bluuebunny/crossref_metadata_2025 huggingface dataset:
Positive selection underlies repeated knockout of ORF8 in SARS-CoV-2 evolution
Authors: Wagner Cassia , Kistler Kathryn E. , Perchetti Garrett A. , Baker Noah , Frisbie Lauren A. , Torres Laura Marcela , Aragona Frank , Yun Cory , Figgins Marlin , Greninger Alexander L. , Cox Alex , Oltean Hanna N. , Roychoudhury Pavitra , Bedford Trevor
Published: September 2023

Knockout of the ORF8 protein has repeatedly spread through the global viral population during SARS-CoV-2 evolution. Here we use both regional and global pathogen sequencing to explore the selection pressures underlying its loss. In Washington State, we identified transmission clusters with ORF8 knockout throughout SARS-CoV-2 evolution, not just on novel, high fitness viral backbones. Indeed, ORF8 is truncated more frequently and knockouts circulate for longer than for any other gene. Using a global phylogeny, we find evidence of positive selection to explain this phenomenon: nonsense mutations resulting in shortened protein products occur more frequently and are associated with faster clade growth rates than synonymous mutations in ORF8. Loss of ORF8 is also associated with reduced clinical severity, highlighting the diverse clinical impacts of SARS-CoV-2 evolution.
The High Price of Equity in Pulse Oximetry: A cost evaluation and need for interim solutions
Authors: Dempsey Katelyn , Lindsay Mary , Tcheng James E. , Wong An-Kwok Ian
Published: September 2023

Importance

Disparities in pulse oximetry accuracy, disproportionately affecting patients of color, have been associated with serious clinical outcomes. Although many have called for pulse oximetry hardware replacement, the cost associated with this replacement is not known.

Objective

To estimate the cost of replacing all pulse oximetry hardware throughout a hospital system.

Design

Single-center survey, 2023

Setting

Single center.

Participant

One academic medical center with three hospitals.

Main Outcomes and Measures

Cost of fleet replacement as identified by current day prices for hardware.

Results

New and used prices for 5,079/5,678 (89.5%) across three hospitals for pulse oximetry devices were found. The average equipment cost to replace pulse oximetry hardware is $15,704.12 per bed. Replacement and integration costs are estimated at $28.5-31.8 million for the entire medical system. Extrapolating these costs to 5,564 hospitals in the United States results in an estimated cost of $14.1 billion.

Conclusions and Relevance

“Simply replacing” pulse oximetry hardware to address disparities may be neither simple, cheap, or timely. Solutions for addressing pulse oximetry accuracy disparities leveraging current technology may be necessary.

Trial Registration

Pro00113724, exempt

Key points

Question

What is the cost and complexity of replacing pulse oximetry technology to improve disparities, both at a single institution and across the US?

Findings

In this observational study of pulse oximetry devices in an academic medical system with three hospitals, new and used prices were found for 5,079/5,678 devices (89.5%), with fleet replacement and integration cost of $28.5-31.8 million and some life cycles extending beyond 18 years. When extrapolated to 5,564 hospitals in the United States, estimated replacement costs are $9.7-$20.1 billion.

Meaning

The monetary and time cost of pulse oximetry hardware replacement is substantial, and solutions utilizing current pulse oximetry technology are essential to delivering equitable care to all patients.
Real-time pooled optical screening with single-cell isolation capability
Authors: Karempudi Praneeth , Amselem Elias , Jones Daniel , Khaji Zahra , Tenje Maria , Elf Johan
Published: September 2023

In a pooled optical screen, a genetically diverse library of living cells is imaged and characterised for phenotypic variations without knowing the genotype of the cells. The genotypes are identified in situ after the cells have been fixed or by physical extraction of interesting phenotypes followed by sequencing. Mother-machine microfluidics devices are efficient tools in pooled optical screens since many strains can be imaged in the same field of view, but the throughput is often limited. In this work, we show a method to extract single bacterial cells from a compact 100,000-trap mother-machine-based fluidic device using an optical tweezer. Unlike previous devices, the fluids in our design are routed in 3D to enable fast loading of cells, increased trap density, and faster imaging. We have also developed software that allows real-time analysis of the phenotyping data.
Validity and reliability of a new whole room indirect calorimeter to assess metabolic response to small-calorie loads
Authors: Baugh Mary Elizabeth , Ahrens Monica L. , Hutelin Zach , Stylianos Charlie , Wohlers-Kariesch Erica , Oster Mary E. , Dotson Jon , Moon Jon , Hanlon Alexandra L. , DiFeliceantonio Alexandra G.
Published: September 2023

Objective

To provide an overview of our whole room indirect calorimeter (WRIC), demonstrate validity and reliability of our WRIC, and explore a novel application of Bayesian hierarchical modeling to assess responses to small carbohydrate loads.

Methods

Seven gas infusion studies were performed using a gas blender and profiles designed to mimic resting and postprandial metabolic events to assess WRIC validity. In a crossover design, 16 participants underwent fasting and postprandial measurements, during which they consumed a 75-kcal drink containing sucrose, dextrose, or fructose. Linear mixed effects models were used to compare resting and postprandial metabolic rate (MR) and CO (CO). Bayesian Hierarchical Modeling was also used to model postprandial CO trajectories for each participant and condition.

