bluuebunny/crossref_metadata_2025 huggingface dataset:
New insights into the involvement of residue D1/V185 in Photosystem II function inSynechocystis 6803andThermosynechococcus vestitus
Authors: Boussac Alain , Sellés Julien , Sugiura Miwa , Burnap Robert L.
Published: October 2024

The effects of D1-V185T and D1-V185N mutations in Photosystem II (PSII) fromThermosynechococcus vestitus(formerlyT. elongatus) andSynechocystis6803, respectively, were studied using both EPR and optical kinetics. EPR spectroscopy reveals the presence of a mixture of a S2state in a high spin configuration (S2HS) and in a low spin configuration (S2LS) in both mutants. In contrast to the S2HSin the wild type, the S2HSstate in the D1-V185T mutant does not progress to the S3state at 198 K. This inability is likely due to alterations in the protonation state and hydrogen-bonding network around the Mn4CaO5cluster. Optical studies show that these mutations significantly affect proton release during the S3-to-S0transition. While the initial fast proton release associated with TyrZ●formation remains unaffected within the resolution of our measurements, the second, and slower, proton release is delayed, suggesting that the mutations disrupt the hydrogen-bonding interactions necessary for efficient deprotonation of substrate water (O6). This disruption in proton transfer also correlates with slower water exchange in the S3state, likely due to non-native hydrogen bonds introduced by the threonine or asparagine side chains at position 185. These findings point to a critical role of D1-V185 in regulating both proton transfer dynamics and water binding, underscoring a complex interplay between structural and functional changes in PSII.
Reconstructing the deep phylogeny of the MAPK signaling network: functional specialization via multi-tier coevolutionary expansion
Authors: Huang EJ , Parksong Jeeun , Peterson Amy F. , Torres Fernando , Regot Sergi , Bever Gabriel S.
Published: October 2024

The mitogen-activated protein kinase (MAPK) signaling network is a three-tier cascade that regulates key cellular responses in eukaryotes. However, the evolutionary origins of its complex interactions and functional diversity remain poorly understood. Here, we conducted a comprehensive phylogenetic analysis of MAPK components across Eukarya to delineate divergences of non-human orthologs of human paralogs along the human evolutionary backbone. We identified two major pulses of coevolutionary expansion: one predating the divergence of fungi and animals, and another predating the origin of animals. Our reconstruction also infers a polyphyletic origin for the atypical MAPKs. Integrating functional literature across eukaryotic taxa with our reconstructed trees reveals that the two clades of MAP3K, Sterile-like (STE) and tyrosine kinase-like (TKL), had distinct evolutionary trajectories and influences on downstream pathway diversification. STEs that function as MAP3Ks are conserved across extant eukaryotes. Despite the absence of TKL MAP3Ks in many early diverging eukaryotes, the expansion of TKL MAP3Ks aligns phylogenetically and functionally with that of the downstream MAP2Ks and MAPKs. We thus propose that the MAPK network originated as a STE-regulated pathway, and that subsequent radiations of the TKLs drove the diversification of downstream components and top-down finetuning of pathway specificity. We thus provide an evolutionary framework for generating novel hypotheses on the functional diversity of this key signaling network, including potential insights into the evolution of animal multicellularity. Our study demonstrates that phylogenetics can offer new perspectives towards understanding complex cellular physiology.

Significance

The mitogen-activated protein kinase (MAPK) signaling network responds to various signals and regulates basic cell physiology including proliferation and apoptosis. This three-tier network is universal in eukaryotes, but there is great functional diversity among different homologs as well as different taxa. Here we compared amino acid sequences to reconstruct MAPK evolutionary history as a network. We found that the three levels expand in parallel, showcasing a special case of coevolution. Two distinct pulses of network expansion predate the origin of animals, indicating that the functional diversity of human MAPK network proteins originate from ancient evolutionary radiations. Together, our study provides a critical look at the deep history of this important network.
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

Transplant 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

DNA 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

Prostate 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.

Significance

Our 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

Diabetes 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

Purpose

Health 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.

Methods

We 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.

Conclusion

Colleges 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

With 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

Iron (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

The 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

Single-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

Many 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

Influenza-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

The 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.
Genderized Gut and Oral Microbiome Shifts: Uncovering Sex-Specific Dysbiosis in Pancreatic Cancer
Authors: Khan Zara Ahmed , Ghorbani Mahin , Heffinger Leon , Damdimopoulos Anastasios , Moro Carlos Fernández , Björnstedt Mikael , Löhr J.-Matthias , Heuchel Rainer , Chen Margaret Sällberg , Sarhan Dhifaf
Published: October 2024

Background

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, responsible for approximately 466,000 deaths globally in 2020. Its incidence increases by about 1% annually, with a higher occurrence in males than females. While differences in immune responses and tumor biology between sexes have been explored, the role of the microbiome in gender-specific PDAC progression is still unclear. Investigating these differences could offer crucial insights for personalized treatment strategies for males and females.

