bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multifaceted Control Interventions for Healthcare-associated Infections in a Kidney Transplant Intensive Care Unit: Clinical Outcome Improvement and Bundle Adherence
Authors: Calegari Luana Oliveira , Peruzzo Maria Bethânia , Foresto Renato Demarchi , Tedesco-Silva Helio , Medina Pestana José , Requião-Moura Lúcio R. 
Published: October 2024

Background.
Healthcare-associated infections (HAIs) are preventable complications that overwhelm the healthcare system. The implementation of multifaceted control intervention actions in the intensive care setting modifies clinical outcomes, but its effectiveness has not been specifically investigated for high-risk patients, such as kidney transplant recipients (KTRs).

Methods.
This observational retrospective natural experiment evaluated the effectiveness of multifaceted control interventions (bundles) in reducing HAIs in a KTR intensive care unit. We also measured the bundle adherence rate during 16 mo in the after era.

Results.
We included 1257 KTRs, 684 before and 573 in the postintervention period. After the bundle implementation, the incidence density of device-associated HAIs decreased from 8.5 to 3.9 per 1000 patient-days (relative risk [RR] = 0.46; 95% confidence interval [CI], 0.25-0.85; P = 0.01), primarily because of the reduction in central line-associated bloodstream infection from 8.0 to 3.4 events per 1000 catheter-days (RR = 0.43; 95% CI, 0.22-0.83; P = 0.012). Reductions in catheter-associated urinary tract infection (2.5 versus 0.6 per 1000 catheter-days; RR = 0.22; 95% CI, 0.03-1.92; P = 0.17) and ventilator-associated pneumonia (3.4 versus 1.0 per 1000 ventilator-days; RR = 0.29; 95% CI, 0.03-2.63; P = 0.27) were not significant. Central venous (P = 0.53) and urinary catheter (P = 0.47) insertion adherence were stable during 16 mo, whereas central venous (P < 0.001) and urinary catheter (P = 0.004) maintenance gradually increased. Finally, ventilator-associated pneumonia prevention bundle adherence slightly decreased over time (P = 0.06).

Conclusions.
The implementation of comprehensive multifaceted control intervention actions in an intensive care unit dedicated to KTR care was effective in significantly reducing device-associated infections. The impact was in line with the reductions observed in populations that have not undergone transplantation, underscoring the effectiveness of these interventions across different patient groups.
SLC4A1MUTATIONS THAT CAUSE DISTAL RENAL TUBULAR ACIDOSIS ALTER CYTOPLASMIC PH AND CELLULAR AUTOPHAGY
Authors: Essuman Grace , Rizvi Midhat , Almomani Ensaf , Ullah Shahid A. K M. , Hasib Sarder M. A. , Chelangarimiyandoab Forough , Mungara Priyanka , Schmitt Manfred J. , Hureaux Marguerite , Vargas-Poussou Rosa , Touret Nicolas , Cordat Emmanuelle 
Published: October 2024

AbstractDistal renal tubular acidosis (dRTA) is a disorder characterized by the inability of the collecting duct system to secrete acids during metabolic acidosis. The pathophysiology of dominant or recessiveSLC4A1variant related dRTA has been linked with the mis trafficking defect of mutant kAE1 protein. However,in vivostudies in kAE1 R607H dRTA mice and humans have revealed a complex pathophysiology implicating a loss of kAE1-expressing intercalated cells and intracellular relocation of the H+-ATPase in the remaining type-A intercalated cells. These cells also displayed accumulation of ubiquitin and p62 autophagy markers. The highly active transport properties of collecting duct cells require the maintenance of cellular energy and homeostasis, a process dependent on intracellular pH. Therefore, we hypothesized that the expression of dRTA variants affect intracellular pH and autophagy pathways. In this study, we report the characterization of newly identified dRTA variants and provide evidence of abnormal autophagy and degradative pathways in mouse inner medullary collecting duct cells and kidneys from mice expressing kAE1 R607H dRTA mutant protein. We show that reduced transport activity of the kAE1 variants correlated with increased cytosolic pH, reduced ATP synthesis, attenuated downstream autophagic pathways pertaining to the fusion of autophagosomes and lysosomes and/or lysosomal degradative activity. Our study elucidated a close relationship between the expression of defective kAE1 proteins, reduced mitochondrial activity and decreased autophagy and protein degradative flux.
Mechanistic insights into structure-based design of a Lyme disease subunit vaccine
Authors: Brangulis Kalvis , Malfetano Jill , Marcinkiewicz Ashley L. , Wang Alan , Chen Yi-Lin , Lee Jungsoon , Liu Zhuyun , Yang Xiuli , Strych Ulrich , Bottazzi Maria-Elena , Pal Utpal , Hsieh Ching-Lin , Chen Wen-Hsiang , Lin Yi-Pin 
Published: October 2024