Results

Mean total error in infusions were 1.27 ± 1.16% and 0.42 ± 1.21% for VO2and VCO2respectively, indicating a high level of validity. Mean resting MR was similar across conditions (=1.05 ± 0.03 kcal/min,p=0.82, ICC: 0.91). While MR increased similarly among all conditions (∼13%,p=0.29), postprandial CO parameters were significantly lower for dextrose compared with sucrose or fructose.

Conclusions

Our WRIC validation and novel application of statistical methods presented here provide important foundations for new research directions using WRIC.
An Integrated Comparative Genomics, Subtractive Proteomics and Immunoinformatics Framework for the Rational Design of a Pan-SalmonellaMulti-Epitope Vaccine
Authors: Bhattacharjee Arittra , Hosen Md. Rakib , Lamisa Anika Bushra , Ahammad Ishtiaque , Chowdhury Zeshan Mahmud , Jamal Tabassum Binte , Sohag Md. Mehadi Hasan , Hossain Mohammad Uzzal , Das Keshob Chandra , Keya Chaman Ara , Salimullah Md
Published: September 2023

Salmonellainfections are a global public health issue due to the high cost of illness surveillance, prevention, and treatment. In this study, we explored the core proteome inSalmonellato design a multi-epitope vaccine through Subtractive Proteomics and immunoinformatics approaches. A total of 2395 core proteins presents in 30 different strains ofSalmonella(reference strain-NZ CP014051) were curated. Utilizing the subtractive proteomics approach on theSalmonellacore proteome, Curlin major subunit A (CsgA) was selected as the vaccine candidate.csgAis a conserved gene that is related with biofilm formation. Immunodominant B and T cell epitopes from CsgA were predicted using numerous immunoinformatics tools. T lymphocyte epitopes had adequate population coverage and their corresponding MHC alleles showed significant binding scores after peptide-protein based molecular docking. Afterward, a multiepitope vaccine was constructed with peptide linkers and Human Beta Defensin-2 (as an adjuvant). The vaccine was found to be highly antigenic, non-toxic, non-allergic, and had physicochemical properties. Additionally, Molecular Dynamics Simulation and Immune Simulation demonstrated that the vaccine can bind with Toll Like Receptor 4 and elicit robust immune response. Usingin vitro,in vivo, and clinical trials, our results would yield a Pan-Salmonellavaccine that will provide protection against variousSalmonellaspecies.
Brain-to-brain coupling forecasts future joint action outcomes
Authors: Markiewicz Roksana , Segaert Katrien , Mazaheri Ali
Published: September 2023

In this study, we investigated whether brain-to-brain coupling patterns could predict performance in a time-estimation task which requires two players to cooperate. The participant pairs, were tasked with synchronising button presses after converging on a shared representation of ’short’, ’medium’, and ’long’ time intervals while utilizing feedback to adjust responses. We employed EEG-hyperscanning and focused on post-feedback brain activity. We found that negative feedback led to increased frontal mid-line theta activity across individuals. Moreover, a correlation in post-feedback theta power between players forecasted failed joint action, while an anti-correlation forecasted success. These findings suggest that temporally coupled feedback related brain activity between two individuals serves as an indicator of redundancy in adjustment of a common goal representation. Additionally, the anti-correlation of this activity reflects cognitive strategic mechanisms that ensure optimal joint action outcomes. Rather than apaired overcompensation, successful cooperation requiresflexible strategic agilityfrom both partners.
Assessing the hydromechanical control of plant growth
Authors: Laplaud Valentin , Muller Elise , Demidova Natalia , Drevensek Stéphanie , Boudaoud Arezki
Published: September 2023

Multicellular organisms grow and acquire their shapes through the differential expansion and deformation of their cells. Recent research has addressed the role of cell and tissue mechanical properties in these processes. In plants, it is believed that growth rate is a function of the mechanical stress exerted on the cell wall, the thin polymeric layer surrounding cells, involving an effective viscosity. Nevertheless, recent studies have questioned this view, suggesting that cell wall elasticity sets growth rate or that uptake of water is limiting for plant growth. To assess these issues, we developed a microfluidic device to quantify growth rates, elastic properties, and hydraulic conductivity of individualMarchantia polymorphaplants in a controlled environment with a high throughput. We characterized the effect of osmotic treatment and of abscisic acid on growth and hydromechanical properties. Overall, the instantaneous growth rate of individuals is correlated to both bulk elastic modulus and hydraulic conductivity. Our results are consistent with a framework in which growth rate is determined primarily by elasticity of the wall and its remodelling, and secondarily by hydraulic conductivity. Accordingly, the coupling between chemistry of the cell wall and hydromechanics of the cell appears as key to set growth patterns during morphogenesis.
Mosquito aging modulates the development, virulence and transmission potential of pathogens
Authors: Somé Bernard , Guissou Edwige , Da Dari F. , Richard Quentin , Choisy Marc , Yameogo Koudraogo Bienvenue , Hien Domombabele FdS , Yerbanga Rakiswende S , Ouedraogo Georges Anicet , Dabiré Kounbobr R , Djidjou-Demasse Ramsès , Cohuet Anna , Lefèvre Thierry
Published: September 2023