Methods

This study reanalyzed oral and gut microbiome data from BioProject: PRJNA832909, comprising 191 samples from PDAC patients and healthy controls. Using shotgun metagenomic sequencing, we examined gender-specific bacterial signatures. Alpha diversity (richness) and beta diversity (community composition) were analyzed. Differentially abundant bacterial taxa were identified via LEfSe, and gender-specific bacterial panels were validated using CombiROC.

Results

Alpha diversity analysis revealed significant differences in microbial richness, particularly between male and female PDAC patients and their healthy controls. Beta diversity demonstrated distinct microbial shifts between the PDAC and control groups across genders. LEfSe identified several pathogenic bacteria contributing to gender-specific dysbiosis, includingStreptococcus, Fusobacterium, andPrevotella. Shared and sex-specific bacterial species in PDAC were highlighted through Venn diagram analysis. CombiROC validated the predictive ability of these bacterial markers, with AUC values exceeding 0.90 for both sexes.

Conclusion

This study uncovered gender-specific microbial patterns in PDAC patients, potentially influenced by sex-specific immune responses. These findings provide important insights into the progression of PDAC and support sex-targeted diagnostic and therapeutic interventions.

Graphical abstract
Characterization of the cellular and subcellular distribution of fms-like tyrosine kinase 3 (FLT3) and other neuronal proteins using an alkaline phosphatase (AP) immunolabeling method
Authors: Yin Yuqin , He Kathleen , Kirby Jane , Harque Ishraq , Tang Xin
Published: October 2024

Precisely localizing the spatial distribution of proteins within various cell types in the brain, and in sub-cellular compartments such as the synapses, is critical for generating and testing hypothesis to elucidating the function of target proteins in the brain. The fms-like tyrosine kinase-3 (FLT3) has been studied extensively in the context of blood cell development and leukemia pathogenesis, but little is known about its role in the brain. Previous work characterizing FLT3 protein expression in the brain have not yielded convincing results, mainly limited by the low expression level of FLT3 and poor sensitivity of standard immunolabeling method using fluorescent secondary antibody. In this study, we report the systematic characterization of FLT3 protein localization during brain development using a highly sensitive immunolabeling methodology based on alkaline phosphatase (AP) polymer biochemistry. Our results reveal a previously unknown neuron-selective FLT3 expression pattern in both mouse and human cerebellum tissue samples, and demonstrate a gradual increase in the total FLT3 protein level and a cytosolic-to-dendritic change in subcellular FLT3 distribution during mouse cerebellum development. Through combining the AP immunolabeling of FLT3 with standard immunostaining of various cell type markers to achieve hybrid co-labeling of multiple antigens in tissue sections, we demonstrate that the main cell type that express FLT3 in the cerebellum is PV+, Calbindin+ Purkinje cells. To expand the use case of AP immunolabeling method in labeling neuronal proteins, we show robust labeling of Kir2.1, a potassium channel protein that is expressed at low level in neurons, in brain tissue sections collected from mouse, pig, and human brains. We further established that the AP immunolabeling method can be used in human stem cell-derived neurons to detect postsynaptic density scaffold protein PSD95 within fine subcellular structures such as dendritic spines and synapses, in cultured primary mouse cortical neurons and human stem cell-derived neurons. To our knowledge, our work represents the first report of applying AP immunolabeling to detect neuronal protein expression in brain tissue and cell samples. Moreover, our work reveals a previously unknown neuron-specific pattern of FLT3 expression in the brain, providing the foundation for further mechanistic studies to uncover its role in brain development and functioning.
Gut Microbial Impact on Colitis and Colitis-Associated Carcinogenesis in a Primary Sclerosing Cholangitis-IBD Model
Authors: Awoniyi Muyiwa , Ngo Billy , Meadows Vik , Coskuner Deniz , Montgomery Stephanie A. , Farmer Morgan , Liu Bo , Zhou Huiping , Roach Jeffery , Stappenbeck Thaddeus , Sartor R. Balfour
Published: October 2024

Background and Aims

Primary sclerosing cholangitis (PSC) associated inflammatory bowel diseases (IBD) increase colorectal dysplasia and malignancy risk. Current mouse models do not adequately replicate human PSC-IBD, limiting mechanistic understanding and therapeutic development. This study usesMdr2/Il10double knockout (DKO) mice to examine microbiota roles in mediating colitis, colitis-associated colorectal dysplasia and hepatobiliary inflammation/fibrosis.

