Long-term relatively high dietary manganese intake could decrease the risk of hyperuricemia: Twelve-year distinct dietary manganese consumption trajectories and the China Health and Nutrition Survey.

BACKGROUND AND AIM: Currently, the relationship between dynamic changes in dietary manganese (Mn) intake and risk of hyperuricemia (HU) is still unclear. This study aimed to identify dietary Mn consumption trajectories in the Chinese adults and assess their relation with the risk of HU. METHODS AND RESULTS: Cohort data from the China Health and Nutrition Survey (CHNS) 1997-2009 were employed in this study. Overall, 6886 adult participants were included. Participants were designated into subgroups based on the trajectories of dietary Mn consumption by sex. Cox proportional hazard models were used to explore the associations between different trajectories and the risk of HU. For men, compared with low stable trajectory group, moderate to high trajectory group was significantly related to reduced risk of HU (HR = 0.61, 95% CI: 0.38 to 0.98) with adjustment for covariates. TC, HDL-C, ApoB, and TG exerted partial regulation function between trajectories and HU. For women, compared with low stable trajectory group, high stable trajectory group was significantly related to reduced risk of HU (HR = 0.76, 95% CI: 0.60 to 0.95) with adjustment for covariates. Similarly, TC, HDL-C, ApoB, and ApoA exerted partial regulation function between trajectories and HU. CONCLUSIONS: Long-term relatively high dietary Mn consumption may have a protective effect against HU in Chinese adults. The differences in HU-related factors among different dietary Mn intake trajectories partially regulated the association between these trajectories and HU.

The Effects of Four Different Thawing Methods on Quality Indicators of Amphioctopus neglectus.

Amphioctopus neglectus is a species of octopus that is favored by consumers due to its rich nutrient profile. To investigate the influence of different thawing methods on the quality of octopus meat, we employed four distinct thawing methods: air thawing (AT), hydrostatic thawing (HT), flowing water thawing (FWT), and microwave thawing (MT). We then explored the differences in texture, color, water retention, pH, total volatile basic nitrogen (TVB-N), total sulfhydryl content, Ca2+-ATPase activity, and myofibrillar protein, among other quality indicators in response to these methods, and used a low-field nuclear magnetic resonance analyzer to assess the water migration that occurred during the thawing process. The results revealed that AT had the longest thawing time, leading to oxidation-induced protein denaturation, myofibrillar protein damage, and a significant decrease in water retention. Additionally, when this method was utilized, the content of TVB-N was significantly higher than in the other three groups. HT, to a certain extent, isolated the oxygen in the meat and thus alleviated protein oxidation, allowing higher levels of Ca2+-ATPase activity, sulfhydryl content, and springiness to be maintained. However, HT had a longer duration: 2.95 times that of FWT, resulting in a 9.84% higher cooking loss and a 28.21% higher TVB-N content compared to FWT. MT had the shortest thawing time, yielding the lowest content of TVB-N. However, uneven heating and in some cases overcooking occurred, severely damaging the protein structure, with a concurrent increase in thawing loss, W value, hardness, and shear force. Meanwhile, FWT improved the L*, W* and b* values of octopus meat, enhancing its color and water retention. The myofibrillar protein (MP) concentration was also the highest after FWT, with clearer subunit bands in SDS-PAGE electrophoresis, indicating that less degradation occurred and allowing greater springiness, increased Ca2+-ATPase activity, and a higher sulfhydryl content to be maintained. This suggests that FWT has an inhibitory effect on oxidation, alleviating protein oxidation degradation and preserving the quality of the meat. In conclusion, FWT outperformed the other three thawing methods, effectively minimizing adverse changes during thawing and successfully maintaining the quality of octopus meat.

Deconvolution of the Voltammetric Features of a Pt(100) Single-Crystal Electrode.

