bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rapamycin Immunomodulation Utilizes Time-Dependent Alterations of Lymph Node Architecture, Leukocyte Trafficking, and Gut Microbiome
Authors: Wu Long , Kensiski Allison , Gavzy Samuel J , Lwin Hnin Wai , Song Yang , France Michael , Lakhan Ram , Kong Dejun , Li Lushen , Saxena Vikas , Piao Wenji , Shirkey Marina W. , Mas Valeria , Ma Bing , Bromberg Jonathan S 
Published: October 2024

ABSTRACTTransplant recipients require lifelong, multimodal immunosuppression to prevent rejection by reducing alloreactive immunity. Rapamycin, a mechanistic target of rapamycin (mTOR) inhibitor, is known to modulate adaptive and innate immunity, while the full spectrum of its immunosuppressive mechanisms remains incompletely understood. Given the broad expression of mTOR, we investigated the understudied effects of rapamycin on lymph node (LN) architecture, leukocyte trafficking, and the gut microbiome and metabolism after 3, 7, and 30 days of rapamycin treatment, to characterize the early, intermediate, and late changes. Rapamycin significantly reduced CD4+ T cells, CD8+ T cells, and regulatory T (Treg) cells in peripheral LNs, mesenteric LNs, and the spleen over time. Rapamycin induced early pro-inflammation transition to pro-tolerogenic status, by modulating the LN laminin α4:α5 expression ratios through LN stromal cells laminin α5 expression and by adjusting Treg numbers and distribution. Additionally, rapamycin significantly altered gut microbiota composition and metabolic functions, shifting the Bacteroides to Firmicutes ratio and increasing amino acid bioavailability in the gut lumen. These effects were evident by 7 days and became most pronounced by 30 days in naïve mice, with notable changes as early as 3 days in allogeneic splenocyte-stimulated mice. These findings reveal a novel mechanism of rapamycin’s action through time-dependent modulation of LN architecture and gut microbiome, which orchestrates changes in immune cell trafficking, providing a new framework for understanding and optimizing immunosuppressive therapies.
High-coverage allele-resolved single-cell DNA methylation profiling by scDEEP-mC reveals cell lineage, X-inactivation state, and replication dynamics
Authors: Spix Nathan J. , Habib Walid Abi , Zhang Zhouwei , Eugster Emily , Milliron Hsiao-yun , Sokol David , Lee KwangHo , Nolte Paula , Endicott Jamie , Krzyzanowski Kelly F. , Hinoue Toshinori , Morrison Jacob , Johnson Benjamin K. , Zhou Wanding , Shen Hui , Laird Peter W. 
Published: October 2024

AbstractDNA methylation is a relatively stable epigenetic mark with important roles in development and disease.1Since cell-to-cell variation in epigenetic programming can reflect important differences in cell state and fate, it is clear that single-cell methods are essential to understanding this key epigenetic mark in heterogeneous tissues. Existing single-cell whole-genome bisulfite sequencing (scWGBS) methods2have significant shortcomings, including very low CpG coverage3–7or inefficient library generation requiring extremely deep sequencing.8These methods offer limited insight into focal regulatory regions and generally preclude direct cell-to-cell comparisons. To address these shortcomings, we have developed an improved method, scDEEP-mC (single-cell Deep and Efficient Epigenomic Profiling of methyl-C). We show that high-coverage promoter methylation profiling by scDEEP-mC can identify multiple cell types, while allele-resolved methylation calls allow assessment of X-inactivation state in single cells and identification of transcription factor binding sites (TFBS) enriched for hemi-methylation. We also use scDEEP-mC to profile single-cell copy number alterations, identify actively replicating cells, and track DNA methylation dynamics during and after DNA replication. The high coverage of scDEEP-mC creates an exceptional opportunity to explore DNA methylation biology in individual cells.
CYP3A5 inhibition causes G1/S blockade and synergizes with CDK4/6 inhibitor to suppress prostate cancer cell growth: Implications in reducing health disparity
Authors: Sharma Jeetesh , Mohammed Imran K. , Tillett Richard L. , McLean Jake , Shen Shirley , Singh Ajay , Goodman Oscar B. , Oh Edwin C. , Mitra Ranjana 
Published: October 2024

