bluuebunny/crossref_metadata_2025 huggingface dataset:
prolfquapp- A User-Friendly Command-Line Tool Simplifying Differential Expression Analysis in Quantitative Proteomics
Authors: Wolski Witold E. , Grossmann Jonas , Schwarz Leonardo , Leary Peter , Türker Can , Nanni Paolo , Schlapbach Ralph , Panse Christian
Published: October 2024

Abstract

Mass spectrometry is a cornerstone of quantitative proteomics, enabling relative protein quantification and differential expression analysis (DEA) of proteins. As experiments grow in complexity, involving more samples, groups, and identified proteins, traditional interactive data analysis methods become impractical. Theprolfquappaddresses this challenge by providing a command-line interface that simplifiesDEA, making it accessible to non-programmers and seamlessly integrating it into workflow management systems.

Prolfquappstreamlines data processing and result visualization by generating dynamic HTML reports that facilitate the exploration of differential expression results. These reports allow for investigating complex experiments, such as those involving repeated measurements and multiple explanatory variables. Additionally,prolfquappsupports various output formats, including XLSX files, SummarizedExperiment objects and rank files, for further interactive analysis using spreadsheet software, theexploreDEShiny application, or gene set enrichment analysis software.

By leveraging advanced statistical models from the prolfqua R package,prolfquappoffers a user-friendly, integrated solution for large-scale quantitative proteomics studies, combining efficient data processing with insightful, publication-ready outputs.

TOC Graphic

This visual table of contents illustrates the workflow and key features of theprolfquapptool for differential expression analysis in proteomics. On the left are the inputs, like the CSV for annotation and quantification results, YAML for parameters, and FASTA files for protein information. In the center are theprolfquappandprolfquaR packages and supporting tools like crosstalk and knitr, representing the core processing components. On the right side, the figure highlights the various outputs generated byprolfquapp

XLSX files containing protein abundances, group summaries, and differential expression results.

HTML reports with text, graphs, interactive volcano plots, and dynamic tables for data exploration.

PDF documents with detailed protein boxplots and peptide-level matrix plots.

Integration withexploreDEfor interactive data visualization.

This diagram concisely summarizes the flow from data input to the creation of analysis-ready outputs, offering a clear overview of the prolfquapp toolset.
The kinetics of bedaquiline diffusion in tuberculous cavities opens a window for emergence of resistance
Authors: Bustion Annamarie E. , Ernest Jacqueline P. , Kaya Firat , Silva Connie , Sarathy Jansy , Blanc Landry , Imperial Marjorie , Gengenbacher Martin , Xie Min , Zimmerman Matthew , Robertson Gregory T. , Weiner Danielle , Via Laura E. , Barry Clifton E. , Savic Radojka M. , Dartois Véronique
Published: October 2024

Cavitary tuberculosis (TB) is difficult to cure and a site of relapse. Bedaquiline has been a wonder drug in the treatment of multidrug resistant TB, but emergence of resistance threatens its sustained success. To investigate the role of drug distribution in resistance development, we designed a novel laser-capture microdissection scheme to spatially resolve the penetration of bedaquiline in the necrotic center (caseum) of cavities, a recalcitrant site of disease. Working with preclinical models that form large necrotic lesions, we profiled bedaquiline and two next generation diarylquinolines TBAJ-587 and TBAJ-876. Drug concentrations were measured in laser-captured areas of cavity caseum as a function of time and distance from blood supply. To simulate drug coverage in patient cavities, the data were modeled, and drug penetration parameter estimates were linked to clinical plasma pharmacokinetics for bedaquiline and the new diarylquinolines. Pharmacokinetic-pharmacodynamic (PK-PD) simulations revealed that bedaquiline reaches efficacious concentrations in outer and deep caseum after several weeks to months and lingers at subtherapeutic concentrations up to 3 years after therapy ends. TBAJ-587 and TBAJ-876, currently in clinical development, achieve bactericidal concentrations in caseum more rapidly and shorten the window of suboptimal concentrations post treatment compared to bedaquiline. Simulations of clinically plausible dosing schemes were conducted to guide the design of clinical trials for cavitary TB and help mitigate resistance development. In summary, the slow kinetics of diffusion of bedaquiline into and out of cavity caseum creates spatio-temporal windows of subtherapeutic concentrations. Site-of-disease simulations of TBAJ-587 and TBAJ-876 predict reduced opportunities for resistance development.