The Pt(100) single-crystal electrode shows four voltammetric features in acid electrolytes, but the precise corresponding surface phenomena remain unresolved. Herein, a deconvolution of the classical "hydrogen region" from the "hydroxyl and anion region" is attempted by the comparison of voltammetric behavior of Pt(100) and GMLPt(100) electrodes. A systematic study performed on Pt(s)-[n(100) × (111)] and Pt(s)-[n(100) × (110)] electrodes reveals that the feature at EPI = 0.30 VRHE corresponds to pure hydrogen adsorption taking place at (111) step sites vicinal to (100) domains, while the peak at EPII = 0.36 VRHE actually involves hydroxyl replacing hydrogen at (100) domains. An analysis examined for H2SO4, HClO4, CH3SO3H, and HF demonstrates that the specific (H)SO4- adsorption commences at EPIII = 0.40 VRHE and effectively suppresses the formation of hydroxyl at the (100) terrace at higher potentials 0.40 < EPIV < 0.75 VRHE. Non-specifically adsorbing anions (ClO4-, CH3SO3- and F-) would only interact with the hydroxyl phase formed on the Pt(100) terrace in both potential regions.

Shared and distinct interactions of type 1 and type 2 Epstein-Barr Nuclear Antigen 2 with the human genome.

BACKGROUND: There are two major genetic types of Epstein-Barr Virus (EBV): type 1 (EBV-1) and type 2 (EBV-2). EBV functions by manipulating gene expression in host B cells, using virus-encoded gene regulatory proteins including Epstein-Barr Nuclear Antigen 2 (EBNA2). While type 1 EBNA2 is known to interact with human transcription factors (hTFs) such as RBPJ, EBF1, and SPI1 (PU.1), type 2 EBNA2 shares only ~ 50% amino acid identity with type 1 and thus may have distinct binding partners, human genome binding locations, and functions. RESULTS: In this study, we examined genome-wide EBNA2 binding in EBV-1 and EBV-2 transformed human B cells to identify shared and unique EBNA2 interactions with the human genome, revealing thousands of type-specific EBNA2 ChIP-seq peaks. Computational predictions based on hTF motifs and subsequent ChIP-seq experiments revealed that both type 1 and 2 EBNA2 co-occupy the genome with SPI1 and AP-1 (BATF and JUNB) hTFs. However, type 1 EBNA2 showed preferential co-occupancy with EBF1, and type 2 EBNA2 preferred RBPJ. These differences in hTF co-occupancy revealed possible mechanisms underlying type-specific gene expression of known EBNA2 human target genes: MYC (shared), CXCR7 (type 1 specific), and CD21 (type 2 specific). Both type 1 and 2 EBNA2 binding events were enriched at systemic lupus erythematosus (SLE) and multiple sclerosis (MS) risk loci, while primary biliary cholangitis (PBC) risk loci were specifically enriched for type 2 peaks. CONCLUSIONS: This study reveals extensive type-specific EBNA2 interactions with the human genome, possible differences in EBNA2 interaction partners, and a possible new role for type 2 EBNA2 in autoimmune disorders. Our results highlight the importance of considering EBV type in the control of human gene expression and disease-related investigations.

Non-coding autoimmune risk variant defines role for ICOS in T peripheral helper cell development.

Fine-mapping and functional studies implicate rs117701653, a non-coding single nucleotide polymorphism in the CD28/CTLA4/ICOS locus, as a risk variant for rheumatoid arthritis and type 1 diabetes. Here, using DNA pulldown, mass spectrometry, genome editing and eQTL analysis, we establish that the disease-associated risk allele is functional, reducing affinity for the inhibitory chromosomal regulator SMCHD1 to enhance expression of inducible T-cell costimulator (ICOS) in memory CD4+ T cells from healthy donors. Higher ICOS expression is paralleled by an increase in circulating T peripheral helper (Tph) cells and, in rheumatoid arthritis patients, of blood and joint fluid Tph cells as well as circulating plasmablasts. Correspondingly, ICOS ligation and carriage of the rs117701653 risk allele accelerate T cell differentiation into CXCR5-PD-1high Tph cells producing IL-21 and CXCL13. Thus, mechanistic dissection of a functional non-coding variant in human autoimmunity discloses a previously undefined pathway through which ICOS regulates Tph development and abundance.