AbstractProstate cancer (PC) is a leading cause of death in men because of the high incidence and long-term inefficacy of the existing treatment options. Furthermore, it exhibits significant health disparities that affect African-American (AA) men more adversely than others do. Previously, we established CYP3A5, a highly expressed protein in AAs PC, as a positive regulator of androgen receptor (AR) signaling. We examined the impact of CYP3A5 depletion on genome-wide transcriptional output using RNA sequencing to gain deeper mechanistic insights. The data revealed that 561 genes were downregulated and 263 were upregulated upon silencing ofCYP3A5in PC cells. Furthermore,in silicopathway analyses of differentially expressed genes suggested that the cell cycle regulation pathway was most significantly affected byCYP3A5inhibition. Cell cycle analysis ofCYP3A5-silenced cells and those treated with clobetasol, a specific CYP3A5 pharmacological inhibitor, showed G1/S phase blockade. Both CYP3A5-depletion and pharmacological inhibition resulted in the downregulation of cyclin D, cyclin B, and CDK2, along with the upregulation of p27kip1but had minimal effects on CDK4/6 levels. Combination treatment with clobetasol and the CDK4/6 inhibitor palbociclib exhibited synergy with combination index (CI) values ranging from 0.28-0.78. Our findings support the utility of CYP3A5 as a druggable therapeutic target that works more effectively in combination with CDK4/6 inhibition to limit the progression of PC, especially for AA patients with AA. This combination addresses CDK4/6 inhibitor resistance, which is often linked to CDK2 overexpression, and can potentially be useful in reducing disparities in the clinical outcomes of PC.SignificanceOur study highlights CYP3A5 as a key regulator of the cell cycle in prostate cancer (PC). Its overexpression in African American (AA) patients may be a key molecular driver of disparities in outcomes. The combination of CYP3A5 and CDK4/6 inhibitors shows a synergistic effect on therapeutic outcomes and addresses CDK2-mediated resistance. Thus, targeting both CYP3A5 and CDK4/6 could improve treatment outcomes, especially in AA PC patients.
Association of climatic determinants with Type 1 and Type 2 Diabetes worldwide: Night length and photoperiod variation linked to T1D and sunshine to T2D
Authors: Lacouchie Julien 
Published: October 2024

AbstractDiabetes is one of the fastest growing diseases today. Whereas its North-South prevalence gradient and seasonality of diagnostics suggest the role of climate in diabetes etiology, only little is known about the impact of climate on diabetes. This article aims to study several climatic variables and their association with type 1 diabetes (T1D) and type 2 diabetes (T2D) worldwide and in Europe. Climatic variables under study are sunshine, temperature, solar irradiance and day length (photoperiod). Prevalence data come from international Diabetes Federation (2021) and T1D monthly incidence come from Eurodiab centers (1989-2008). Diabetes prevalence are associated with latitude in a curvilinear manner (r2=0,43 for T1D and r2=0,29 for T2D, p<0,001), T1D is more prevalent at extreme latitudes whereas T2D prevalence is higher near equator. Each climatic variable studied is negatively associated with T1D and positively associated with T2D prevalence in simple regression (p<0,001). Multicollinearity is assessed with Variance inflation factor (VIF) and reduced with multiple regression. After adjustment for other climatic variables, only photoperiod (daylength) is associated with T1D prevalence (r2=0,45) and sunshine with T2D prevalence (r2=0,48). T1D monthly incidences are approximated with a cosine regression (RR=1,53, r2=0,71) which is significantly associated with photoperiod variation along the year in Europe once adjusted for irradiance (p=1,77.e-2). The relation between photoperiod and T1D has never been reported before in an ecological study and a short review is developed in the discussion. This research advocates for the basic understanding of circadian-circannual rhythm and the prevention of circadian disturbances for individuals prone to T1D.
An evolving case for centering health equity as a research priority in predominantly White academic medical centers
Authors: Bonney Elizabeth A. , Bajaj Gagan Deep , Darko Olivia O. , Avila Maria Mercedes , Williams Brittany M. 
Published: October 2024