Goal

Develop and phenotype a chronic spontaneous PSC-IBD mouse model, emphasizing colitis, colonic dysplasia, hepatobiliary inflammation/ fibrosis and the functional roles of resident microbiota.

Methods

We utilized germ-free (GF) and specific-pathogen-freeMdr2/Il10DKO,Il10-/-andMdr2-/-mice to model PSC-IBD. We monitored colonic dysplasia progression, colitis kinetics and severity by lipocalin-2, cytokine measurement, and tissue evaluations of colon and liver. We manipulated the microbiome to assess its functional effects.

Results

DKO mice exhibited age- and region-specific accelerated colitis and spontaneous colonic dysplasia progressing to high-grade invasive adenocarcinomas. Despite aggressive colonic inflammation, DKO mice showed reduced hepatic fibrosis, increased hepatic reparative macrophages, and matrix metalloproteinase activity compared toMdr2-/-mice. GF DKO had heightened liver inflammation and mortality with absent colitis and colonic dysplasia, reversed with microbial reconstitution from DKO mice. Changes in DKO primary/secondary bile acid profiles mirrored those in PSC-IBD.

Conclusion

TheMdr2/Il10DKO model mirrors key factors in PSC-IBD patients in terms of inflammation and carcinogenesis. We found an important role for the dysbiotic microbiota in DKO mice for disease onset and progression. Targeting microbiota and bile acid metabolism may provide promising strategies for developing effective PSC-IBD therapies.
Harvesting physical predictions from asymptotically safe quantum field theories
Authors: Saueressig Frank , Silva Agustín
Published: October 2024

Asymptotic safety is a powerful mechanism for obtaining a consistent and predictive quantum field theory beyond the realm of perturbation theory. It hinges on an interacting fixed point of the Wilsonian renormalization group flow which controls the microscopic dynamics. Connecting the fixed point to observations requires constructing the set of effective actions compatible with this microscopic dynamics. Technically, this information is stored in the UV-critical surface of the fixed point. In this work, we describe a novel approach for extracting this information based on analytical and pseudospectral methods. Our construction is illustrated at the level of the three-dimensional Ising model and easily generalizes to any asymptotically safe quantum field theory. It also constitutes an important step toward setting up a well-founded swampland program within the gravitational asymptotic safety program.

Published by the American Physical Society
2024
Dark Photon Limits from Patchy Dark Screening of the Cosmic Microwave Background
Authors: McCarthy Fiona , Pîrvu Dalila , Hill J. Colin , Huang Junwu , Johnson Matthew C. , Rogers Keir K.
Published: October 2024

Dark photons that kinetically mix with the Standard Model photon give rise to new spectral anisotropies (patchy dark screening) in the cosmic microwave background (CMB) due to conversion of photons to dark photons within large-scale structure. We utilize predictions for this patchy dark screening signal to provide the tightest constraints to date on the dark photon kinetic mixing parameter [ϵ≲4.5×10−8 (95% confidence level)] over the mass range 10−13  eV≲mA′≲10−11  eV, almost an order of magnitude stronger than previous limits, by applying state-of-the-art component separation techniques to the cross-correlation of CMB and unWISE galaxy survey data.

Published by the American Physical Society
2024
Look busy do nothing: does professional isolation and psychological strain of overqualified employee leads to goldbricking behaviour?
Authors: Khan Jawad , Zhang Qingyu , Salameh Anas A.
Published: October 2024

Purpose

Drawing on person-job fit theory, this study examined the link between perceived overqualification (POQ), professional isolation, psychological strain and goldbricking behaviour. We also investigated the moderating influence of employee career self-management on the association between the POQ and professional isolation.

Design/methodology/approach

A time-lagged data approach were used to collect data from service sector organisations. The study model was analysed using PLS-SEM.

Findings

The results show that POQ is positively related to goldbricking behaviour. Professional isolation and psychological strain mediate the link between POQ and employee goldbricking behaviour. The mediated relationship between POQ and goldbricking behaviour through professional isolation was moderated by employee career self-management.