Jian-Pi-Gu-Shen-Hua-Yu Decoction Alleviated Diabetic Nephropathy in Mice through Reducing Ferroptosis.

Background: Diabetic nephropathy (DN), one of the most frequent complications of diabetes mellitus, is a leading cause of end-stage renal disease. However, the current treatment methods still cannot effectively halt the progression of DN. Jian-Pi-Gu-Shen-Hua-Yu (JPGS) decoction can be used for the treatment of chronic kidney diseases such as DN, but the specific mechanism of action has not been fully elucidated yet. Purpose: The aim of this study is to clarify whether JPGS alleviates the progression of diabetic nephropathy by inhibiting ferroptosis. Materials and Methods: We established a DN mouse model to investigate the therapeutic effect of JPGS in a DN mouse model. Subsequently, we examined the effects of JPGS on ferroptosis- and glutathione peroxidase 4 (GPX4) pathway-related indices. Finally, we validated whether JPGS inhibited ferroptosis in DN mice via the GPX4 pathway using GPX4 inhibitor and ferroptosis inhibitors. Results: The results indicate that JPGS has a therapeutic effect on DN mice by improving kidney function and reducing inflammation. Additionally, JPGS treatment decreased iron overload and oxidative stress levels while upregulating the expression of GPX4 pathway-related proteins. Moreover, JPGS demonstrated a similar therapeutic effect as Fer-1 in the context of DN treatment, and RSL3 was able to counteract the therapeutic effect of JPGS and antiferroptotic effect. Conclusion: JPGS has significant therapeutic and anti-inflammatory effects on DN mice, and its mechanism is mainly achieved by upregulating the expression of GPX4 pathway-related proteins, thereby alleviating iron overload and ultimately reducing ferroptosis.

Was antiviral prophylaxis necessary after kidney transplantation utilizing HBcAb+ donors? A systematic review and meta-analysis.

BACKGROUND: Current guidelines lack consensus on whether antiviral prophylaxes should be administered after kidney transplantation from HBcAb+ donors. This systematic review and meta-analysis aimed to evaluate the incidence and risk factors of de novo HBV (DNH) infection, as well as graft and patient survival. METHODS: We searched PubMed, Embase, and the Cochrane Library up to December 31, 2023. We included relevant studies that assessed clinical outcomes following transplantation utilizing HBcAb+ kidneys. Summary measures of effect and 95% confidence intervals (CI) for prevalence, risk factors, as well as graft and patient survival were estimated using random-effects meta-analysis. RESULTS: Thirteen studies were included for the final analysis. The DNH incidence was at 0.36% (9/2516) with low heterogeneity (I2 = 6%). HBsAb+ recipients (OR: 0.78, 95%CI: 0.25-2.38), HBcAb+ recipients (OR: 3.11, 95%CI: 0.91-10.66, P = 0.071), and recipients not receiving any antiviral prophylaxis (OR: 1.26, 95%CI: 0.15-10.58) were not associated with higher DNH risk. Specifically, HBsAb-/HBcAb+ recipients had the highest DNH incidence (4.65%), followed by HBsAb-/HBcAb- (0.49%), HBsAb+/HBcAb- recipients (0.45%), and HBsAb+/HBcAb+ (0%). Furthermore, recipients receiving HBcAb+ kidneys had comparable graft survival (HR: 1.06, 95%CI: 0.94-1.19, P = 0.55) and patient survival (HR:1.16, 95%CI: 0.98-1.38, P = 0.090) compared with recipients receiving HBcAb- kidneys. CONCLUSION: Kidney transplantation utilizing HBcAb+ kidneys contributed to comparable graft and patient survival with an extremely low risk of HBV transmission. Antiviral prophylaxes may only be administered in HBsAb-/HBcAb+ recipients.