ABSTRACTPurposeHealth disparities impact those minoritized by race, class, gender nonconformance, and rurality. There is an urgent need to shift scholarly focus from merely documenting health disparities to effecting change through health equity research. The present mixed-methods study explores the motivation, opportunities, and barriers in performing health equity research in a majority white college of medicine.MethodsWe use landscape analysis: surveys, focus groups, and interviews with expressly interested faculty. Results: Our findings suggest there are barriers to communication, access, and recognition for health equity research that impact and influence the existence and possibilities of health equity scholarship in Vermont.ConclusionColleges of medicine are increasingly recognized as being responsible for advancing Health Equity. Our findings underscore the necessity of this work within the state of Vermont and offer recommendations to remove barriers at our institution and others similarly situated.
Mosaic integration of spatial multi-omics with SpaMosaic
Authors: Yan Xuhua , Ang Kok Siong , van Olst Lynn , Edwards Alex , Watson Thomas , Zheng Ruiqing , Fan Rong , Li Min , Gate David , Chen Jinmiao 
Published: October 2024

AbstractWith the advent of spatial multi-omics, we can mosaic integrate diverse datasets with partially overlapping modalities to construct consensus multi-modal spatial atlases of the source tissue. SpaMosaic is a spatial multi-omics mosaic integration tool that employs contrastive learning and graph neural networks to construct a modality-agnostic and batch-corrected latent space suited for analyses like spatial domain identification and imputing missing omes. Using simulated and experimentally acquired datasets, we benchmarked SpaMosaic against single-cell multi-omics mosaic integration methods. The experimental data encompassed RNA and protein abundance, chromatin accessibility or histone modifications, acquired from brain, embryo, tonsil, and lymph node tissues. SpaMosaic achieved superior performance over existing methods in identifying known spatial domains with enhanced resolution and clarity while reducing noise and batch effects. It also ranked top for modality alignment, enabling seamless diagonal integration without the need for image registration. After integration, SpaMosaic can also impute missing modalities. With a mosaic set of mouse brain data with RNA and different epigenomic modalities, we integrated and imputed the missing omics. There we found the imputed gene activity scores of activating and silencing histone marks show the correct correlation with RNA. Moreover, we uncovered more region-specific genes and pathways showing the correct transcriptome-epigenome correlations in the imputed histone modification than in the measured chromatin accessibility modalities. Lastly, SpaMosaic’s imputation also allows the inference of relationships between different modalities without requiring co-profiling from the same section.
Proline-2’-deoxymugineic acid (PDMA) increases seed quality and yield by alleviating iron deficiency symptoms in soybean under calcareous-alkaline conditions
Authors: Kaya Zahit , Maqbool Amir , Suzuki Motofumi , Aksoy Emre 
Published: October 2024

AbstractIron (Fe) deficiency in crops, particularly in calcareous-alkaline soils, poses a major challenge due to Fe immobilization. While synthetic chelators like EDTA and EDDHA are commonly used to improve Fe availability, proline-2’-deoxymugineic acid (PDMA) has emerged as a promising alternative, enhancing Fe nutrition in crops such as rice and cucumber. This study aimed to assess the effectiveness of PDMA on soybean growth and yield under calcareous-alkaline conditions. A pot trial demonstrated that PDMA improves Fe uptake, translocation, and storage in soybeans, leading to increased chlorophyll content, and enhanced root and shoot growth. Even at low dosages, PDMA significantly improved plant development, with the highest dosage (30 μM) resulting in notable increases in Fe, Zn, Mn, and Mg concentrations in roots, leaves, and seeds, surpassing the effects of the synthetic chelator Fe-EDDHA in several parameters. Additionally, 30 μM PDMA substantially boosted soybean yield, increasing pod and seed number, and 100-seed weight. It also improved seed quality by increasing protein and oil content. These findings suggest that PDMA offers a sustainable, effective alternative to traditional Fe chelators, providing a viable solution for addressing Fe deficiency and enhancing crop biofortification in challenging soil conditions.
Pathogenicity across variation in microbial virulence and host resistance
Authors: Gupta Anjali , Unckless Robert L. 
Published: October 2024