SIGNIFICANCE

Clinical resistance to bedaquiline has emerged faster than anticipated. Understanding potential contributing factors could help curb further resistance development, not only for bedaquiline but also for the next generation diarylquinolines currently in phase 2, TBAJ-587 and TBAJ-876. Here we hypothesized and confirmed that the extended time to reach steady state and slow clearance of bedaquiline leads to extremely slow diffusion into and out of cavity caseum, a recalcitrant site of TB disease and relapse. Through modeling of experimental data in a preclinical model of cavitary TB and clinical simulations, we show that the next generation diarylquinolines may reduce spatio-temporal windows of resistance development compared to bedaquiline. Our results can inform dosing schemes of diarylquinoline-based therapies that limit resistance development.
Dynamics of the distribution of fitness effects during adaptation
Authors: Morales Tenoch , Kushnir Abigail , Wahl Lindi M.
Published: October 2024

Mutations drive adaptive evolution due to their heritable effects on fitness. Empirical measures of the distribution of fitness effects of new mutations (the DFE) have been increasingly successful, and have recently highlighted the fact that the DFE changes during adaptation. Here, we analyze these dynamic changes to the DFE during a simplified adaptive process: an adaptive walk across additive and multiplicative fitness landscapes. First, we derive analytical approximations for the underlying fitness distributions of alleles present in the genotype and available through mutation and use these to derive expressions for the DFE at each step of the adaptive walk. We then confirm these predictions with independent simulations that relax several simplifying assumptions made in the analysis. As expected, our analysis predicts that as adaptation proceeds, the DFE is reshaped through an increase in deleterious mutations (a shift to the left). Surprisingly, this change occurs through different mechanisms depending on the number of alleles available per site: for a small number of available alleles, we observe a depletion of high-fitness alleles available through mutation as expected, however for a large number of alleles we observe that adaptation may be more limited by the availability of low-fitness alleles to be replaced, rather than by the availability of high-fitness alleles to replace them.
Chromatin interaction maps of human arterioles reveal new mechanisms for the genetic regulation of blood pressure
Authors: Liu Yong , Pandey Rajan , Qiu Qiongzi , Liu Pengyuan , Xue Hong , Wang Jingli , Therani Bhavika , Ying Rong , Usa Kristie , Grzybowski Michael , Yang Chun , Mishra Manoj K. , Greene Andrew S. , Cowley Allen W. , Rao Sridhar , Geurts Aron M. , Widlansky Michael E. , Liang Mingyu
Published: October 2024

Arterioles are small blood vessels located just upstream of capillaries in nearly all tissues. The constriction and dilation of arterioles regulate tissue perfusion and are primary determinants of systemic blood pressure (BP). Abnormalities in arterioles are central to the development of major diseases such as hypertension, stroke, and microvascular complications of diabetes. Despite the broad and essential role of arterioles in physiology and disease, current knowledge of the functional genomics of arterioles is largely absent, partly because it is challenging to obtain and analyze human arteriole samples. Here, we report extensive maps of chromatin interactions, single-cell expression, and other molecular features in human arterioles and uncover new mechanisms linking human genetic variants to gene expression in vascular cells and the development of hypertension. Compared to large arteries, arterioles exhibited a higher proportion of pericytes which were strongly associated with BP traits. BP-associated single nucleotide polymorphisms (SNPs) were enriched in chromatin interaction regions in arterioles, particularly through enhancer SNP-promoter interactions, which were further linked to gene expression specificity across tissue components and cell types. Using genomic editing in animal models and human induced pluripotent stem cells, we discovered novel mechanisms linking BP-associated noncoding SNP rs1882961 to gene expression through long-range chromatin contacts and revealed remarkable effects of a 4-bp noncoding genomic segment on hypertension in vivo. We anticipate that our rich data and findings will advance the study of the numerous diseases involving arterioles. Moreover, our approach of integrating chromatin interaction mapping in trait-relevant tissues with SNP analysis and in vivo and in vitro genome editing can be applied broadly to bridge the critical gap between genetic discoveries and physiological understanding.
Quantifying the genetic contributions in unexplained kidney failure revealsAPOL1-HLAinteraction
Authors: Sadeghi-Alavijeh Omid , Chan Melanie MY , Tzoumkas Konstantinos , Doctor Gabriel T. , Gale Daniel P
Published: October 2024

Background

Unexplained kidney failure (uKF) affects 15% of individuals requiring kidney replacement therapy. Absence of a diagnosis creates uncertainty around recurrence after transplantation, familial risk, and participation in therapeutic trials. Whole genome sequencing (WGS) was used to identify genetic variants contributing to uKF.

Methods

218 patients who presented with uKF < 50 years old were recruited to the UK’s 100,000 Genomes Project. Candidate variants in 183 genes were reviewed for pathogenicity by a multidisciplinary team. Gene-based association testing, structural variant analyses, and assessment of high-riskAPOL1genotypes were performed. Polygenic risk scores (PRS) were calculated for chronic kidney disease (CKD), and various glomerulonephritides. HLA associations in those withAPOL1high-risk genotype were also investigated.

Results

A positive genetic diagnosis was made in 17% (38/218) of patients. The median age of uKF onset was 36 years. Fewer genetic diagnoses were found in those aged ≥ 36 years compared to younger individuals, both with (11% vs. 35%, P=0.03) and without (5% vs. 19%, P=0.05) a family history. Three patients ≥ 36 years without a family history had pathogenic variants in type IV collagen genes. High-risk APOL1 genotypes were enriched in patients with recent African ancestry (52% vs 8.4%, P=5.97×10−8). Dividing the uKF cohort by subsequent identification of monogenic diagnosis, High-risk APOL1 genotype, or neither, we found that the SSNS PRS was higher in those with High-risk APOL1 (P=0.048), driven by differences atHLA-DQB1*03:19(P=0.001).