Cation Effects on Hydrogen Oxidation Reaction on Pt Single-Crystal Electrodes in Alkaline Media.

The exact mechanism behind the cation-assisted hydrogen oxidation reaction (HOR) on platinum electrodes in alkaline media remains disputed. We show that the cation effects at platinum display a remarkable structure sensitivity: not only the H adsorption but also the HOR activity on (111) terrace sites are independent of the nature of cation and cation concentration. On (110) step sites, at low cation concentration and mildly alkaline media, cations promote the HOR, whereas at more alkaline pH and consequently higher near-surface cation concentrations, the HOR is inhibition by the cations. Moreover, the role of the cation on terrace-OHad is different from that on step-OHad, as can also be observed from the inhibition of the HOR current by terrace-OHad at higher potentials. These results suggest that near the onset potential, HOR mainly takes place on steps, but under diffusion-limited conditions at higher overpotential, HOR mainly takes place on terraces.

COPD Assessment Test and risk of readmission in patients with bronchiectasis: a prospective cohort study.

Introduction: Readmission following bronchiectasis exacerbation is a common and challenging clinical problem and few simple predictive tools exist. The COPD Assessment Test (CAT) is an easy-to-use questionnaire. This study aims to evaluate the predictive value of CAT scores in determining the risk of readmission in patients with bronchiectasis exacerbation. Methods: We conducted a prospective cohort study in 106 bronchiectasis patients admitted with exacerbation. All patients completed the CAT at admission and at discharge. Patients were followed-up for 12 months to collect data on readmission. The area under the curve was used to measure the predictive value of CAT at admission, CAT at discharge and change in CAT for readmission due to bronchiectasis exacerbation. Results: 46 patients were readmitted for bronchiectasis exacerbation within 12 months. High CAT at admission was an independent risk factor for readmission within 12 months in patients with acute exacerbation of bronchiectasis (hazard ratio 3.201, 95% CI 1.065-9.624; p<0.038) after adjustment for confounding variables. The cut-off value of CAT at admission and CAT at discharge to predict 12-month readmission in patients with acute exacerbation of bronchiectasis was 23.5 (sensitivity 62.2%, specificity 83.6%) and 15.5 (sensitivity 52.2%, specificity 87.0%). Conclusions: CAT at admission is a strong predictor of readmission in patients with bronchiectasis exacerbation.

Multi-Functional Integration of Phosphor, Initiator, and Crosslinker for the Photo-Polymerization of Flexible Phosphorescent Polymer Gels.

A general approach to constructing room temperature phosphorescence (RTP) materials involves the incorporation of a phosphorescent emitter into a rigid host or polymers with high glass transition temperature. However, these materials often suffer from poor processability and suboptimal mechanical properties, limiting their practical applications. In this work, we developed benzothiadiazole-based dialkene (BTD-HEA), a multifunctional phosphorescent emitter with a remarkable yield of intersystem crossing (ΦISC, 99.83 %). Its high triplet exciton generation ability and dialkene structure enable BTD-HEA to act as a photoinitiator and crosslinker, efficiently initiating the polymerization of various monomers within 120 seconds. A range of flexible phosphorescence gels, including hydrogels, organogels, ionogels, and aerogels were fabricated, which exhibit outstanding stretchability and recoverability. Furthermore, the unique fluorescent-phosphorescent colorimetric properties of the gels provide a more sensitive method for the visual determination of the polymerization process. Notably, the phosphorescent emission intensity of the hydrogel can be increased by the formation of ice, allowing for the precise detection of hydrogel freezing. The versatility of this emitter paves the way for fabricating various flexible phosphorescence gels with diverse morphologies using microfluidics, film-shearing, roll coating process, and two/three-dimensional printing, showcasing its potential applications in the fields of bioimaging and bioengineering.

