bluuebunny/crossref_metadata_2025_split 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

AbstractMass 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 GraphicThis 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 byprolfquappXLSX 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

ABSTRACTCavitary 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.SIGNIFICANCEClinical 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

AbstractMutations 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

ABSTRACTArterioles 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

AbstractBackgroundUnexplained 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.Methods218 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.ResultsA 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).ConclusionsThese 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

AbstractBackgroundThe 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.MethodsThe 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.ResultsThe 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.ConclusionIn 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 ImplicationsThe 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 summaryThe 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 statementThe 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

AbstractClonal 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

AbstractRecruitment 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

AbstractChitin, 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

AbstractLead, 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 summaryLead 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.