Host age variation is a striking source of heterogeneity that can shape the evolution and transmission dynamic of pathogens. Compared to vertebrate systems, our understanding of the impact of host age on invertebrate-pathogen interactions remains limited. We examined the influence of mosquito age on key life-history traits driving human malaria transmission. Females ofAnopheles coluzzii, a major malaria vector, belonging to three age classes (4, 8, and 12 day-old), were experimentally infected withPlasmodium falciparumfield isolates. Our findings revealed reduced competence in 12-day-old mosquitoes, characterized by lower oocyst/sporozoite rates and intensities compared to younger mosquitoes. Despite shorter median longevities in older age classes, infected 12-day-old mosquitoes exhibited improved survival, suggesting that the infection might act as a fountain of youth for older mosquitoes specifically. The timing of sporozoite appearance in the salivary glands remained consistent across mosquito age classes, with an extrinsic incubation period of approximately 13 days. Integrating these results into an epidemiological model revealed a lower vectorial capacity for older mosquitoes compared to younger ones, albeit still substantial due to extended longevity in the presence of infection. Considering age heterogeneity provides valuable insights for ecological and epidemiological studies, informing targeted control strategies to mitigate pathogen transmission.
MGX 2.0: Shotgun- and assembly-based metagenome and metatranscriptome analysis from a single source
Authors: Jaenicke Sebastian , Diedrich Sonja , Goesmann Alexander
Published: September 2023

Metagenomics studies have enabled scientists to analyze the genetic information of natural habitats or even complete ecosystems, including otherwise unculturable microbes. The processing of such datasets, however, remains a challenging task requiring extensive computational resources. MGX 2.0 is a versatile solution for the analysis and interpretation of microbial community sequence data. MGX 2.0 supports the processing of raw metagenomes and metatranscriptomes, but also enables assembly-based strategies, including downstream taxonomic binning, bin quality assessment, abundance quantification, and subsequent annotation coming from a single source. Due to the modular design of MGX, users are able to choose from a wide range of different methods for microbial community sequence data analysis, allowing them to directly compare between read-based and assembly-based approaches or to evaluate different strategies to analyze their data.
Evaluating functional brain organization in individuals and identifying contributions to network overlap
Authors: Bijsterbosch Janine D. , Farahibozorg Seyedeh-Rezvan , Glasser Matthew F. , Van Essen David , Snyder Lawrence H. , Woolrich Mark W. , Smith Stephen M.
Published: September 2023

Individual differences in the spatial organization of resting state networks have received increased attention in recent years. Measures of individual-specific spatial organization of brain networks and overlapping network organization have been linked to important behavioral and clinical traits and are therefore potential biomarker targets for personalized psychiatry approaches. To better understand individual-specific spatial brain organization, this paper addressed three key goals. First, we determined whether it is possible to reliably estimate weighted (non-binarized) resting state network maps using data from only a single individual, while also maintaining maximum spatial correspondence across individuals. Second, we determined the degree of spatial overlap between distinct networks, using test-retest and twin data. Third, we systematically tested multiple hypotheses (spatial mixing, temporal switching, and coupling) as candidate explanations for why networks overlap spatially. To estimate weighted network organization, we adopt the Probabilistic Functional Modes (PROFUMO) algorithm, which implements a Bayesian framework with hemodynamic and connectivity priors to supplement optimization for spatial sparsity/independence. Our findings showed that replicable individual-specific estimates of weighted resting state networks can be derived using high quality fMRI data within individual subjects. Network organization estimates using only data from each individual subject closely resembled group-informed network estimates (which was not explicitly modeled in our individual-specific analyses), suggesting that cross-subject correspondence was largely maintained. Furthermore, our results confirmed the presence of spatial overlap in network organization, which was replicable across sessions within individuals and in monozygotic twin pairs. Intriguingly, our findings provide evidence that network overlap is indicative of linear additive coupling. These results suggest that regions of network overlap concurrently process information from all contributing networks, potentially pointing to the role of overlapping network organization in the integration of information across multiple brain systems.
BaRDIC: robust peak calling for RNA-DNA interaction data
Authors: Mylarshchikov Dmitry E. , Nikolskaya Arina I. , Bogomaz Olesja D. , Zharikova Anastasia A. , Mironov Andrey A.
Published: September 2023

Chromatin-associated non-coding RNAs play important roles in various cellular processes by targeting genomic loci. Two types of genome-wide NGS experiments exist to detect such targets: “one-to-all”, which focuses on targets of a single RNA, and “all-to-all”, which captures targets of all RNAs in a sample. As with many NGS experiments, they are prone to biases and noise, so it becomes essential to detect “peaks” – specific interactions of an RNA with genomic targets. Here we present BaRDIC – Binomial RNA-DNA Interaction Caller – a tailored method to detect peaks in both types of RNA-DNA interaction data. BaRDIC is the first tool to simultaneously take into account the two most prominent biases in the data: chromatin heterogeneity and distance-dependent decay of interaction frequency. Since RNAs differ in their interaction preferences, BaRDIC adapts peak sizes according to the abundances and contact patterns of individual RNAs. These features enable BaRDIC to make more robust predictions than currently applied peak-calling algorithms and better handle the characteristic sparsity of all-to-all data. BaRDIC package is freely available athttps://github.com/dmitrymyl/BaRDIC.
Falling shoulders ahead: adaptive alien genes are maintained amid vanishing introgression footprint in sea squirts
Authors: Touchard Fanny , Cerqueira Frédérique , Bierne Nicolas , Viard Frédérique
Published: September 2023