Accessible chromatin maps of inflammatory bowel disease intestine nominate cell-type mediators of genetic disease risk.

Inflammatory Bowel Disease ( IBD ) is a chronic and often debilitating autoinflammatory condition, with an increasing incidence in children. Standard-of-care therapies lead to sustained transmural healing and clinical remission in fewer than one-third of patients. For children, TNFα inhibition remains the only FDA-approved biologic therapy, providing an even greater urgency to understanding mechanisms of response. Genome-wide association studies ( GWAS ) have identified 418 independent genetic risk loci contributing to IBD, yet the majority are noncoding and their mechanisms of action are difficult to decipher. If causal, they likely alter transcription factor ( TF ) binding and downstream gene expression in particular cell types and contexts. To bridge this knowledge gap, we built a novel resource: multiome-seq (tandem single-nuclei ( sn )RNA-seq and chromatin accessibility ( snATAC )-seq) of intestinal tissue from pediatric IBD patients, where anti-TNF response was defined by endoscopic healing. From the snATAC-seq data, we generated a first-time atlas of chromatin accessibility (putative regulatory elements) for diverse intestinal cell types in the context of IBD. For cell types/contexts mediating genetic risk, we reasoned that accessible chromatin will co-localize with genetic disease risk loci. We systematically tested for significant co-localization of our chromatin accessibility maps and risk variants for 758 GWAS traits. Globally, genetic risk variants for IBD, autoimmune and inflammatory diseases are enriched in accessible chromatin of immune populations, while other traits (e.g., colorectal cancer, metabolic) are enriched in epithelial and stromal populations. This resource opens new avenues to uncover the complex molecular and cellular mechanisms mediating genetic disease risk.

Ultrasound-activated piezo-hot carriers trigger tandem catalysis coordinating cuproptosis-like bacterial death against implant infections.

Implant-associated infections due to the formation of bacterial biofilms pose a serious threat in medical healthcare, which needs effective therapeutic methods. Here, we propose a multifunctional nanoreactor by spatiotemporal ultrasound-driven tandem catalysis to amplify the efficacy of sonodynamic and chemodynamic therapy. By combining piezoelectric barium titanate with polydopamine and copper, the ultrasound-activated piezo-hot carriers transfer easily to copper by polydopamine. It boosts reactive oxygen species production by piezoelectrics, and facilitates the interconversion between Cu2+ and Cu+ to promote hydroxyl radical generation via Cu+ -catalyzed chemodynamic reactions. Finally, the elevated reactive oxygen species cause bacterial membrane structure loosening and DNA damage. Transcriptomics and metabolomics analysis reveal that intracellular copper overload restricts the tricarboxylic acid cycle, promoting bacterial cuproptosis-like death. Therefore, the polyetherketoneketone scaffold engineered with the designed nanoreactor shows excellent antibacterial performance with ultrasound stimulation and promotes angiogenesis and osteogenesis on-demand in vivo.

Targeted Affinity Purification and Mechanism of Action of Angiotensin-Converting Enzyme (ACE) Inhibitory Peptides from Sea Cucumber Gonads.

