DNA analysis provides a marked improvement over conventional standards used for next generation sequencing analysis. We find that ATLAS outperforms GATK and SAMtools, achieving over 90% genotyping accuracy for the four largest SNP panels with coverages greater than 10X. For lower coverages, decreased concordance rates are correlated with increased rates of heterozygosity. Genotype refinement and imputation improve the accuracy at lower coverages by leveraging population reference data. For all five SNP panels, we find that using a population reference panel representative of worldwide populations (e.g., the 1000 Genomes Project) results in increased genotype accuracies across genetic ancestries, compared to ancestry-matched population reference panels. Importantly, we find that the low SNP density of commonly used forensics SNP panels can impact the reliability and performance of genotype refinement and imputation. This highlights a critical trade-off between enhancing privacy by using panels with fewer SNPs and maintaining the effectiveness of genomic tools. We provide benchmarks and recommendations for analyzing degraded DNA from diverse populations with widely used genomic methods in forensic casework.

Highlights

Biallelic SNP panels: >92% genotyping accuracy for 10X data with ATLAS

Degraded DNA impacts accuracy under sequencing depth of 10X coverage

Higher accuracies across genetic ancestries achieved with a diverse reference panel

Leveraging population reference data is not applicable for small SNP panels

Trade-off between genotype accuracy and privacy when considering SNP panel size
Machine learning-based forecasting of daily acute ischemic stroke admissions using weather data
Authors: Santhanam Nandhini , Kim Hee E. , Rügamer David , Bender Andreas , Muthers Stefan , Cho Chang Gyu , Alonso Angelika , Szabo Kristina , Centner Franz-Simon , Wenz Holger , Ganslandt Thomas , Platten Michael , Groden Christoph , Neumaier Michael , Siegel Fabian , Maros Máté E.
Published: July 2024

Background

In the midst of the emerging climate crisis, healthcare providers lack locally validated, disease-specific surveillance models. Stroke, a significant contributor to the global disease burden, has been linked to climate change. Therefore, we developed and benchmarked machine learning (ML) models based on locoregional weather systems to forecast the number of daily acute ischemic stroke (AIS) admissions.

Methods

AIS patients diagnosed between 2015 and 2021 at the tertiary University Medical Center (UMC) Mannheim, Germany were extracted from the local data integration center and geospatially matched to weather data from the German Weather Service (DWD) based on the clinic’s, patients’ home and closest tower’s locations at the time of admission. Statistical- (Poisson), boosted generalized additive model (GAM), support vector machines (SVR), and tree-based models including random forest (RF) and extreme gradient boosting (XGB) were evaluated in regression settings within time-stratified nested cross-validation setup (training-validation: 2015-2020, test set: 2021) to predict the number of daily AIS admissions.

Findings

The cohort included 7,914 AIS patients (4,244 male, 53·6%). XGB showed the best test performance with lowest mean absolute error (MAE) of 1·21 cases/day. Maximum air pressure was identified as the top predictive variable. Shapley additive explanations analyses revealed that temperature extremes of extended cold-(lag-3 minimum temperature <-2 °C; minimum perceived temperature <-1·4 °C) and hot stressors (lag-7 minimum temperature >15 °C), as well as stormy conditions (lag-1 and lag-2 maximum wind gust >14 m/s and speed >10·4 m/s), increased stroke incidences substantially with distinct seasonal associations.

Interpretation

ML models can sufficiently forecast AIS admissions based on weather patterns allowing for improved resource allocation and preparedness.
Costs of typhoid vaccination for international travelers from the United States
Authors: Joo Heesoo , Maskery Brian A. , Francois Watkins Louise K. , Park Joohyun , Angelo Kristina M. , Halsey Eric S.
Published: July 2024

In the United States, typhoid vaccination is recommended for international travelers to areas with a recognized risk of typhoid exposure. Using MarketScan® Commercial Database from 2016 through 2022, we estimated typhoid vaccination costs by route (injectable vs. oral) and provider setting (clinic vs. pharmacy). Of 165,930 vaccinated individuals, 99,471 received injectable and 66,459 received oral typhoid vaccines, with 88% and 17% respectively administered at clinics. Average costs for injectable vaccination were $132.91 per person [95% confidence interval (CI): $132.68–$133.13], with clinic and pharmacy costs at $136.38 [95% CI: $136.14–$136.63], and $107.45 [95% CI: $107.13–$107.77] respectively. Oral vaccination costs averaged $81.23 per person [95% CI: $81.14–$81.33], encompassing $86.61 [95% CI: $86.13– $87.10] at clinics and $80.14 [95% CI: $80.09–$80.19] at pharmacies. Out-of-pocket costs comprised 21% and 33% of total costs for injectable and oral vaccinations. These findings may inform clinical decision-making to protect international travelers’ health.
Biallelic variants inCOX18cause a mitochondrial disorder primarily manifesting as peripheral neuropathy
Authors: Armirola-Ricaurte Camila , Morant Laura , Adant Isabelle , Hamed Sherifa Ahmed , Pipis Menelaos , Efthymiou Stephanie , Amor-Barris Silvia , Atkinson Derek , Van de Vondel Liedewei , Tomic Aleksandra , de Vriendt Els , Zuchner Stephan , Ghesquiere Bart , Hanna Michael , Houlden Henry , Lunn Michael P , Reilly Mary M , Rasic Vedrana Milic , Jordanova Albena
Published: July 2024