Conclusions

These findings estimate the likelihood of a genetic diagnosis using WGS in uKF patients, showing fewer diagnoses in older patients without a family history.APOL1contributes significantly to uKF in those with recent African ancestry, potentially interacting withHLA-DQB1. The lack of PRS signal for CKD suggests distinct biology between uKF and more common causes of CKD.
Blood Eosinophil Reference Values and Determinants in a Representative Adult Population
Authors: Abohalaka Reshed , Ercan Selin , Lehtimäki Lauri , Ermis Saliha Selin Özuygur , Lisik Daniil , Bashir Muwada Bashir Awad , Jadhav Radhika , Ekerljung Linda , Wennergren Göran , Lötvall Jan , Pullerits Teet , Backman Helena , Rådinger Madeleine , Nwaru Bright I. , Kankaanranta Hannu
Published: October 2024

Background

The use of blood eosinophil count (BEC) as a prognostic biomarker in the management of conditions such as asthma and chronic obstructive pulmonary disease (COPD) may be complicated by factors like atopy, age, sex, smoking, and comorbidities. Therefore, we aimed to produce reference values for BEC, considering age, asthma, COPD, and clinical allergy for the general adult population.

Methods

The West Sweden Asthma Study constitutes a population-representative clinical epidemiological cohort of randomly selected adults in western Sweden. From this cohort,n=1,145 took part in clinical examinations, including e.g. skin prick testing, specific immunoglobulin E, and BEC.

Results

The upper limit (95thpercentile) of BEC varied by age. It ranged between 400 to 500 cells/μL in the full sample, and from 300 to 400 cells/μL in subjects without asthma, COPD, and clinical allergy (n=710). Sex, smoking, atopy, clinical allergy, obesity, asthma, COPD, diabetes, and hypertension were statistically significantly associated with higher BEC levels. However, only asthma and clinical allergy in the full sample, and obesity and diabetes in those without asthma, COPD, or clinical allergy, remained statistically significant in multiple regression analyses.

Conclusion

In a population-representative sample, the upper limit of BEC in healthy adults ranged between 300 and 400 cells/μL, varying by age. Age, smoking, obesity, asthma, COPD, and clinical allergy influence BEC levels and should be considered in clinical interpretation.

Clinical Implications

The upper limit of normal blood eosinophil count (BEC) in participants free from asthma, COPD, and clinical allergy ranged between 300 and 400 cells/μL depending on age. These results facilitate the interpretation of BEC in clinical practice.

Capsule summary

The upper limit of normal blood eosinophil count (BEC) in healthy individuals ranged between 300 and 400 cells/μL depending on age. Determinants of BEC values include age, smoking, obesity, asthma, and clinical allergy.

Support statement

The study was supported by the VBG Group Herman Krefting Foundation for Asthma and Allergy Research (Trollhättan, Sweden), Swedish Research Council (Stockholm, Sweden), the Swedish Heart-Lung Foundation (Stockholm, Sweden), the Swedish Asthma and Allergy Foundation (Stockholm, Sweden), Tampere Tuberculosis Foundation (Tampere, Finland), and ALF agreement (grant from the Swedish state under the agreement between the Swedish Government and the county councils, Sweden).
Clonal hematopoiesis is associated with distinct rheumatoid arthritis phenotypes
Authors: Hiitola E , Korhonen J , Kokkonen H , Koskela J , Kankainen M , Alakuijala M , Liu A , Lundgren S , Häppölä P , Almusa H , Ellonen P , Savola P , Kelkka T , Leirisalo-Repo M , Koivuniemi R , Peltomaa R , Pirilä L , Isomäki P , Kauppi M , Kaipiainen-Seppänen O , Starskaia I , Virtanen AT , Lahesmaa R , Silvennoinen O ,   FinnGen, Genovese G , Ganna A , Rantapää-Dahlqvist S , Mustjoki S , Myllymäki M
Published: October 2024

Clonal hematopoiesis (CH) becomes more prevalent with age and may impact the pathophysiology of inflammatory diseases by altering immune cell function. While clonal hematopoiesis of indeterminate potential (CHIP) can promote inflammation in non-malignant conditions, the relationship with rheumatoid arthritis (RA) has not been systematically investigated. We tested whether CHIP mutations are more common in RA using two population-level cohorts and newly diagnosed RA patients. CHIP was associated with prevalent RA in the FINRISK study of 10 089 participants with whole exome sequencing (odds ratio (OR)=2.06, 95% CI=1.08-3.94, P=0.029) and in the FinnGen cohort (N=520 210, OR=1.42, 95% CI=1.09-1.84, P=0.009) using single nucleotide polymorphism (SNP) array-based CHIP annotation. In the FinnGen cohort,DNMT3Amutations were associated with seropositive RA (OR=1.73, 95% CI=1.16-2.58, P=0.007), whereas CHIP overall was more common in participants with history of seronegative RA (OR=2.16, 95% CI=1.24-3.76, P=0.006). Furthermore, CHIP was associated with inferior overall survival among FinnGen participants with prevalent RA (P=0.010). In newly diagnosed RA (N=632), seropositive, but not seronegative, patients withDNMT3Amutations had higher erythrocyte sedimentation rate (P=0.014) and disease-activity scores (P=0.030). In contrast,TET2mutations were significantly more common in patients with seronegative RA both in univariable (P=0.009) and multivariable models (OR=0.42; 95% CI=0.20-0.89, P=0.024). In conclusion, CHIP is associated with RA and distinct RA subtypes. Although the causality and underlying mechanisms of these observations remain unknown, our findings provide further evidence for the association between CHIP and inflammation in distinct disease contexts that may have therapeutic implications in the future.
Equity in Action: A Four-Year journey towards Gender Parity and Racial Diversity in Biochemistry Hiring
Authors: Christian Sherri L. , Booth Valerie , Harding Scott , Todd Amy M. , Berry Mark D.
Published: October 2024