Human transport of species across oceans disrupts natural dispersal barriers and facilitates hybridisation between previously allopatric species. The recent introduction of the North Pacific sea squirt,Ciona robusta, into the native range of the North Atlantic sea squirt,C. intestinalis, is a good example of this outcome. Recent studies have revealed an adaptive introgression, in a single chromosomal region, from the introduced into the native species. Here, we monitored this adaptive introgression over time, examining both the frequency of adaptive alien genes at the core and the hitchhiking footprint in the shoulders of the introgression island, by studying a thousandCiona spp.individuals collected in 22 ports of the contact zone, 14 of which were sampled 20 generations apart. For that purpose, we developed a KASP multiplex genotyping approach, which proved effective in identifying native, non-indigenous and hybrid individuals and in detecting introgressed haplotypes. Adaptive alien genes were detected where they had been found 20 generations ago, as well as in some newly sampled ports. The core region of the introgression, where the frequency ofC. robustaalleles is the highest and locally adaptive genes must be, remains stable in both space and time. In contrast, we observed an erosion ofC. robustaancestry tracts in flanking chromosomal shoulders on the edges of the core, consistent with the second phase of a local sweep and a purge of incompatible introgressed alleles. Our study reveals how the shoulders of an adaptive introgression island fall over time after the initial sweep.
A hepatocyte-specific transcriptional program driven by Rela and Stat3 exacerbates experimental colitis in mice by modulating bile synthesis
Authors: Jyotsna  , Sarkar Binayak , Yadav Mohit , Deka Alvina , Markandey Manasvini , Sanyal Priyadarshini , Nagarajan Perumal , Gaikward Nilesh , Ahuja Vineet , Mohanty Debasisa , Basak Soumen , Gokhale Rajesh S
Published: September 2023

Hepatic factors secreted by the liver promote homeostasis and are pivotal for maintaining the liver-gut axis. Bile acid metabolism is one such example wherein, bile acid synthesis occurs in the liver and its biotransformation happens in the intestine. Dysfunctional interactions between the liver and the intestine stimulate varied pathological outcomes through its bidirectional portal communication. Indeed, aberrant bile acid metabolism has been reported in inflammatory bowel disease (IBD). However, the molecular mechanisms underlying these crosstalks that perpetuate intestinal permeability and inflammation remain obscure. Here, we identify a novel hepatic gene program regulated by Rela and Stat3 that accentuates the inflammation in an acute experimental colitis model. Hepatocyte-specific ablation of Rela and Stat3 reduces the levels of primary bile acids in both the liver and the gut and shows a restricted colitogenic phenotype. On supplementation of chenodeoxycholic acid (CDCA), knock-out mice exhibit enhanced colitis-induced alterations. This study provides persuasive evidence for the development of multi-organ strategies for treating IBD and identifies a hepatocyte-specificrela-stat3network as a promising therapeutic target.
NEUROMETABOLOMIC IMPACTS OF MODELED WILDFIRE SMOKE AND PROTECTIVE BENEFITS OF ANTI-AGING THERAPEUTICS IN AGED FEMALE C57BL/6J MICE
Authors: Scieszka David , Gu Haiwei , Barkley-Levenson Amanda , Barr Ed , Garcia Marcus , Begay Jessica G , Herbert Guy , Bhaskar Kiran , McCormick Mark , Brigman Jonathan , Ottens Andrew , Bleske Barry , Campen Matthew J
Published: September 2023

Wildland fires have become progressively more extensive over the past 30 years in the US, and now routinely generate smoke that deteriorates air quality for most of the country. We explored the neurometabolomic impact that smoke derived from biomass has on older (18 months) female C57BL/6J mice, both acutely and after 10 weeks of recovery from exposures. Mice (N=6/group) were exposed to wood smoke (WS) 4 hours/day, every other day, for 2 weeks (7 exposures total) to an average concentration of 0.448mg/m3per exposure. One group was euthanized 24 hours after the last exposure. Other groups were then placed on 1 of 4 treatment regimens for 10 weeks after wood smoke exposures: vehicle; resveratrol in chow plus nicotinamide mononucleotide in water (RNMN); senolytics via gavage (dasatanib+quercetin; DQ); or both RNMN with DQ (RNDQ). Among the findings, the aging from 18 months to 21 months was associated with the greatest metabolic shift, including changes in nicotinamide metabolism, with WS exposure effects that were relatively modest. WS caused a reduction in NAD+ within the prefrontal cortex immediately after exposure and a long-term reduction in serotonin that persisted for 10 weeks. The serotonin reductions were corroborated by forced swim tests, which revealed an increased immobility (reduction in motivation) immediately post-exposure and persisted for 10 weeks. RNMN had the most beneficial effects after WS exposure, while RNDQ caused markers of brain aging to be upregulated within WS-exposed mice. Findings highlight the persistent neurometabolomic and behavioral effects of woodsmoke exposure in an aged mouse model.