Defects in mitochondrial dynamics are a common cause of Charcot-Marie-Tooth disease (CMT), while primary deficiencies in the mitochondrial respiratory chain (MRC) are rare and atypical for this etiology. This study aims to reportCOX18as a novel CMT-causing gene. This gene encodes an assembly factor of mitochondrial Complex IV (CIV) that translocates the C-terminal tail of MTCO2 across the mitochondrial inner membrane.

Exome sequencing was performed in four affected individuals. The patients and available family members underwent thorough neurological and electrophysiological assessment. The impact of one of the identified variants on splicing, protein levels, and mitochondrial bioenergetics was investigated in patient-derived lymphoblasts. The functionality of the mutant protein was assessed using a Proteinase K protection assay and immunoblotting. Neuronal relevance of COX18 was assessed in aDrosophila melanogasterknockdown model.

Exome sequencing coupled with homozygosity mapping revealed a homozygous splice variant c.435-6A>G inCOX18in two siblings with early-onset progressive axonal sensory-motor peripheral neuropathy. By querying external databases, we identified two additional families with rare deleterious biallelic variants inCOX18. All affected individuals presented with axonal CMT and some patients also exhibited central nervous system symptoms, such as dystonia and spasticity. Functional characterization of the c.435-6A>G variant demonstrated that it leads to the expression of an alternative transcript that lacks exon 2, resulting in a stable but defective COX18 isoform. The mutant protein impairs CIV assembly and activity, leading to a reduction in mitochondrial membrane potential. Downregulation of theCOX18homolog inDrosophila melanogasterdisplayed signs of neurodegeneration, including locomotor deficit and progressive axonal degeneration of sensory neurons.

Our study presents genetic and functional evidence that supportsCOX18as a newly identified gene candidate for autosomal recessive axonal CMT with or without central nervous system involvement. These findings emphasize the significance of peripheral neuropathy within the spectrum of primary mitochondrial disorders and the role of mitochondrial CIV in the development of CMT. Our research has important implications for the diagnostic workup of CMT patients.
Kidney transcriptomics signature of prospective rapid diabetic kidney disease progression
Authors: Acoba Dianne , Levin Anna , Witasp Anna , Ebefors Kerstin , Mölne Johan , Greasley Peter J. , Nyström Jenny , Wernerson Annika , Reznichenko Anna
Published: July 2024

Previous cross-sectional transcriptomic studies on diabetic kidney disease (DKD) kidney tissue have shown correlations between gene expression and both disease status and kidney function at time of biopsy, but longitudinal data is scarce. We utilized clinical follow-up data up to five years post-biopsy, linking the transcriptomes of diagnostic kidney biopsies to progression rates and outcomes in 19 DKD patients. Patients were stratified into “rapid progressors” and “non-rapid progressors” based on clinical parameters (eGFR slope, CKD stage advancement, degree of albuminuria, composite of kidney failure or 40% eGFR decline). Differential expression and pathway enrichment analyses were performed to identify dysregulated genes and pathways associated with rapid progression. We identified 265 genes in glomeruli and tubulointerstitium that were significantly modulated in rapid vs non-rapid DKD progression. Rapid progression-associated genes showed enrichment for well-established (extracellular matrix organization, inflammation) as well as novel pathways in the context of DKD (circadian rhythm, cytoskeleton reorganization,NOTCHsignaling). This study illuminates kidney gene expression patterns that may be predictive of rapid progression in DKD and are distinct from those associated with cross-sectional kidney function.
Geospatial Analysis of Multilevel Socio-environmental Factors Impacting theCampylobacterBurden Among Infants in Rural Eastern Ethiopia: A One Health Perspective
Authors: Li Xiaolong , Chen Dehao , Liang Song , Hassen Jemal Yousuf , McKune Sarah L. , Havelaar Arie H. , Blackburn Jason K.
Published: July 2024