Recruitment of faculty members in academic departments shapes the department for decades in both research and teaching arenas. Having a diverse department is beneficial for undergraduate and graduate students as representation of underrepresented minority groups in the professoriate can inspire a greater diversity of students to pursue higher levels of education or research-focused careers. Increased diversity benefits research directly as diverse teams have been shown to have better ideas and outcomes. In 2020, our department had lower gender diversity than would be expected based on the pool of PhD students and post-doctoral fellows in Canada. Therefore, we altered our hiring process, primarily by redacting applications, for recruitment into entry-level tenure-track faculty positions. With this change in process, female hires increased from 17% in the previous ten years (5 hires) to 80% in the subsequent four years (5 hires) with no substantial change in hiring of racially diverse individuals (50% to 40%). Overall, combined with retirements, the percentage of female faculty in the department went from 25% to 50% and the percentage of racialized faculty went from 38% to 44%. The new hires have met or exceeded expectations of success with respect to grant funding and are on track to meet or exceed expectations for other metrics of success. Thus, our intervention was very successful in increasing the diversity of our department within a short timeframe. We believe that our experience could provide other departments with a template for making substantive change, even in the absence of internal expertise in the area.

Graphical Abstract
Protection against Poly Microbial Sepsis by Chitin oligomers is fine tuned by N-Acetyl D-Glucosamine residues
Authors: Patel Paresh , Agnihotri Geetanjali , Siddappa Shilpa , Ravindran Balachandran , Saiyed Taslimarif
Published: October 2024

Chitin, poly-N Acetyl D-glucosamine, is an abundant polysaccharide produced by fungal cell walls, insect epicuticle and nematodes cuticles. Its immunomodulatory function has curious attributes - paradoxically opposing host responses using different host receptors resulting in immunostimulatory or immunosuppressive propertis depending on the size/length of the oligomers as well as aceytylation levels have been reported in literature. Here we demonstrate that Hepta-N-Acetyl Chitoheptaose (7 mer) is a TLR2 ligand, 8 mer activates immune cells through TLR4 while, 6 mer is a relatively poor ligand for both TLR2 and TLR4 in generating inflammatory host cytokines. Significantly enhanced inflammatory response characterized by increased TNF-a, IL-1b, IL-6 and IL-10 was a feature of only 8 mer while, 6 and 7 mers induced modest activation in both HEK cells (transfected with specific TLRs) and in human THP2 cells in vitro. The translational significance of these features were addressed in an experimental model of Sepsis using Cecal Ligation Puncture (CLP) protocol, a murine model, considered a gold standard for human Sepsis. More significantly, therapeutic rather than prophylactic administration, that simulates real life scenerio of human and animal sepsis, of 7 mer rather than 6 or 8 residues of Chitin oligomer, significantly protected mice against sepsis as shown by decreased mortality and decreased induction of inflammatory cytokines. These findings suggest that modulation of immune response by chitopolysaccaridesin-vivois precisely caliberated.
Lead as a toxic environmental toxicant in models of synucleinopathies
Authors: Shvachiy Liana , Amaro-Leal Ângela , Machado Filipa , Rocha Isabel , Geraldes Vera , Outeiro Tiago F.
Published: October 2024

Lead, a toxic heavy metal, is prevalent in various industrial applications, contributing to environmental contamination and significant health concerns. Lead affects various body systems, especially the brain, causing long-lasting cognitive and behavioral changes. While most studies have focused on continuous lead exposure, intermittent exposure, such as that caused by migration or relocations, has received less attention. Importantly, lead exposure intensifies the severity of Parkinson’s disease (PD) and dementia with Lewy bodies, diseases involving the accumulation of alpha-synuclein (aSyn) in the brain and in the gut. Although, the precise mechanisms underlying these observations remain unclear, oxidative stress and mitochondrial dysfunction likely play a role. Here, we investigated how two different profiles of lead exposure - continuous and intermittent - affect models of synucleinopathies. We found that lead exposure enhances the formation of aSyn inclusions, resulting in an increase in both their number and size in cell models. In addition, we found that animals injected with aSyn pre-formed fibrils display serine 129-phosphorylated aSyn inclusions and a reduction in astrocytes in the substantia nigra. These animals also display neuronal damage and alterations in locomotor activity, exploratory behavior, anxiety, memory impairments and hypertension. Our results suggest a mechanistic link between environmental lead exposure and the onset and progression of diseases associated with aSyn pathology. Understanding the molecular and cellular interactions between lead and aSyn is crucial for shaping public health policies and may provide novel insight into strategies for mitigating the impact of environmental toxins on neurodegenerative processes involved in Parkinson’s disease and related synucleinopathies.