Protein hydrolysates from sea cucumber (Apostichopus japonicus) gonads are rich in active materials with remarkable angiotensin-converting enzyme (ACE) inhibitory activity. Alcalase was used to hydrolyze sea cucumber gonads, and the hydrolysate was separated by the ultrafiltration membrane to produce a low-molecular-weight peptide component (less than 3 kDa) with good ACE inhibitory activity. The peptide component (less than 3 kDa) was isolated and purified using a combination method of ACE gel affinity chromatography and reverse high-performance liquid chromatography. The purified fractions were identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and the resulting products were filtered using structure-based virtual screening (SBVS) to obtain 20 peptides. Of those, three noncompetitive inhibitory peptides (DDQIHIF with an IC50 value of 333.5 µmol·L-1, HDWWKER with an IC50 value of 583.6 µmol·L-1, and THDWWKER with an IC50 value of 1291.8 µmol·L-1) were further investigated based on their favorable pharmacochemical properties and ACE inhibitory activity. Molecular docking studies indicated that the three peptides were entirely enclosed within the ACE protein cavity, improving the overall stability of the complex through interaction forces with the ACE active site. The total free binding energies (ΔGtotal) for DDQIHIF, HDWWKER, and THDWWKER were -21.9 Kcal·mol-1, -71.6 Kcal·mol-1, and -69.1 Kcal·mol-1, respectively. Furthermore, a short-term assay of antihypertensive activity in spontaneously hypertensive rats (SHRs) revealed that HDWWKER could significantly decrease the systolic blood pressure (SBP) of SHRs after intravenous administration. The results showed that based on the better antihypertensive activity of the peptide in SHRs, the feasibility of targeted affinity purification and computer-aided drug discovery (CADD) for the efficient screening and preparation of ACE inhibitory peptide was verified, which provided a new idea of modern drug development method for clinical use.

Broad de-regulated U2AF1 splicing is prognostic and augments leukemic transformation via protein arginine methyltransferase activation.

The role of splicing dysregulation in cancer is underscored by splicing factor mutations; however, its impact in the absence of such rare mutations is poorly understood. To reveal complex patient subtypes and putative regulators of pathogenic splicing in Acute Myeloid Leukemia (AML), we developed a new approach called OncoSplice. Among diverse new subtypes, OncoSplice identified a biphasic poor prognosis signature that partially phenocopies U2AF1-mutant splicing, impacting thousands of genes in over 40% of adult and pediatric AML cases. U2AF1-like splicing co-opted a healthy circadian splicing program, was stable over time and induced a leukemia stem cell (LSC) program. Pharmacological inhibition of the implicated U2AF1-like splicing regulator, PRMT5, rescued leukemia mis-splicing and inhibited leukemic cell growth. Genetic deletion of IRAK4, a common target of U2AF1-like and PRMT5 treated cells, blocked leukemia development in xenograft models and induced differentiation. These analyses reveal a new prognostic alternative-splicing mechanism in malignancy, independent of splicing-factor mutations.

Site-specific reactivity of stepped Pt surfaces driven by stress release.

Heterogeneous catalysts are widely used to promote chemical reactions. Although it is known that chemical reactions usually happen on catalyst surfaces, only specific surface sites have high catalytic activity. Thus, identifying active sites and maximizing their presence lies at the heart of catalysis research1-4, in which the classic model is to categorize active sites in terms of distinct surface motifs, such as terraces and steps1,5-10. However, such a simple categorization often leads to orders of magnitude errors in catalyst activity predictions and qualitative uncertainties of active sites7,8,11,12, thus limiting opportunities for catalyst design. Here, using stepped Pt(111) surfaces and the electrochemical oxygen reduction reaction (ORR) as examples, we demonstrate that the root cause of larger errors and uncertainties is a simplified categorization that overlooks atomic site-specific reactivity driven by surface stress release. Specifically, surface stress release at steps introduces inhomogeneous strain fields, with up to 5.5% compression, leading to distinct electronic structures and reactivity for terrace atoms with identical local coordination, and resulting in atomic site-specific enhancement of ORR activity. For the terrace atoms flanking both sides of the step edge, the enhancement is up to 50 times higher than that of the atoms in the middle of the terrace, which permits control of ORR reactivity by either varying terrace widths or controlling external stress. Thus, the discovery of the above synergy provides a new perspective for both fundamental understanding of catalytically active atomic sites and design principles of heterogeneous catalysts.

Bioinformatic analysis reveals prognostic value and immunotherapy potential of Siglec-15 in laryngeal squamous cell carcinoma.