Significance Statement

Neurological impacts of wildfire smoke are largely underexplored but include neuroinflammation and metabolic changes. The present study highlights modulation of major metabolites in the prefrontal cortex and behavioral consequences in aged (18 month) female mice that persists 10 weeks after wood smoke exposure ended. Supplements derived from the anti-aging field were able to mitigate much of the woodsmoke effect, especially a combination of resveratrol and nicotinamide mononucleotide.
Protein-DNA Clusters Explain the Non-Exponential DNA Residence Time Distributions of Transcription Factors
Authors: Kosar Zafer , Erbas Aykut
Published: September 2023

The transcription process is regulated by temporal interactions of transcription factors with DNA. In the last decade, computational and experimental studies revealed the residence times of transcription factors on DNA correlate with transcriptional output. Biochemical studies suggest that transcription factor bindings exhibit bi-exponential dynamics, often explained by the binary affinity model composed of nonspecific and specific protein-DNA interactions. Recently, transcription factor residence times were shown to display a power lawin vivoimplicating effective protein-DNA interactions controlling the dissociation kinetics are rather more complex than suggested. One contribution that can cause such continuous residence-time distributions could be higher-order protein-DNA complexes or protein coacervates. Here, by using molecular dynamics simulations of a coarse-grained polymer model for bacterial chromosomes interacting with homodimeric transcription factors at physiologically relevant concentrations, we demonstrate that residence time distributions of dimeric proteins follow a multi-exponential pattern even when a single interaction describes the affinity between DNA and protein. Our simulations reveal that this emergent behavior is due to the formation of DNA-protein clusters of various sizes at a wide range of protein concentrations and affinities. These findings add another layer to transcriptional regulation and, consequently, to gene expression by connecting transcription factor concentrations and affinities, DNA-protein clusters, and DNA residence times of transcription factors.
Evidence for admixture and rapid evolution during glacial climate change in an alpine specialist
Authors: Weng Yi-Ming , Kavanaugh David H. , Ralph Peter L. , Patterson Gilia , Schoville Sean D.
Published: September 2023

The pace of current climate change is expected to be problematic for alpine flora and fauna, as their adaptive capacity may be limited by small population size. Yet despite substantial genetic drift following post-glacial recolonization of alpine habitats, alpine species are notable for their success in surviving highly heterogeneous environments. Population genomic analyses demonstrating how alpine species have adapted to novel environments with limited genetic diversity remain rare, yet are important in understanding the potential for species to respond to contemporary climate change. In this study, we explored the evolutionary history of alpine ground beetles in theNebria ingenscomplex, including the demographic and adaptive changes that followed the last glacier retreat. Using whole genome data from hundreds of beetles, to test alternative models of evolutionary divergence in the species complex, we found evidence that theNebria ingenscomplex has been formed by past admixture of lineages responding to glacial cycles. Recolonization of alpine sites involved a distributional range shift to higher elevation, which was accompanied by a reduction in suitable habitat and the emergence of complex spatial genetic structure. We also used genome-wide association and genotype-environment association methods to look for genetic pathways involved in adaptation to heterogeneous new environments during this range shift. The identified genes were enriched for functions broadly associated with abiotic stress responses, with strong evidence for adaptation to hypoxia-related pathways. The results demonstrate that despite rapid environmental changes, alpine beetles in theN. ingenscomplex have shown rapid physiological evolution.
starTracer: An Accelerated Approach for Precise Marker Gene Identification in Single-Cell RNA-Seq Analysis
Authors: Zhang Feiyang , Huang Kaixin , Chen Ruixi , Zhao Qiongyi , Liu Zechen , Ma Wenhao , Hou Shengqun , Wang Dan Ohtan , Wei Wei , Li Xiang
Published: September 2023

We introduce starTracer, a novel R package designed to enhance the specificity and efficiency of marker gene identification in single-cell RNA-seq data analysis. The package consists of two primary functional modules: “searchMarker” and “filterMarker”. The “searchMarker” module, operating as an independent pipeline, exhibits superior flexibility by accepting a variety of input file types. Its primary output is a marker gene matrix, where genes are sorted by their potential to function as cluster-specific markers, with those exhibiting the greatest potential positioned at the top of the matrix for each respective cluster. In contrast, the “filterMarker” module is designed as a complementary pipeline to the Seurat “FindAllMarkers” function, providing a more accurate marker gene list for each cluster in conjunction with Seurat results. Benchmark analyses demonstrate that starTracer not only achieves excellent specificity in identifying marker genes compared to Seurat but also significantly surpasses it in processing speed. Impressively, the speed improvement ranges by 1~2 orders of magnitude compared to Seurat, as observed across three independent datasets. It is worth noting that starTracer exhibits increasing speed improvement with larger data volumes. It also excels in identifying markers in smaller clusters. Furthermore, the “filterMarker” reordering process considerably enhances Seurat’s marker matrix specificity. These advantages solidify starTracer as an invaluable tool for researchers working with single-cell RNA-seq data, merging robust accuracy with exceptional speed.
Radiomic-Based Prediction of Lesion-Specific Systemic Treatment Response in Metastatic Disease
Authors: Geady Caryn , Abbas-Aghababazadeh Farnoosh , Kohan Andres , Schuetze Scott , Shultz David , Haibe-Kains Benjamin
Published: September 2023