ABSTRACTThe quality of protective immunity plays a critical role in modulating vaccine efficacy, with native antigens often not able to trigger sufficiently strong immune responses for pathogen killing. This warrants creation of structure-based vaccine design, leveraging high-resolution antigen structures for mutagenesis to improve protein stability and efficient immunization strategies. Here, we investigated the mechanisms underlying structure-based vaccine design using CspZ-YA, a vaccine antigen fromBorrelia burgdorferi, the bacteria causing Lyme disease (LD), the most common vector-borne disease in the Northern Hemisphere. Compared to wild-type CspZ-YA, we found CspZ-YAI183Yand CspZ-YAC187Srequired lower immunization frequency to protect mice from LD-associated manifestations and bacterial colonization. We observed indistinguishable human and mouse antigenicity between wild-type and mutant CspZ-YA proteins after native infection or active immunization. This supports our newly generated, high-resolution structures of CspZ-YAI183Yand CspZ-YAC187S, showing no altered surface epitopes after mutagenesis. However, CspZ-YAI183Yand CspZ-YAC187Sfavored the interactions between helices H and I, consistent with their elevated thermostability. Such findings are further strengthened by increasing ability of protective CspZ-YA monoclonal antibodies in binding to CspZ-YA at a physiological temperature (37°C). Overall, this study demonstrated enhanced intramolecular interactions improved long-term stability of antigens while maintaining protective epitopes, providing a mechanism for structure-based vaccine design. These findings can ultimately be extended to other vaccine antigens against newly emerging pathogens for the improvement of protective immunity.
Tuning Spatial Distributions of Selection Pressure to Suppress Emergence of Resistance
Authors: Tunstall Thomas , Madgwick Philip G. , Kanitz Ricardo , Möbius Wolfram 
Published: October 2024

AbstractControl measures such as insecticides or antimicrobials are used to contain biological agents such as pathogenic bacteria and vectors of human and plant diseases, respectively. Following control measure application, a resistant subpopulation may eventually rise to such frequency that the control measure will be rendered ineffective: The timescale over which this occurs is the ‘effective lifetime’ of the control measure. Prolonging this timescale relaxes urgency at which novel control measure needs to be developed. Spatial heterogeneity in control measure application can influence the rate at which resistance to the control measure evolves; in the agricultural context, this fact is exploited by distributing insecticides in mosaics across cropping regions in order to slow the rate of resistance evolution.Contemporary and historical modeling practices, which aim to inform agricultural practices, often employ assumptions which squeeze out the impact of the spatio-temporal heterogeneity endemic to nature. In this paper, we present a minimal model of continuous dispersal and spatio-temporal heterogeneity in selection pressure distribution which exhibits a novel dynamic: The spatial distribution of selection pressure may be tuned in order to minimize the initial rate at which resistance evolves, thus increasing the effective lifetime of a pesticide.Author summaryThere are many contexts in which humans apply control measures to biological agents: pesticides are applied in fields to kill the pests that damage crops, mosquito nests are distributed to prevent the spread of malaria, and cancer drugs are applied to kill off tumors in humans. These control measures are examples of ‘selection pressures’, which select against strains which are susceptible to them. If a mutation occurs which confers resistance, the control agent will select for the resistant strain, thus reducing the efficacy of the control agent as the frequency of resistance increases in the population. This necessitates more of the control agent to be applied, or for a novel control agent to be developed. The former may have unintended consequences on the local environment, and the latter is expensive and time-intensive. It is preferable to carefully tunehowthe control agent is applied - perhaps instead of one massive compact region of control measure application, it is better to apply the control measure over multiple smaller regions? Here, we use a toy model of motile organisms to demonstrate that an optimal distribution exists for a variety of scenarios.
Anti-PTHrP blockade limits CD8+ T-cell exhaustion in anti-cancer immunotherapy
Authors: Moës Bastien , Gao Yunfeng , Demina Ekaterina , Kremer Richard , Rudd Christopher E. 
Published: October 2024