Background: Laryngeal squamous cell carcinoma (LSCC) is the ultimate common malignant head and neck cancer with dismal prognosis. The expression pattern and clinical significance of Siglec-15 (Sialic acid-binding immunoglobulin-like lectin 15) in LSCC are poorly understood. In order to lay the groundwork for future immune-related research on Siglec-15 in LSCC, we set out to study its expression and prognostic importance in the disease, as well as to use bioinformatics to investigate the immune features modulated by Siglec-15 in LSCC. Methods: ① In order to get the gene expression profile and clinical data for TCGA head and neck cancer (TCGA-HNSC), you may access the relevant data from UCSC xena and use 110 cases of laryngeal cancer as a training set. Two datasets, GSE27020 and GSE25727, were obtained from the GEO databank and utilized as validation sets. These datasets include expression profiles and clinical information. The Siglec-15 gene and immune characteristics were analyzed by bioinformatics methods. ② Retrospectively collected routine paraffin specimens from patients with pathological diagnosis of squamous cell carcinoma from December 2012 to November 2015 in Sun Yat-sen Memorial Hospital and fresh frozen tissue of patients from June 2021 to March 2022. Immunohistochemistry method, immunofluorescence technique and real-time quantitative PCR was used to examine the difference of Siglec-15 appearance in LSCC tissue and adjacent tissue, and its correlation of prognosis, clinic pathological characteristics and CD8+T lymphocyte infiltration. Using human laryngeal cancer cell line (LCC), we studied the influence of Siglec-15 in cell proliferation and invasion. Results: We identified Siglec-15 was upregulated in LSCC. The patients in Siglec-15 high expression group had a poor overall survival (OS) based on the clinical information from TGCA and 111 LSCC patients that hospitalized in Sun Yat-sen Memorial Hospital. The COX regression analysis indicated Siglec-15 as an independent predictor for poor prognosis of LSCC. Bioinformatic analysis suggested that the high expression of Siglec-15 shape an immune suppressive tumor microenvironment (TEM), leading to poor response to immunotherapy in LSCC. Siglec-15 enhanced cell invasion and proliferation, as we showed in vitro. Conclusion: Our study support Siglec-15 as a potential predictor for LSCC prognosis and an attractive target for LSCC immunotherapy.

Systematic identification of genotype-dependent enhancer variants in eosinophilic esophagitis.

Eosinophilic esophagitis (EoE) is a rare atopic disorder associated with esophageal dysfunction, including difficulty swallowing, food impaction, and inflammation, that develops in a small subset of people with food allergies. Genome-wide association studies (GWASs) have identified 9 independent EoE risk loci reaching genome-wide significance (p < 5 × 10-8) and 27 additional loci of suggestive significance (5 × 10-8 < p < 1 × 10-5). In the current study, we perform linkage disequilibrium (LD) expansion of these loci to nominate a set of 531 variants that are potentially causal. To systematically interrogate the gene regulatory activity of these variants, we designed a massively parallel reporter assay (MPRA) containing the alleles of each variant within their genomic sequence context cloned into a GFP reporter library. Analysis of reporter gene expression in TE-7, HaCaT, and Jurkat cells revealed cell-type-specific gene regulation. We identify 32 allelic enhancer variants, representing 6 genome-wide significant EoE loci and 7 suggestive EoE loci, that regulate reporter gene expression in a genotype-dependent manner in at least one cellular context. By annotating these variants with expression quantitative trait loci (eQTL) and chromatin looping data in related tissues and cell types, we identify putative target genes affected by genetic variation in individuals with EoE. Transcription factor enrichment analyses reveal possible roles for cell-type-specific regulators, including GATA3. Our approach reduces the large set of EoE-associated variants to a set of 32 with allelic regulatory activity, providing functional insights into the effects of genetic variation in this disease.