AbstractThe pathogenicity of a microbe is difficult to define in a comparative context: across microbes with varying virulence or across host genotypes with varying susceptibilities. Several different statistical approaches have been employed to investigate pathogenicity and susceptibility. Simple measures like proportional mortality or morbidity at a given time are attractive due to their simplicity but represent a single snapshot. Survival curve approaches, such as the Cox proportional hazards model and risk scores provide a more nuanced picture of the course of infection. More recently, Casadevall introduced the concept of pathogenic potential, a composite measure encompassing both host susceptibility and pathogen virulence, which focuses on the pathogenicity of a single pathogenic microbe, and later expanded to include additional nuances. UsingDrosophila melanogaster, we conducted infection experiments with diverse species ofProvidenciathat naturally vary in virulence. We also used several infectious doses to tune infections. We employed different host genotypes that vary in susceptibility toProvidenciainfection. Our analysis incorporates factors such as host genotype, pathogen type, inoculum load, symptomatic fraction, and mortality to compare host- and pathogen-based measures of pathogenicity. We discuss the advantages and limitations of each method, providing insights into their applicability in deciphering the intricacies of host-pathogen interactions and guiding the choice of analytical approaches in infectious disease research.
A thermoplastic chip for correlative assays combining screening and high-resolution imaging of immune cell responses
Authors: van Ooijen Hanna , Verron Quentin , Zhang Hanqing , Sandoz Patrick A. , Frisk Thomas W. , Carannante Valentina , Olofsson Karl , Wagner Arnika K. , Sandström Niklas , Önfelt Björn 
Published: October 2024

SummarySingle-cell immune assays are developed for the identification and characterization of individual immune cell responses. Some methods provide snapshots of the phenotype of the cell, such as flow cytometry and single-cell RNA sequencing, whereas others, almost exclusively microscopy-based, can be used for longitudinal studies of individual cells. However, obtaining correlative data on cell dynamics and phenotype of individual immune cells is challenging but can provide more nuanced information of heterogeneous immune cell responses. In this work, we have addressed this challenge by developing an easy-to-use, disposable, thermoplastic microwell chip, designed to support screening and high-resolution imaging of single-cell behavior in two-and three-dimensional cell cultures. We show that the chip has excellent optical properties and we provide simple protocols for efficient long-term cell culture of suspension and adherent cells, the latter grown either as monolayers or as hundreds of single, uniformly-sized spheroids. We demonstrate the applicability of the system for single-cell analysis by correlating the dynamic cytotoxic response of single immune cells grown under different metabolic conditions to their intracellular cytolytic load at the end of the assay. Additionally, we illustrate highly multiplex cytotoxicity screening of tumor spheroids in the chip, comparing the effect of environment cues characteristic of the tumor microenvironment on natural killer (NK) cell-induced killing. Following the functional screening, we perform high-resolution 3D immunofluorescent imaging of infiltrating NK cells within the spheroid volumes.
The contribution of aquatic foods to human nutrient intake and adequacy in a Small Island Developing State
Authors: Zamborain-Mason Jessica , Eurich Jacob G. , Friedman Whitney R. , Gephart Jessica A. , Kelahan Heather M. , Seto Katherine L. , Andrew Neil L. , Sharp Michael K. , Tekaieti Aritita , Timeon Eretii , Golden Christopher D. 
Published: October 2024