AbstractCancer is a major global health concern, with immune suppression hindering treatment. Immunotherapy, specifically immune checkpoint blockage on T cells, has revolutionized cancer treatment. T-cell exhaustion is an abnormal activation state that develops when continuous exposure to antigens, like cancer. In this context, recent evidence suggests that parathyroid hormone-related protein (PTHrP) plays a previously underappreciated role in fostering an immunosuppressive tumor microenvironment. Further, blocking PTHrP activity reduces primary tumor growth, prevents metastasis, and prolongs survival in mice with various cancers. Here, we confirm that administration of anti-PTHrP monoclonal antibodies can reduce the growth of B16-PDL1 melanoma tumors and that although the therapy did not alter the presence of CD4+ and CD8+ TILs, we noted that all stages of T-cell exhaustion were reduced. Further, the expression of cytolytic proteins PERFORIN and GZMB also increased. By contrast, anti-PTHrP therapy increased the relative presence of pre-pro B cells with a decline in mature B cells in the bone marrow. Overall, our data indicates that anti-PTHrP therapy acts by reducing T-cell exhaustion and by affecting B-cell development. These provide further mechanistic evidence to support the application of anti-PTHrP blockade as an alternate therapeutic approach to boost anti-tumor immunity.
Single-Cell Proteomic and Transcriptomic Characterization of Drug-Resistant Prostate Cancer Cells Reveals Molecular Signatures Associated with Morphological Changes
Authors: Woo Jongmin , Loycano Michael , Amanullah Md , Qian Jiang , Amend Sarah , Pienta Kenneth , Zhang Hui 
Published: October 2024

AbstractThis study delves into the proteomic intricacies of drug-resistant cells (DRCs) within prostate cancer, which are known for their pivotal roles in therapeutic resistance, relapse, and metastasis. Utilizing single-cell proteomics (SCP) with an optimized high-throughput Data Independent Acquisition (DIA) approach with the throughput of 60 sample per day, we characterized the proteomic landscape of DRCs in comparison to parental PC3 cells. This optimized DIA method allowed for robust and reproducible protein quantification at the single-cell level, enabling the identification and quantification of over 1,300 proteins per cell on average. Distinct proteomic sub-clusters within the DRC population were identified, closely linked to variations in cell size. The study uncovered novel protein signatures, including the regulation of proteins critical for cell adhesion and metabolic processes, as well as the upregulation of surface proteins and transcription factors pivotal for cancer progression. Furthermore, by integrating SCP and single-cell RNA-seq (scRNA-seq) data, we identified six upregulated and ten downregulated genes consistently altered in drug-treated cells across both SCP and scRNA-seq platforms. These findings underscore the heterogeneity of DRCs and their unique molecular signatures, providing valuable insights into their biological behavior and potential therapeutic targets.
Focused learning by antibody language models using preferential masking of non-templated regions
Authors: Ng Karenna , Briney Bryan 
Published: October 2024