Despite sharing the same histologic classification, individual tumors in multi metastatic patients may present with different characteristics and varying sensitivities to anticancer therapies. In this study, we investigate the utility of radiomic biomarkers for prediction of lesion-specific treatment resistance in multi metastatic leiomyosarcoma patients. Using a dataset of n=202 lung metastases (LM) from n=80 patients with 1648 pre-treatment computed tomography (CT) radiomics features and LM progression determined from follow-up CT, we developed a radiomic model to predict the progression of each lesion. Repeat experiments assessed the relative predictive performance across LM volume groups. Lesion-specific radiomic models indicate up to a 4.5-fold increase in predictive capacity compared with a no-skill classifier, with an area under the precision-recall curve of 0.70 for the most precise model (FDR = 0.05). Precision varied by administered drug and LM volume. The effect of LM volume was controlled by removing radiomic features at a volume-correlation coefficient threshold of 0.20. Predicting lesion-specific responses using radiomic features represents a novel strategy by which to assess treatment response that acknowledges biological diversity within metastatic subclones, which could facilitate management strategies involving selective ablation of resistant clones in the setting of systemic therapy.

Highlights

Intensity values in CT scans and their corresponding spatial distribution convey important information.

A model to predict lesion-specific response to systemic treatment using image-derived features is proposed.

Up to a 4.5-fold increase in predictive capacity compared to a no-skill classifier was obtained, with AUPRC of 0.70 for the most precise model (FDR = 0.05).

Assessing treatment response on a lesion-level acknowledges biological diversity within metastatic subclones, which could facilitate management strategies involving selective ablation of resistant clones in the setting of systemic therapy.
What does it mean to use the mean? The impact of different data handling strategies on the proportion of children classified as meeting 24-hr movement guidelines and associations with overweight and obesity
Authors: Pfledderer Christopher D. , Burkart Sarah , Dugger Roddrick , Parker Hannah , von Klinggraeff Lauren , Okely Anthony D. , Weaver R. Glenn , Beets Michael W.
Published: September 2023

Background

Despite the widespread endorsement of 24-hour movement guidelines (physical activity, sleep, screentime) for youth, no standardized processes for categorizing guideline achievement exists. The purpose of this study was to illustrate the impact of different data handling strategies on the proportion of children meeting 24-hour movement guidelines (24hrG) and associations with overweight and obesity.

Methods

A subset of 524 children (ages 5-12yrs) with complete 24-hour behavior measures on at least 10 days was used to compare the impact of data handling strategies on estimates of meeting 24hrG. Physical activity and sleep were measured via accelerometry. Screentime was measured via parent self-report. Comparison of meeting 24hrG were made using 1) average of behaviors across all days (AVG-24hr), 2) classifying each day and evaluating the percentage meeting 24hrG from 10-100% of their measured days (DAYS-24hr), and 3) the average of a random sample of 4 days across 10 iterations (RAND-24hr). A second subset of children (N=475) with height and weight data was used to explore the influence of each data handling strategy on children meeting guidelines and the odds of overweight/obesity via logistic regression.

Results

Classification for AVG-24hr resulted in 14.7% of participants meeting 24hrG. Classification for DAYS-24hr resulted in 63.5% meeting 24hrG on 10% of measured days with <1% meeting 24hrG on 100% of days. Classification for RAND-24hr resulted in 15.9% of participants meeting 24hrG. Across 10 iterations, 63.6% of participants never met 24hrG regardless of the days sampled, 3.4% always met 24hrG, with the remaining 33.0% classified as meeting 24hrG for at least one of the 10 random iterations of days. Using AVG-24hr as a strategy, meeting all three guidelines associated with lower odds of having overweight obesity (OR=0.38, p<0.05). The RAND-24hr strategy produced a range of odds from 0.27 to 0.56. Using the criteria of needing to meet 24hrG on 100% of days, meeting all three guidelines associated with the lowest odds of having overweight and obesity as well (OR=0.04, p<0.05).

Conclusions

Varying estimates of meeting the 24hrG and the odds of overweight and obesity results from different data handling strategies and days sampled.
A digital twin model incorporating generalized metabolic fluxes to predict chronic kidney disease in type 2 diabetes mellitus
Authors: Surian Naveenah Udaya , Batagov Arsen , Wu Andrew , Lai Wen Bin , Sun Yan , Bee Yong Mong , Dalan Rinkoo
Published: September 2023