Increasing attention has focused on health outcomes ofCampylobacterinfections among children under five years in low-resource settings. Recent evidence suggests colonization ofCampylobacterspecies contributes to environmental enteric dysfunction, malnutrition, and growth faltering in young children.Campylobacterspecies are zoonotic, and factors from humans, animals, and the environment are involved in transmission. Few studies have assessed geospatial effects of environmental factors along with human and animal factors onCampylobacterinfections. Here, we leveragedCampylobacterGenomics and Environmental Enteric Dysfunction (CAGED) project data to model multiple socio-environmental factors onCampylobacterburden among infants in Eastern Ethiopia. Stool samples from 106 infants were collected monthly from birth through the first year of life (December 2020 – June 2022). Genus-specific Taqman real-time PCR was performed to detect and quantifyCampylobacterspp. and calculate cumulativeCampylobacterburden for each child as the outcome variable. Thirteen regional environmental covariates describing topography, climate, vegetation, soil, and human population density were combined with household demographics, livelihoods/wealth, livestock ownership, and child-animal interactions as explanatory variables. We dichotomized all continuous outcome and explanatory variables and built logistic regression models for the first and second half of the infant’s first year of life. Infants being female, living in households with cattle, reported to have physical contact with animals, or reported to have mouthed soil or animal feces had increased odds of higher cumulativeCampylobacterburden in Eastern Ethiopia. Future interventions should focus on infant-specific transmission pathways and create adequate separation of domestic animals from humans to prevent potential fecal exposures.
Effects of sub-anesthetic oro-mucosal dexmedetomidine on sleep in humans: A pharmacokinetics-pharmacodynamics study
Authors: Schnider Laura Katharina , Ratajczak Marta , Wespi Rafael , Kientsch Jacqueline , Bavato Francesco , Marten Laurenz , Kost Jonas , Puchkov Maxim , Eicher Corinne , Boxler Martina , Voegel Clarissa , Bosch Oliver Gero , van Someren Eus , Dornbierer Dario , Landolt Hans-Peter
Published: July 2024

Background: The locus coeruleus noradrenergic (LC-NE) system may provide a potential new target for pharmacological insomnia treatment, particularly in patients suffering from elevated stress. The selective alpha-2 noradrenergic agonist dexmedetomidine (DEX) attenuates LC-NE activity in sub-anesthetic doses, yet no adequate non-parental delivery systems of DEX are currently available. To examine the feasibility of oro-mucosal DEX administration, we developed two distinct - one sublingual and one buccal - oro-mucosal, fast-disintegrating DEX formulas tailored for self-administration. Here we established their pharmacokinetic and pharmacodynamic (PK-PD) profiles. Methods: In two separate studies in 8 male good sleepers and 17 men with subclinical insomnia, we administered sub-anesthetic doses (20 & 40 ug) of the two formulas following a randomized, double-blind, placebo-controlled, cross-over design. We complemented the PK assessments with all-night polysomnography, nocturnal cortisol and melatonin measurements, assessments of cardiovascular functions during and after sleep, cortisol awakening response, and post-awakening examination of subjective state and vigilance. Results: Particularly buccal DEX was rapidly absorbed and exhibited excellent dose-proportionality with minimal between-subject variation in exposure. In poor sleepers, 40 ug of buccal DEX shortened the sleep latency by 11 min, increased the time spent in non-rapid-eye-movement sleep by 38 min, and elevated electroencephalographic slow wave energy (0.75-4.0 Hz) in the first half of the night by 23 % (pall < 0.05). Rapid-eye-movement sleep latency was dose-dependently prolonged (20 ug: 48 min; 40 ug: 117 min; pall < 0.01). Nocturnal cortisol, melatonin and heart rate, and morning cortisol were not significantly affected by DEX, nor did post-awakening orthostatic regulation, subjective sleepiness and mood, and psychomotor vigilance differ among the conditions. Conclusions: The favorable PK-PD profile of oro-mucosal DEX delivery warrants further dose-finding and clinical studies, to establish the exact roles of α2 receptor agonism in pharmacological sleep enhancement and as possible novel mechanism to alleviate stress-related insomnia.
The ERK5 MAP kinase regulates annexin complexes and membrane dynamics in embryonic stem cells
Authors: Brown Helen A. , Guillet Ludivine , Williams Charles A. C. , Shaw Hayley , Zhou Houjiang , Rios-Szwed Diana , Fernandez-Alonso Rosalia , McMulkin Liam , Stavridis Marios P. , Findlay Greg M.
Published: July 2024

The ERK5 MAP kinase signalling pathway controls key processes in mouse Embryonic Stem Cells (mESCs) maintenance, including expression of naïve pluripotency genes and a transcriptional programme for stem cell rejuvenation. However, quantitative proteomics suggests that ERK5 signalling controls levels of proteins implicated in diverse biological processes. Here, we show that Annexin A2 (ANXA2) and its accessory protein S100A10, which are implicated in regulation of membrane dynamics, are major targets of the ERK5 signalling pathway in mESCs. ERK5 activation promotes expression of the ANXA2/S100A10 protein complex via transcriptional induction of the KLF2 pluripotency factor. Furthermore, either ERK5 signalling or ectopic expression of the ANXA2/S100A10 complex promotes formation of membrane protrusions in mESCs. Our data therefore identify a new function for the ERK5 pathway in regulation of an Annexin complex and membrane dynamics, which may have implications for development and disease.