ABSTRACTExisting antibody language models (LMs) are pre-trained using a masked language modeling (MLM) objective with uniform masking probabilities. While these models excel at predicting germline residues, they often struggle with mutated and non-templated residues, which are crucial for antigen-binding specificity and concentrate in the complementarity-determining regions (CDRs). Here, we demonstrate that preferential masking of the non-templated CDR3 is a compute-efficient strategy to enhance model performance. We pre-trained two antibody LMs (AbLMs) using either uniform or preferential masking and observed that the latter improves residue prediction accuracy in the highly variable CDR3. Preferential masking also improves antibody classification by native chain pairing and binding specificity, suggesting improved CDR3 understanding and indicating that non-random, learnable patterns help govern antibody chain pairing. We further show that specificity classification is largely informed by residues in the CDRs, demonstrating that AbLMs learn meaningful patterns that align with immunological understanding.
Profiling of epithelial functional states and fibroblast phenotypes in hormone therapy-naïve localised prostate cancer
Authors: Apostolov Eva , Roden Daniel L , Holliday Holly , Cazet Aurélie , Harvey Kate , Zhang Hanyun , Wu Sunny Z , van der Leij Sophie , Selth Luke A , Bartonicek Nenad , Al-Eryani Ghamdan , He Mengxiao , Lundeberg Joakim , Reeves John , Kench James G , Potter Alison J , Stricker Phillip , Joshua Anthony M , Horvath Lisa , Swarbrick Alexander 
Published: October 2024

AbstractLocalised prostate cancers (PCa) are heterogeneous and multifocal, with diverse outcomes. Current prognostic methods are epithelium-centric, overlooking the complex cellular landscape within the tumour microenvironment (TME), which remains incompletely characterised. We performed a comprehensive analysis of cancerous and adjacent-benign cores from 24 patients with hormone therapy-naïve localised PCa using single-cell RNA-sequencing. By integrating copy number variation and transcriptional signatures, we classified epithelial cells across a malignant spectrum, revealing widespread molecular perturbation. We found an expansion of Club cell phenotypes, suggestive of Luminal dedifferentiation. We also performed a detailed annotation of stromal phenotypes, focusing on fibroblasts, and identified a novel peri-neural fibroblast population. Spatial transcriptomics elucidated the precise anatomical distribution of CAFs within the PCa TME. This study provides a valuable foundation for advancing our understanding of PCa pathobiology and developing a comprehensive cellular model of the disease.Statement of SignificanceOur study leverages single-cell RNA-sequencing and spatial transcriptomics to provide a comprehensive cellular annotation of hormone therapy-naïve localised PCa. We reveal widespread molecular perturbations in epithelial cells and map distinct fibroblast populations to specific anatomical niches. Notably, we identify a novel peri-neural phenotype associated with nerves, which merits further functional characterisation and exploration as a potential therapeutic target.
Limits to the inference of gene regulation from bulk tissue expression data
Authors: Chu C. Pan , Morin Alexander , Pavlidis Paul 
Published: October 2024

AbstractMotivationThousands of studies have used co-expression analysis of bulk tissue samples to probe gene regulation. However, the extent that intracellular regulatory signals are present in these data is unclear. Specifically, we lack clarity of the factors that promote or impede the propagation of intracellular regulatory signals from the single cell level to the bulk tissue level. To bring these issues into focus, we developed a novel computational simulator, grounded in real data, to explore the theoretical relationship between events in single cells and bulk tissue expression profiles, and clarify the conditions required for the propagation of intracellular regulatory signals in complex tissues such as the brain.ResultsOur simulator first generates single cell expression profiles and subsequently samples and aggregates these single cells to produce bulk tissue expression profiles. Using this framework, we found that there are very specific and unlikely conditions under which intracellular dynamic regulatory signals can be propagated to the bulk tissue level. For the most part, such regulatory relationships, however strong at the single cell level, are unlikely to be detectable. Our results provide a quantitative explanation for why regulatory network inference from co-expression has proved challenging - even with the assistance of other data modalities - and gives the scientific community a set of tools to further explore these issues in both single-cell and bulk tissue data.Availability and implementationAll relevant data are within the manuscript and supplementary files. The code for all data analyses and generation of figures are available on GitHub (https://github.com/PavlidisLab/coex-simulation). A copy of the data has been deposited in Borealis, the Canadian Dataverse Repository (https://borealisdata.ca/dataset.xhtml?persistentId=doi:10.5683/SP3/2CWXY6).
CCAFE: Estimating Case and Control Allele Frequencies from GWAS Summary Statistics
Authors: Stoneman Hayley R , Price Adelle , Gignoux Christopher R , Hendricks Audrey E 
Published: October 2024