One of the biggest complication in diabetes patients is chronic kidney disease (CKD), making it a tremendous burden on the country’s public healthcare system. We have developed HealthVector Diabetes (HVD), a digital twin model that leverages generalized metabolic fluxes (GMF) to proficiently predict the onset of CKD and facilitate its early detection. Our HVD GMF model utilized commonly available clinical and physiological biomarkers as inputs for identification and prediction of CKD. We employed four diverse multi-ethnic cohorts (n=7072): one Singaporean cohort (EVAS, n=289) and one North American cohort (NHANES, n=1044) for baseline CKD identification, and two multi-center Singaporean cohorts (CDMD, n=2119 and SDR, n=3627) for 3-year CKD prediction. We developed one identification model and two prediction models (with complete or incomplete parameters). The identification model demonstrated strong performance with an AUC ranging from 0.80 to 0.82. For prediction, with incomplete parameters, we achieved an AUC of 0.75, while the complete parameter model achieved an improved AUC of 0.86. Our model also effectively stratifies patients into low, moderate, and high-risk categories, with the high-risk category having the highest proportion (53.3-62.9%) of patients with CKD. Our method also reveals metabolic health profile differences among patient subgroups at baseline, indicating that patient subgroups who develop future CKD exhibit more deteriorated profiles compared to future non-CKD patients. Furthermore, we also show that GMF-based clustering reveals distinct metabolic profile differences that act as drivers for CKD progression, and the distance between different patient clusters can be used to map patient health trajectories. Our HVD GMF digital twin model has the ability to identify patients with baseline CKD and predict future CKD within a 3-year time frame. Furthermore, our approach enables risk stratification, sub-grouping and clustering based on metabolic health profiles, positioning our model as a valuable clinical application tool for healthcare practitioners.
Impact of lesion location and functional parameters on vision-related quality of life in geographic atrophy secondary to AMD
Authors: Künzel Sandrine H. , Broadbent Eliza , Möller Philipp T , Lindner Moritz , Goerdt Lukas , Czauderna Joanna , Schmitz-Valckenberg Steffen , Holz Frank G , Pfau Maximilian , Fleckenstein Monika
Published: September 2023

Background/Aims

The primary objective was to determine how structural and functional parameters influence the vision-related quality of life (VRQoL) in patients with geographic atrophy (GA) secondary to age-related macular degeneration (AMD).

Methods

This prospective, non-interventional, natural-history ‘Directional Spread in Geographic-Atrophy’ study was conducted at the University Eye Hospital in Bonn, enrolling 82 patients with bilateral GA. Parameters such as GA location (assessed by the Early Treatment Diabetic Retinopathy Study grid), best-corrected visual acuity (BCVA), low-luminance visual acuity (LLVA), reading acuity, and speed were examined. The association between these parameters and VRQoL, as gauged using the National Eye Institute Visual Function Questionnaire 25 (NEI VFQ-25), was analyzed through least absolute shrinkage and selection operator with linear mixed-effects models.

Results

The average total GA area observed was 2.9 ± 1.2 mm2(better eye) and 3.1 ± 1.3 mm2(worse eye). The VRQoL scores for distance and near activities were most associated with the inner lower and inner left subfields of the better eye. For foveal-sparing patients, the LLVA of the better eye was the predominant determinate impacting all VRQoL scales.

Conclusion

GA location, specifically the inner lower and inner left subfields of the better eye, has a notable effect on VRQoL in GA patients. LLVA stands out as especially vital in foveal-sparing patients, underscoring the importance for clinicians to incorporate considerations of GA location and functional parameters into their risk-benefit assessments for emerging treatments.

Key messenges

What is already known on this topic

Despite recent therapeutic advancements, the relationship between GA markers and VRQoL remains unclear.

What this study adds

This research reveals the distinct value of specific structural and functional GA markers, notably the inner left and inner lower subfields, and LLVA, in relation to VRQoL in GA patients.

How this study might affect research, practice, or policy

Understanding these structural and functional markers will guide clinicians in personalized treatment decisions and encourage further research into more tailored therapeutic interventions.
Distinct explanations underlie gene-environment interactions in the UK Biobank
Authors: Durvasula Arun , Price Alkes L.
Published: September 2023

The role of gene-environment (GxE) interaction in disease and complex trait architectures is widely hypothesized, but currently unknown. Here, we apply three statistical approaches to quantify and distinguish three different types of GxE interaction for a given trait and E variable. First, we detect locus-specific GxE interaction by testing for genetic correlation (rg) < 1 across E bins. Second, we detect genome-wide effects of the E variable on genetic variance by leveraging polygenic risk scores (PRS) to test for significant PRSxE in a regression of phenotypes on PRS, E, and PRSxE, together with differences in SNP-heritability across E bins. Third, we detect genome-wide proportional amplification of genetic and environmental effects as a function of the E variable by testing for significant PRSxE with no differences in SNP-heritability across E bins. Simulations show that these approaches achieve high sensitivity and specificity in distinguishing these three GxE scenarios. We applied our framework to 33 UK Biobank traits (25 quantitative traits and 8 diseases; averageN=325K) and 10 E variables spanning lifestyle, diet, and other environmental exposures. First, we identified 19 trait-E pairs withrgsignificantly < 1 (FDR<5%) (averagerg=0.95); for example, white blood cell count hadrg=0.95 (s.e. 0.01) between smokers and non-smokers. Second, we identified 28 trait-E pairs with significant PRSxE and significant SNP-heritability differences across E bins; for example, BMI had a significant PRSxE for physical activity (P=4.6e-5) with 5% larger SNP-heritability in the largest versus smallest quintiles of physical activity (P=7e-4). Third, we identified 15 trait-E pairs with significant PRSxE with no SNP-heritability differences across E bins; for example, waist-hip ratio adjusted for BMI had a significant PRSxE effect for time spent watching television (P=5e-3) with no SNP-heritability differences. Across the three scenarios, 8 of the trait-E pairs involved disease traits, whose interpretation is complicated by scale effects. Analyses using biological sex as the E variable produced additional significant findings in each of the three scenarios. Overall, we infer a significant contribution of GxE and GxSex effects to complex trait and disease variance.
Breathing zone pollutant levels are associated with asthma exacerbations in high-risk children
Authors: Moore Camille M. , Thornburg Jonathan , Secor Elizabeth A. , Hamlington Katharine L. , Schiltz Allison M. , Freeman Kristy L. , Everman Jamie L. , Fingerlin Tasha E. , Liu Andrew H. , Seibold Max A.
Published: September 2023

Background

Indoor and outdoor air pollution levels are associated with poor asthma outcomes in children. However, few studies have evaluated whether breathing zone pollutant levels associate with asthma outcomes.