Key points summary

Lead exposure increases the number and size of alpha-synuclein (aSyn) inclusions in cell models.∼

Animals exposed to aSyn fibrils and lead show increased phosphorylation of aSyn, neuronal damage and reduced astrogliosis in thesubstantia nigra.

Lead-exposed animals exhibit impaired locomotion, anxiety, memory deficits, hypertension and chemoreceptor reflex hypersensitivity.

The study suggests a mechanistic link between environmental lead exposure and the progression of diseases involving aSyn pathology, such as Parkinson’s disease.
Rapid speciation in the holopelagic ctenophoreMnemiopsisfollowing glacial recession
Authors: Ketchum Remi N. , Smith Edward G. , Toledo Leandra M. , Leach Whitney B. , Padillo-Anthemides Natalia , Baxevanis Andreas D. , Reitzel Adam M. , Ryan Joseph F.
Published: October 2024

Understanding how populations diverge is one of the oldest and most compelling questions in evolutionary biology. An in depth understanding of how this process operates in planktonic marine animals, where barriers for gene flow are seemingly absent, is critical to understanding the past, present, and future of ocean life.Mnemiopsisplays an important ecological role in its native habitat along the Atlantic coast of the Americas and is highly destructive in its non-native habitats in European waters. Although historical literature described three species ofMnemiopsis, the lack of stable morphological characters has led to the collapse of this group into a single species,Mnemiopsis leidyi. We generate high-quality reference genomes and use a whole-genome sequencing approach to reveal that there are two species ofMnemiopsisalong its native range and show that historical divergence between the two species coincides with historical glacial melting. We define a hybridization zone between species and highlight that environmental sensing genes likely contribute to the invasive success ofMnemiopsis. Overall, this study provides insights into the fundamental question of how holopelagic species arise without clear barriers to gene flow and sheds light on the genomic mechanisms important for invasion success in a highly invasive species.
Large Serine Integrase Off-Target Discovery with Deep Learning for Genome Wide Prediction
Authors: Bakalar Matthew H. , Biondi Thomas , Liang Xiaoyu , Santesmasses Didac , Bara Anne M. , Mehta Japan B. , Wang Jie , Hazelbaker Dane Z. , Finn Jonathan D. , O’Connell Daniel J.
Published: October 2024

Large Serine Integrases (LSIs) hold significant therapeutic promise due to their ability to efficiently incorporate gene-sized DNA into the human genome, offering a method to integrate healthy genes in patients with monogenic disorders or to insert gene circuits for the development of advanced cell therapies. To advance the application of LSIs for human therapeutic applications, new technologies and analytical methods for predicting and characterizing off-target recombination by LSIs are required. It is not experimentally tractable to validate off-target editing at all potential off-target sites in therapeutically relevant cell types because of sample limitations and genetic variation in the human population. To address this gap, we constructed a deep learning model named IntQuery that can predict LSI activity genome-wide. For Bxb1 integrase, IntQuery was trained on quantitative off-target data from 410,776 crypticattBsequences discovered by Cryptic-seq, an unbiased in vitro discovery technology for LSI off-target recombination. We show that IntQuery can accurately predict in vitro LSI activity, providing a tool forin silicooff-target prediction of large serine integrases to advance therapeutic applications.
Elevated developmental temperatures below the lethal limit reduceAedes aegyptifertility
Authors: Pekľanská Miriama , van Heerwaarden Belinda , Hoffmann Ary A. , Nouzová Marcela , Šíma Radek , Ross Perran A.
Published: October 2024

Aedes aegyptimosquitoes are the principal vectors of dengue and continue to pose a threat to human health, with ongoing urbanization, climate change, and trade all impacting the distribution and abundance of this species. Hot periods are becoming increasingly common and their impacts on insect mortality have been well established, but they may have even greater impacts on insect fertility. In this study, we investigated the impacts of high temperatures onAe. aegyptifertility both within and across generations. Mosquitoes developing under elevated temperatures exhibited higher critical thermal maxima (CTmax) reflecting developmental acclimation, but their fertility declined with increasing developmental temperature. In females, elevated developmental temperatures decreased fecundity while in males it tended to decrease egg hatch proportions and the proportion of individuals producing viable offspring. Rearing both sexes at 35°C increased fecundity in the subsequent generation but effects of elevated temperatures persisted across gonotrophic cycles within the same generation. Moreover, exposure of adults to 35°C further decreased fertility beyond the effects of developmental temperature alone. These findings highlight sub-lethal impacts of elevated temperatures onAe. aegyptifertility and plastic responses to thermal stress within and across generations. This has significant implications for mosquito populations thriving in increasingly warmer environments.
Inferring Gene Regulatory Network Based on scATAC-seq Data with Gene Perturbation
Authors: Shao Wei , Liu Yuti , Zhang Shuang , Chen Shuang , Liu Qiao , Zeng Wanwen
Published: October 2024