Originality/value

This research contributes to the existing literature by examining the novel concept of goldbricking behaviour in the context of person-job fit theory. The originality of this study lies in its nuanced investigation of the mediating role of professional isolation and psychological strain in the relationship between POQ and goldbricking behaviour. Additionally, this study adds value by examining the moderating influence of employee career self-management, offering practical insights for organisations.
A high-fidelity personalised 3d printed simulator for the left atrial appendage occlusion procedure
Authors: Fanni Benigno Marco , Gasparotti Emanuele , Esposito Augusto , Danielli Francesca , Berti Francesca , Berti Sergio , Pennati Giancarlo , Petrini Lorenza , Celi Simona
Published: October 2024

Purpose

This study aims to develop a realistic 3D printing-based simulator for the training and planning of the left atrial appendage occlusion (LAAO) to be used in the cath lab.

Design/methodology/approach

Starting from a pre-operative computed tomography dataset of a patient already treated with LAAO, the model was obtained, consisting in the right and left heart, opportunely assembled to replicate the position and orientation of the patient's anatomy while lying on the cath lab table. Different 3D printing techniques and materials were used to mimic the interaction between the cardiac tissue and the clinical instrumentation. The simulator was tested in the cath lab under proper image guidance by three LAAO expert operators. The clinicians were required to assign a score in terms of realism to each material used to fabricate the fossa ovalis and the LAA.

Findings

The simulated interventions were successfully performed by the operators, who were able to navigate in the system and release the occluder device as during a real procedure. The intraoperative images acquired during the simulations were highly comparable with data from a real intervention, with a mean percentage difference below 10%.

Originality/value

This study demonstrated the feasibility of the proposed simulator to faithfully replicate the LAAO procedure and its potentiality to be used for multiple purposes, including the training of the young clinicians, the evaluation of the most complicated cases and the design of novel occluder devices, in a fully realistic setting.
Clinical and genetic insights into ABCA12 variants in three Chinese families with ichthyosis: Genotype–phenotype correlation
Authors: Wang Bing , Yang Jinxiang , Wang Yumeng , Liang Fuh‐Miin , Yao Zhirong , Chen Jiawen , Liang Jianying
Published: October 2024

Autosomal recessive congenital ichthyosis (ARCI) comprises a series of non‐syndromic ichthyoses. Pathogenic variants in several genes associated with ARCI have so far been identified. Notably, the variants in ABCA12 play a pivotal role in the pathology of ARCI. In this study, we report three Chinese families with compound heterozygous variants in the ABCA12 gene, including two novel variants and four reported variants. Clinical and genetic analyses were conducted to explore the genotype–phenotype correlation among the patients. Immunohistochemistry and transcriptome sequencing were utilized to assess the impact of pathogenic ABCA12 variants on skin homeostasis, revealing decreased levels of ABCA12 and claudin‐1, alongside increased levels of involucrin and S100A8. In conclusion, our findings contribute to updating the genotype–phenotypic correlation and provide additional evidence for the long‐term use of retinoic acid drugs in patients with causative ABCA12 variants.
Macroeconomic adjustments to Russia–Ukraine war‐induced energy prices shocks in sub‐Saharan Africa: Effects based on countries' resource status
Authors: Taiwo Shakirudeen , Uwilingiye Josine , Osei‐Assibey Kwame
Published: October 2024

The Russia–Ukraine crisis has significantly disrupted global supply chains, leading to sharp oil and natural gas price increases. These energy price surges have impacted productivity in sub‐Saharan Africa (SSA), with potential long‐term effects on purchasing power and economic growth. Additionally, the crisis has highlighted varying impacts of commodity price shocks across the region due to country‐specific conditions, which prompted this study to examine how energy price shocks influence macroeconomic performance in SSA based on countries' resource status. This study utilised a quarterly dataset of macroeconomic variables—real gross domestic product (GDP) (rGDP), inflation and exchange rates—across 21 SSA countries, along with crude oil and natural gas prices. The Bootstrap Granger Causality test confirmed a long‐run relationship between energy prices and these macroeconomic variables. Furthermore, the Panel Structural Vector Autoregressive model demonstrated varying spillover effects based on countries' resource status. The results indicate that resource status significantly affects the magnitude and nature of energy price shocks on macroeconomic variables. Specifically, oil‐rich nations experience the most intense effects, followed by other resource‐endowed countries. These findings offer a nuanced understanding of the complex dynamics triggered by the Russia–Ukraine crisis in the SSA region, highlighting the critical role of resource endowment in shaping economic resilience.
Persistent low inequality despite compositional shifts in Austria
Authors: Halla Martin , Weber Andrea
Published: October 2024

Overall, income inequality in Austria is moderate and has been stable in recent years. However, a look at employment statistics reveals important inequality trends in the labour market. This paper highlights five important shifts in the composition of the labour force: (i) a massive increase in female labour force participation; (ii) large shifts in the distribution of education; (iii) trends towards part‐time work among women as well as men; (iv) persistent gender gaps in market and non‐market work of parents; and (v) an increase in labour migration with a substantial share of cross‐border commuters.
Equally poorer: inequality and the Greek debt crisis
Authors: Danchev Svetoslav , Gatopoulos Georgios , Kalavrezou Niki , Mavropoulos Antonis , Pavlou Grigoris , Vettas Nikolaos
Published: October 2024