Objective

Determine breathing zone exposure levels of NO2, O3, total PM10and PM10constituents among children with exacerbation-prone asthma, and examine correspondence with in-home and community measurements and associations with outcomes.

Methods

We assessed children’s personal breathing zone exposures using wearable monitors. Personal exposures were compared to in-home and community measurements and tested for association with lung function, asthma control, and asthma exacerbations.

Results

81 children completed 219 monitoring sessions. Correlations between personal and community levels of PM10, NO2, and O3were poor, whereas personal PM10and NO2levels correlated with in-home measurements. However, in-home monitoring underdetected brown carbon (Personal:79%, Home:36.8%) and ETS (Personal:83.7%, Home:4.1%) personal exposures, and detected black carbon in participants without these personal exposures (Personal: 26.5%, Home: 96%). Personal exposures were not associated with lung function or asthma control. Children experiencing an asthma exacerbation within 60 days of personal exposure monitoring had 1.98, 2.21 and 2.04 times higher brown carbon (p<0.001), ETS (p=0.007), and endotoxin (p=0.012), respectively. These outcomes were not associated with community or in-home exposure levels.

Conclusions

Monitoring pollutant levels in the breathing zone is essential to understand how exposures influence asthma outcomes, as agreement between personal and in-home monitors is limited. Inhaled exposure to PM10constituents modifies asthma exacerbation risk, suggesting efforts to limit these exposures among high-risk children may decrease their asthma burden.

CLINICAL IMPLICATIONS

In-home and community monitoring of environmental pollutants may underestimate personal exposures. Levels of inhaled exposure to PM10constituents appear to strongly influence asthma exacerbation risk. Therefore, efforts should be made to mitigate these exposures.

CAPSULE SUMMARY

Leveraging wearable, breathing-zone monitors, we show exposures to inhaled pollutants are poorly proxied by in-home and community monitors, among children with exacerbation-prone asthma. Inhaled exposure to multiple PM10constituents is associated with asthma exacerbation risk.
Cortical lesions uniquely predict motor disability accrual and form rarely in the absence of new white matter lesions in multiple sclerosis
Authors: Beck Erin S , Mullins W Andrew , Silva Jonadab dos Santos , Filippini Stefano , Parvathaneni Prasanna , Maranzano Josefina , Morrison Mark , Suto Daniel J , Donnay Corinne , Dieckhaus Henry , Luciano Nicholas J , Sharma Kanika , Gaitán María Ines , Liu Jiaen , de Zwart Jacco A , van Gelderen Peter , Cortese Irene , Narayanan Sridar , Duyn Jeff H , Nair Govind , Sati Pascal , Reich Daniel S
Published: September 2023

Background and objectives

Cortical lesions (CL) are common in multiple sclerosis (MS) and associate with disability and progressive disease. We asked whether CL continue to form in people with stable white matter lesions (WML) and whether the association of CL with worsening disability relates to pre-existing or new CL.

Methods

A cohort of adults with MS were evaluated annually with 7 tesla (T) brain magnetic resonance imaging (MRI) and 3T brain and spine MRI for 2 years, and clinical assessments for 3 years. CL were identified on 7T images at each timepoint. WML and brain tissue segmentation were performed using 3T images at baseline and year 2.

Results

59 adults with MS had ≥1 7T follow-up visit (mean follow-up time 2±0.5 years). 9 had “active” relapsing-remitting MS (RRMS), defined as new WML in the year prior to enrollment. Of the remaining 50, 33 had “stable” RRMS, 14 secondary progressive MS (SPMS), and 3 primary progressive MS. 16 total new CL formed in the active RRMS group (median 1, range 0-10), 7 in the stable RRMS group (median 0, range 0-5), and 4 in the progressive MS group (median 0, range 0-1) (p=0.006, stable RR vs PMS p=0.88). New CL were not associated with greater change in any individual disability measure or in a composite measure of disability worsening (worsening Expanded Disability Status Scale or 9-hole peg test or 25-foot timed walk). Baseline CL volume was higher in people with worsening disability (median 1010μl, range 13-9888 vs median 267μl, range 0-3539, p=0.001, adjusted for age and sex) and in individuals with RRMS who subsequently transitioned to SPMS (median 2183μl, range 270-9888 vs median 321μl, range 0-6392 in those who remained RRMS, p=0.01, adjusted for age and sex). Baseline WML volume was not associated with worsening disability or transition from RRMS to SPMS.

Discussion

CL formation is rare in people with stable WML, even in those with worsening disability. CL but not WML burden predicts future worsening of disability, suggesting that the relationship between CL and disability progression is related to long-term effects of lesions that form in the earlier stages of disease, rather than to ongoing lesion formation.