Gene regulatory networks (GRNs) are critical blueprints for understanding gene regulation and the intricate interactions that drive biological processes. Recent advances have highlighted the potential of single-cell ATAC-seq (scATAC-seq) data in GRN inference, offering unprecedented insights into how chromatin accessibility plays an important part in gene regulation. However, existing methods often fall short in providing a quantitative and holistic depiction of regulatory relationships, particularly in capturing the strength, direction, and type of gene regulation simultaneously. In this paper, we present a novel approach that addresses these limitations by leveraging genetically perturbed scATAC-seq data to infer more comprehensive and accurate GRNs. Our method advances the field by integrating pre- and post-perturbation chromatin accessibility data, enabling the construction of GRNs that more accurately reflect the dynamic regulatory landscape. Through rigorous evaluation on seven real datasets, we demonstrate the method’s superior performance in reconstructing GRNs with enhanced precision and interpretability. This work significantly contributes to the field by providing a robust framework for GRN inference, with broad implications for understanding gene regulation in complex biological systems.
Prognostic Stratification of Familial Hypercholesterolemia Patients Using AI Algorithms: A Gender-Specific Approach
Authors: Zamora A , Masana L , Civeira F , Ibarretxe D , Fanlo-Maresma M , Vila A , Tembra Manuel Suárez , Victoria Marco-Benedí , Alvarez-Sala-Walther Luis A. , Camacho C
Published: October 2024

Background

Familial Hypercholesterolemia (FH) is the most prevalent autosomal dominant disorder, affecting about 1 in 200-250 individuals, with an estimated 30 million patients globally. It is the leading cause of early and aggressive coronary artery disease (CAD).

Objective

To developed an artificial intelligence (AI) and machine learning (ML) algorithm for cardiovascular risk stratification in a FH population, emphasizing sex-specific differences and model explainability.

Methods

We analyzed patients with genetically confirmed FH or a score greater than 8 on the Dutch Lipid Clinics Network (DLCN) criteria from the National Registry of the Spanish Atherosclerosis Society, including individuals enrolled from January 2010 to December 2017. The model utilized a comprehensive dataset incorporating family history, clinical characteristics, laboratory results, genetic data, imaging studies, and lipid-lowering treatment details. Eighty percent of the population was allocated for training the AI algorithm, while the remaining 20% was used for testing and 70/30 population for internal validation. A Histogram-based Gradient Boosting Classification Tree was used. The stability of the AI system was assessed using K-fold cross-validation. Shap methodology analyzed the influence of different variables by sex. Youden’s J statistic established the optimal cutoff point for identifying very high cardiovascular risk.

Results

A total of 1.764 patients were included (51.8% women), among whom 264 experienced major adverse cardiovascular events (MACE), with 8% being women. Notably, 52% experienced a cardiovascular event before age 50, and 37% had subclinical atherosclerosis. The final model incorporated 82 variables, achieving metrics of precision for MACE accuracy (0.92), recall (0.89), F1 score (0.91), and ROC (0.88; 95% CI, 0.85-0.90), revealing significant sex-based differences. Women showed a lower association with MACE compared to men, although this effect diminished with the inclusion of multiple variables, particularly in younger women. In the model, age, GGT levels, and subclinical disease significantly impacted risk for women, while year of birth, age at initiation of statin treatment and HbA1c levels were more influential for men. The optimal risk threshold was 0.25 for the association with of MACE

Conclusion

AI-ML algorithms are promising tools for enhancing vascular risk stratification in patients with FH, revealing critical sex-based differences.
Effect of high-altitude exposure on skeletal muscle mitochondrial subcellular distribution, ultrastructure and respiration in sea-level residents
Authors: Schytz Camilla Tvede , Nielsen Joachim , Ørtenblad Niels , Lundby Anne-Kristine Meinild , Jacobs Robert Acton , Lundby Carsten
Published: October 2024

Endurance exercise performance is associated with a well-developed skeletal muscle mitochondrial network, which is composed of subsarcolemmal mitochondria interconnected with intermyofibrillar mitochondria bending around the myofibrils. High-altitude exposure is typically incorporated in elite sport training regimens, but little is known about how this network adapts to an environment characterised by tissue hypoxia. For this reason, we investigated how high-altitude exposure affects mitochondrial subcellular distribution, ultrastructure, respiratory control, and intrinsic mitochondrial respiratory capacity. Nine healthy and recreationally active sea-level residents (eight males and one female) resided at an altitude of 3454 m with biopsies collected from the vastus lateralis muscle before and after 7 and 28 days at high altitude. The muscular mitochondrial volume density (MitoVD) increased after high-altitude exposure, driven by an increase in the intermyofibrillarMitoVD. This was however accompanied by a decreased cristae surface area per skeletal muscle fibre volume (MuscularCD) because of a decline in the cristae surface area per mitochondrial volume (MitoCD). Despite a reducedMuscularCD, mass-specific maximal coupled respiration (OXPHOS_CII+CI+ETF) increased slightly, and was considerably elevated when normalised toMuscularCD, suggesting intrinsic adaptations to high altitude. The difference between cristae-specificOXPHOS_CII+CI+ETFand an associated cristae-specific leak respiration (Leak_CII+CI+ETF) indicated a markedly higher degree of coupling between the electron flow in the electron transport system and ATP production. As the effect size 95% confidence intervals includes trivial effects the results need to be substantiated. In conclusion, high-altitude exposure altered mitochondrial subcellular distribution, ultrastructure and induced intrinsic respiratory adaptations.
Cascading consequences of shifting ice phenology in an exploited lake
Authors: Goto Daisuke , Dunlop Erin S. , Young Joelle D. , Jackson Donald A.
Published: October 2024