In this paper, we discuss the evolution of inequality in Greece from 2004 to 2021 in light of the Greek debt crisis that led to a sharp drop in gross domestic product per capita between 2008 and 2013. While aggregate measures of income inequality, such as the Gini coefficient, suggest a marginal improvement, domestic perceptions of social fairness remain bleak. To delve deeper into this paradox, we explore additional aggregate and distributional aspects of Greece's social landscape during this period. Our analysis reveals several contributing factors: a compression of earnings, benefits and pensions; a sharp increase in social exclusion; and high inequality in access to basic public services and housing. These factors go beyond what headline inequality indices indicate, illustrating how the sovereign debt crisis and subsequent austerity measures have affected individuals differently based on their socio‐economic background, while also reducing overall welfare across the Greek population. Moreover, chronic institutional inefficiencies and widening disparities in access to services and housing significantly influence perceptions of inequality and contribute negatively to the country's social cohesion.
Inequality trends in a slow‐growing economy: Italy, 1990–2020
Authors: Checchi Daniele , Jappelli Tullio , Marino Immacolata , Scognamiglio Annalisa
Published: October 2024

This paper presents stylised facts on the labour supply and income inequality of individuals aged 25–55, drawn from the 1989–2020 Bank of Italy Survey of Household Income and Wealth. Over the sample period, earnings inequality has increased considerably although the gap is smaller when considered in terms of household disposable income. We investigate the possible drivers of this increase using administrative data on employees. The evidence suggests that labour market reforms implemented since the start of the 1990s are the most plausible explanation for this growth in earnings inequality. Comparison between earnings and disposable income suggests that both government and households are important for reducing inequalities.
Storytelling and good relations: Indigenous youth capabilities in climate futures
Authors: McMeeking S. , Tetini‐Timoteo M. , Hayward B. , Prendergast K. , Ratuva S. , Crichton‐Hill Y. , Mayall‐Nahi M. , Wood B. , Tolbert S. , Harré N. , Macfarlane A.
Published: October 2024

How can we support young citizens facing chaotic climate futures? This question is urgent, particularly for Indigenous communities who face disproportionate risks and impacts of climate change. For the past three decades, climate‐related education has focused largely on the acquisition of scientific knowledge in instrumental ways, while encouraging individual behaviour change. This approach centres the problem rather than human capabilities to generate solutions, which is especially misaligned with the increasing practice and significance of Indigenous communities’ regenerating self‐determining capabilities. This article reports on a pilot study that uses intergenerational storytelling methods or pūrākau to support leadership capabilities among Indigenous Māori and Pacific young people aged 10 to 14 years in communities at high risk of flooding in Ōtautahi/Christchurch, Aotearoa/New Zealand. The study showed how storytelling locates and scaffolds Indigenous young people into positions of individual and collective responsibility for grappling with “wicked problems” such as climate and injustice and climate‐related challenges as part of the future they will inherit and shape within a broader intergenerational journey of resilience and reclamation.
Pro‐inflammatory cytokine 11 plays a pivotal role in inflammaging‐associated pathologies
Authors: Izquierdo José M.
Published: October 2024

Chronic sterile inflammation contributes to aging‐associated pathologies/malignancies like cancer and autoimmune disorders. In their recent Nature article, Widjaja et al. established the pro‐inflammatory, pro‐fibrotic cytokine 11 (IL11) as a regulatory driver/hub of aging‐associated inflammation (inflammaging) in mice. Genetic and pharmacological IL11 blockade reduces inflammaging, improving healthspan, lifespan, and longevity in male and female mice, highlighting IL11 as a new inflammatory aging clock and a potential molecular target in inflammaging‐associated human degenerative diseases.
Does digital transformation drive more comment letters?
Authors: Li Hongquan , Yang Yang
Published: October 2024

Corporate digital transformation has a systematic impact on companies, thereby becoming a significant focus for both investors and regulatory authorities. This study focuses on Chinese A‐share listed companies and demonstrates that corporate digital transformation can lead to an increase in comment letters. The research also proves that investor attention toward digital transformation and opportunistic insider sales both play a mediating role in this relationship. Additionally, the study reveals that this impact is weaker in companies with higher levels of internal control and corporate social responsibility. The findings have significant implications for corporate governance and regulatory oversight.