AbstractMethods involving summary statistics in genetics can be quite powerful but can be limited in utility. For instance, many post-hoc analyses of disease studies require case and control allele frequencies (AFs), which are not always published. We present two frameworks to derive case and control AFs from GWAS summary statistics using the odds ratio, case and control sample sizes, and either the total (case and control aggregated) AF or standard error (SE). In simulations and real data, derivations of case and controls AFs using total AF is highly accurate across all settings (e.g., minor AF, condition prevalence). Conversely, derivations using SE underestimate common variant AFs (e.g. minor allele frequency >0.3) in the presence of covariates. We develop an adjustment using gnomAD AFs as a proxy for true AFs, which reduces the bias when using SE. While estimating case and control AFs using the total AF is preferred due to its high accuracy, estimating from the SE can be used more broadly since SE can be derived from p-values and beta estimates, which are commonly provided. The methods provided here expand the utility of publicly available genetic summary statistics and promote the reusability of genomic data. The R packageCCAFE, with implementations of both methods, is freely available on Bioconductor and GitHub.
Pervasive and recurrent hybridisation prevents inbreeding depression in Europe’s most threatened seabird
Authors: Izquierdo-Arànega Guillem , Cuevas-Caballé Cristian , Giannelli Francesco , Paris Josephine Rosanna , Bourgeois Karen , Trucchi Emiliano , González-Solís Jacob , Riutort Marta , Obiol Joan Ferrer , Rozas Julio 
Published: October 2024

ABSTRACTHybridisation is a double-edged sword: while it can erode distinct evolutionary lineages, it can also introduce genetic diversity and adaptive potential into dwindling populations. In the Critically Endangered Balearic shearwater (Puffinus mauretanicus), this dilemma is exacerbated by a limited understanding of the extent and consequences of hybridisation with the Yelkouan shearwater (P. yelkouan). This knowledge gap has limited the scope of science-based conservation strategies to avoid the Balearic shearwater’s imminent extinction. Here, we investigate shearwater hybridisation dynamics and their effect on genome-wide diversity in the Balearic shearwater. Divergence dating, demographic modelling and admixture analyses suggest that these two poorly-differentiated shearwater lineages experienced recurrent episodes of divergence and widespread hybridisation during glacial cycles. Selection scans reveal a 500 kb region hosting an adaptive haplotype that potentially underpins interspecific differences in migratory behaviour, and which has been repeatedly introgressed between taxa. Moreover, we show that interspecific gene flow has prevented increases in homozygosity and genetic load, and through forward simulations we illustrate how it can enhance the Balearic shearwater’s resilience to future population bottlenecks. Our findings illustrate how introgression can be crucial for maintaining genetic diversity in threatened taxa, and highlight the need for considering the protection of hybridisation in conservation plans.
IL-13/IL-13Rα2 axis promotes proliferation of angiosarcoma cells
Authors: Saito Hinako , Omori Issei , Iwasawa Okuto , Sugimori Ayaka , Nakajima Hibari , Ichimura Ryuzo , Sato Shinichi , Sumida Hayakazu 
Published: October 2024

AbstractAngiosarcoma is a rare and aggressive soft tissue sarcoma with a poor prognosis and limited treatment options. The role of interleukin-13 (IL-13) and its receptors in angiosarcoma pathogenesis has been largely unknown. We detected high IL-13 receptor α2 (IL-13Rα2) expression in angiosarcoma cell lines and patient samples compared to other cell types and benign vascular tumors. Moreover, histological analysis showed the presence of IL-13 in the angiosarcoma microenvironment. Functional studies using angiosarcoma cell lines, MO-LAS-B cells, revealed the promoting effect of IL-13 on cell proliferation. The effect was inhibited by siRNA-mediated knockdown ofIL13RA2or neutralizing antibodies against IL-13, suggesting the direct impact of IL-13/IL-13Rα2 axis in the angiosarcoma proliferation. In addition, IL-13 stimulation increased mRNA levels ofIL13RA2andVEGFA, suggesting an underlying positive feedback mechanism, which was attenuated by a STAT6 inhibitor. These findings highlight the importance of the IL-13/IL-13Rα2 axis in angiosarcoma progression and its potential as a novel therapeutic target for this challenging malignancy.