Ice phenology (onset and breakup of ice cover) regulates the timings of seasonal life history events of many animal and plant species in high-latitude lakes in the Northern Hemisphere, promoting the coexistence of species that share resources like food and shelter. Increasingly warmer, more variable Earth’s climate is, however, shifting ice phenology, modifying habitat conditions, and in turn reshaping the population and interaction dynamics of many species, threatening their persistence. Applying multivariate autoregressive state-space time series modeling to extensive historical and contemporary monitoring records (spanning 36 to 113 years) of limnological and biological surveys and fishery catches, we explore how shifting ice phenology propagates through a food web over time by modulating thermal profiles and limnological properties in Lake Simcoe, a large, intensely exploited system in southern Ontario, Canada. Analysis shows that increasingly earlier ice breakups, later ice freeze-ups, earlier thermal stratification onset, and later turnover since the early 1980s, attenuated algal production. This in turn, combined with increasingly more abundant invasive species (dreissenids) that promoted greater water clarity over prolonged stratification periods, diminished zooplankton abundances. These limnological changes filtered through plankton communities further modified the population and community dynamics of higher trophic-level species like fish with differential thermal preferences, interactively with time-varying non-climate drivers. Although management interventions–reductions in nutrient loading and fishing effort in particular–in recent decades aided the recoveries of depleted cold-adapted fish populations (including lake trout, lake whitefish, and cisco), their interaction patterns and strengths with species adapted to warmer conditions were reshuffled by advanced timings of ice breakup and delayed timings of ice freeze-up. These findings reveal how complex food web dynamics can emerge from ecologically divergent responses that reshape species interactions within and among trophic levels under shifting ice phenology filtered through bottom-up processes, likely buffering destabilizing effects of a changing climate.
Preserving Hidden Hierarchical Structure: Poincaré Distance for Enhanced Genomic Sequence Analysis
Authors: Ali Sarwan , Mansoor Haris , Chourasia Prakash , Khan Imdad Ulla , Pattersn Murray
Published: October 2024

The analysis of large volumes of molecular (genomic, proteomic, etc.) sequences has become a significant research field, especially after the recent coronavirus pandemic. Although it has proven beneficial to sequence analysis, machine learning (ML) is not without its difficulties, particularly when the feature space becomes highly dimensional. While most ML models operate with the conventional Euclidean distance, the hidden hierarchical structure present among a set of phylogenetically related sequences is difficult to represent in Euclidean space without losing much information or requiring many dimensions. Since such hierarchical structure can be informative to analysis tasks such as clustering and classification, we propose two measures for generating a distance matrix from a set of sequences based on distance in the Poincaré disk model of hyperbolic geometry, or thePoincaré distance, for short. Such a distance measure can allow to embedding of even a fully resolved phylogenetic tree in just two dimensions with minimal distortion to any hierarchical structure. Our first approach is based purely on the classical Poincaré distance, while the other approach modifies this distance by combining the Euclidean norms and the dot product between the sequence representations. A thorough analysis of both measures demonstrates its superiority in a variety of genomic and proteomic sequence classification tasks in terms of efficiency, accuracy, predictive performance, and the capacity to capture significant sequence correlations. These approaches perform better than existing state-of-the-art methods across the majority of evaluation metrics.
Predicting low birth weight risks in pregnant women in Brazil using machine learning algorithms: Data from the Araraquara Cohort Study
Authors: Victor Audêncio , Almeida Francielly , Xavier Sancho Pedro , Rondó Patrícia H.C.
Published: October 2024

Background

Low birth weight (LBW) is a critical factor linked to neonatal morbidity and mortality. Early prediction is essential for timely interventions. This study aimed to develop and evaluate predictive models for LBW using machine learning algorithms, including Random Forest, XGBoost, Catboost, and LightGBM.

Methods

Machine learning algorithms (Random Forest, XGBoost, Catboost, and LightGBM) were trained and evaluated using cross-validation and the SMOTE technique to correct class imbalance. Model performance was measured using the AUROC metric, and variable importance was analyzed with Shapley values to ensure model interpretability.

Results

The XGBoost model achieved the best performance with an AUROC of 0.94. Catboost and Random Forest also showed excellent results, confirming the effectiveness of these models in predicting LBW.