ABSTRACTMany Small Island Developing States (SIDS) are experiencing a nutrition transition, wherein high prevalence of malnutrition co-occurs with growing rates of diet-related non-communicable diseases. Sustainably managed and accessible aquatic foods can serve as a rich and bioavailable source of nutrients, helping communities achieve healthy diets and meet key sustainable development goals (e.g., SDG 1 No Poverty, SDG 2 Zero Hunger, and SDG 14 Life Below Water). However, to properly harness aquatic food systems in nutrition interventions, we must first understand aquatic food’s role in nutrient intake and adequacy. Here, using a nationally representative survey from Kiribati, we quantify the contribution of aquatic foods to nutrient intake and adequacy, and examine the spatial variability in nutrient intake adequacies. We find aquatic foods are the main contributors of most nutrients we examined, providing > 80% of vitamin B12, retinol, and heme iron, and > 50% of niacin, vitamin A, protein, vitamin E, potassium, and total iron consumed. Consumption of aquatic foods contributes to meeting key nutrient adequacies (e.g., niacin) and provides complete adequacy for vitamin B12and protein. However, despite high aquatic food consumption, we find high levels of nutrient inadequacies (11 of the 17 nutrients with dietary reference intakes). Overall, our study quantifies the nutritional importance of aquatic foods in an emblematic SIDS, emphasizing their vulnerability to declining aquatic resources. We also highlight the need for cross-scale context-specific targeted nutrition interventions, even when aquatic food consumption is high, to enable SIDS to meet key SDGs.
Immunotherapy with nebulized pattern recognition receptor agonists restores severe immune paralysis and improves outcomes in mice with influenza-associated pulmonary aspergillosis
Authors: García Jezreel Pantaleón , Wurster Sebastian , Albert Nathaniel D. , Bharadwaj Uddalak , Bhoda Keerthi , Kulkarni Vikram K , Ntita Mbaya , Carstens Paris Rodríguez , Burch-Eapen Madeleine , López Daniela Covarrubias , Wang Yongxing , Kontoyiannis Dimitrios P. , Evans Scott E. 
Published: October 2024

AbstractInfluenza-associated pulmonary aspergillosis (IAPA) is a potentially deadly super-infection in patients with influenza pneumonia, especially those with severe disease, underlying immunosuppression, corticosteroid therapy, or requiring intensive care support. Given the high mortality of IAPA, adjunct immunomodulatory strategies remain a critical unmet need. Previously, desensitization of pattern recognition pathways has been described as a hallmark of IAPA pathogenesis and predictor of mortality in IAPA patients. Therefore, we studied the impact of nebulized Toll-like receptor 2/6/9 agonists Pam2 CSK4 (Pam2) and CpG oligodeoxynucleotides (ODN) on infection outcomes and pulmonary immunopathology in a corticosteroid-immunosuppressed murine IAPA model. Mice with IAPA receiving mock therapy showed rapidly progressing disease and a paralyzed immune response to secondaryA. fumigatusinfection. Nebulized Pam2ODN was well tolerated and significantly prolonged event-free survival. Specifically, dual-dose Pam2ODN therapy before and afterA. fumigatusinfection led to 81% survival and full recovery of all survivors. Additionally, transcriptional analysis of lung tissue homogenates revealed induction of PRR signaling and several key effector cytokine pathways after Pam2ODN therapy. Moreover, transcriptional and flow cytometric analyses suggested enhanced recruitment of macrophages, natural killer cells, and T cells in Pam2ODN-treated mice. Collectively, immunomodulatory treatment with nebulized Pam2ODN strongly improved morbidity and mortality outcomes and alleviated paralyzed antifungal immunity in an otherwise lethal IAPA model. These findings suggest that Pam2ODN might be a promising candidate for locally delivered immunomodulatory therapy to improve outcomes of virus-associated mold infections such as IAPA.
Making Aptamers More Antibody-like: Targeting AXLin VivoUsing a Bottlebrush Polymer-Conjugated Aptamer
Authors: Sun Tingyu , Lin Jiachen , Xue Chenyang , Wang Yuyan , Chen Peiru , Wei Yun , Xu Guobin , Sidonia Anais , Nenopoulos Chris , Tashkandi Hossam , Zhang Ke 
Published: October 2024

AbstractThe overexpression of receptor tyrosine kinase AXL is linked to acquired drug resistance in cancer treatments. Aptamers, acting as antibody surrogates, have been envisioned as potential inhibitors for AXL. However, aptamers face difficult pharmacological challenges including rapid degradation and clearance. Herein, we report a phosphodiester-backboned bottlebrush polymer as a carrier for conjugated aptamers. Termed pacDNA, the conjugate improves aptamer specificityin vivo, prolongs blood retention, and enhances overall aptamer bioactivity. Treatment with pacDNA in AXL-overexpressing cell lines significantly inhibits AXL phosphorylation, resulting in reduced cancer cell migration and invasion. In a non-small cell lung cancer xenograft model (NCI-H1299), pacDNA treatment leads to single-agent reduction in tumor growth. These results highlight the potential of bottlebrush polymers in the field of aptamer therapeutics.