Conclusion

Machine learning, combined with SMOTE, proved to be an effective approach for predicting LBW. XGBoost stood out as the most accurate model, but Catboost and Random Forest also provided solid results. These models can be applied to identify high-risk pregnancies, improving perinatal outcomes through early interventions.
Men’s Internet Sex Addiction Predicts Sexual Objectification of Women Even After Taking Pornography Consumption Frequency into Account
Authors: Nováková Pavla , Chvojka Edita , Ševčíková Anna , Blinka Lukas , Wright Paul , Kane Steven
Published: October 2024

Excessive online video pornography consumption is associated with sexual objectification, particularly in male consumers. However, previous studies have not considered that there is a subgroup of internet users whose consumption may become excessive due to their internet sex addiction. Such users may, in response to internet sex addiction symptoms such as craving, have increased levels of sexual objectification. In a sample of 1,272 male consumers of online video pornography (Mage = 32.93, SDage = 9.44), we examined whether internet sex addiction is linked to sexual objectification. We fitted a series of structural equation models and found that men who scored higher on internet sex addiction were more likely to objectify women. More importantly, this link did not cease when controlling for the frequency of online video pornography consumption. Our findings suggest that there are other mechanisms related to addictive symptomatology, than just the link through online video pornography consumption, that may contribute to sexual objectification. Addiction-related factors may have a unique role in fostering sexual objectification. Isolating internet sex addiction as a potential driver highlights the need to address objectifying behaviors in individuals struggling with this addiction.
Urban Rural Disparities of Determinants of Antenatal Care in Senegal among Women of Reproductive Age: Evidence from 2023 Senegal Demographic Health Survey
Authors: Khan Majlish Mushfiqur Rahman , Tawhid Sultanul Arafean , Kibria Gulam
Published: October 2024

Background

Antenatal care (ANC) is critical for ensuring positive pregnancy outcomes. Despite global efforts, ANC utilization remains suboptimal in many developing countries, including Senegal. This study aims to identify and distinguish between the key socio-demographic and economic factors influencing ANC utilization among urban and rural women in Senegal.

Methods

The analysis was conducted on 5107 women who had at least one birth in the last five years preceding the survey. Data were obtained from the 2023 Senegal Demographic and Health Survey (DHS). ANC utilization, defined as receiving four or more ANC visits during pregnancy, was the outcome variable. Independent variables included age, region, education, wealth index, total children ever born, pregnancy intention, employment status, media exposure, births in last five years and women autonomy. Bivariate analyses and multiple logistic regression were conducted to identify the significant variables.

Results

The final sample included 4,785 women after excluding those with missing data. Higher education level (Adjusted Odds Ratio (AOR) = 3.649), rich wealth index (AOR=1.581), low (AOR=1.792) and high (AOR=1.692) media exposure were significantly associated with higher ANC in urban residences. On the contrary, in rural residences, primary (AOR=1.60), secondary (AOR=2.01) and higher (AOR=5.79) education level, intended pregnancy (AOR=1.33), low (AOR=1.48) and high (OR=1.35) media exposure and women autonomy (AOR=1.29) were significantly associated with higher ANC.

Conclusions

This study underscores the influence of different socio-economic and demographic factors on ANC utilization in urban and rural residences in Senegal. Policy interventions should prioritize enhancing education, economic opportunities, media awareness and women’s autonomy, particularly in rural areas, to improve ANC coverage.
Health worker acceptability of an HIV testing mobile health application within a rural Zambian HIV treatment programme
Authors: Montaner Andrés , Mumbalanga Mulundu , Umuhoza Marie-Chantal , Kinge Constance Wose , Okonji Emeka , Ligenda Godfrey , Mothibi Eula , Chirwa Ben , Pisa Pedro , Chasela Charles
Published: October 2024

Background

As more people living with HIV are identified and prescribed antiretroviral treatment in Zambia, detecting new HIV infections to complete the last mile of epidemic control is challenging. To address this, innovative targeted testing strategies are essential. Therefore, Right to Care Zambia developed and implemented a novel digital health surveillance application, Lynx, in three Zambian provinces—Northern, Luapula, and Muchinga in 2018. Lynx offers real-time HIV testing data with geo-spatial analysis for targeted testing, and has proven effective in enhancing HIV testing yield. This cross-sectional mixed methods study assessed the acceptability of Lynx among HIV testing healthcare workers in Zambia.

Methods

A quantitative Likert scale (1–5) survey was administered to 176 healthcare workers to gauge Lynx’s acceptability. Additionally, six qualitative key person interviews and five focus group discussions were conducted to gain an in-depth understanding of acceptability, and identify relevant barriers and facilitators. Quantitative data were analysed by averaging survey responses and running descriptive statistics. Qualitative data were transcribed and analysed in thematic coding. Data triangulation was utilised between the data sources to verify findings.

Results

Overall, the average survey score of perceived ease of use was 3.926 (agree), perceived usefulness was 4.179 (strongly agree) and perceived compatibility was 3.574 (agree). Survey questions related to network requirements, resource availability, and IT support had the most “strongly disagree” responses. The qualitative data collection revealed that Lynx was perceived as useful, and easy to use. Training for staff and regular updates were identified as facilitators, while conflicting work priorities and inconsistent IT support were identified barriers.

Conclusion

Lynx was identified as acceptable by health workers due to its perceived usefulness, staff trainings, and regular updates. For a mobile health intervention to be embraced in rural Zambian settings, key facilitators include robust IT support, comprehensive training, user feedback-based updates, and consideration of facility staff priorities.