The clinical characteristics of non-cystic fibrosis bronchiectasis patients with positive serum tumor markers: a retrospective study.

BACKGROUND: Serum tumor markers (STM), extensively used for the diagnosis, monitoring and prognostic assessment of tumors, can be increased in some non-malignant lung diseases. To date, there is a paucity of studies regarding the clinical characteristics of non-cystic fibrosis bronchiectasis patients with positive STMs. OBJECTIVE: To investigate the clinical characteristics and indicators of bronchiectasis with positive STMs. METHODS: The clinical data of 377 bronchiectasis patients was retrospectively collected from January 2017 to December 2019 from Beijing Chaoyang Hospital. Patients were divided into the STM negative group, the single STM positive group and the ≥2 STMs positive group according to the number of the positive STMs. The clinical characteristics are described and compared separately. The multivariate logistic regression analysis model was used to investigate the indicators regarding positive STMs. RESULTS: Patients in the ≥2 STMs positive group were older (P = 0.015), had higher mMRC scores (P < 0.001) and developed higher fever (P = 0.027). Additionally, these patients also had lower Albumin/Globulin Ratio (A/G), albumin (ALB), prealbumin (PAB) (P < 0.001, P < 0.001, P < 0.001, respectively) and higher CRP, ESR and Fbg (P < 0.001, P < 0.001 and P < 0.001, respectively). Age (OR 1.022, 95%CI 1.003-1.042; P = 0.026) and the number of affected lobes (OR 1.443, 95%CI 1.233-1.690; P < 0.001) were independently associated with one and ≥ 2 positive STMs in bronchiectasis patients. CONCLUSION: The ≥2 positive STMs are associated with a higher inflammation status and severer radiologic manifestations in bronchiectasis patients.

Omega-3 polyunsaturated fatty acids protect peritoneal mesothelial cells from hyperglycolysis and mesothelial-mesenchymal transition through the FFAR4/CaMKKß/AMPK/mTOR signaling pathway.

Peritoneal fibrosis is a severe clinical complication associated with peritoneal dialysis (PD) and impacts its efficacy and patient outcomes. The process of mesothelial-mesenchymal transition (MMT) in peritoneal mesothelial cells plays a pivotal role in fibrogenesis, whereas metabolic reprogramming, characterized by excessive glycolysis, is essential in MMT development. No reliable therapies are available despite substantial progress made in understanding the mechanisms underlying peritoneal fibrosis. Protective effect of omega-3 polyunsaturated fatty acids (ω3 PUFAs) has been described in PD-induced peritoneal fibrosis, although the detailed mechanisms remain unknown. It is known that ω3 PUFAs bind to and activate the free fatty acid receptor 4 (FFAR4). However, the expression and role of FFAR4 in the peritoneum have not been investigated. Thus, we hypothesized that ω3 PUFAs would alleviate peritoneal fibrosis by inhibiting hyperglycolysis and MMT through FFAR4 activation. First, we determined FFAR4 expression in peritoneal mesothelium in humans and mice. FFAR4 expression was abnormally decreased in patients on PD and mice and HMrSV5 mesothelial cells exposed to PD fluid (PDF); this change was restored by the ω3 PUFAs (EPA and DHA). ω3 PUFAs significantly inhibited peritoneal hyperglycolysis, MMT, and fibrosis in PDF-treated mice and HMrSV5 mesothelial cells; these changes induced by ω3 PUFAs were blunted by treatment with the FFAR4 antagonist AH7614 and FFAR4 siRNA. Additionally, ω3 PUFAs induced FFAR4, Ca2+/calmodulin-dependent protein kinase kinase ß (CaMKKß), and AMPK and suppressed mTOR, leading to the inhibition of hyperglycolysis, demonstrating that the ω3 PUFAs-mediated FFAR4 activation ameliorated peritoneal fibrosis by inhibiting hyperglycolysis and MMT via CaMKKß/AMPK/mTOR signaling. As natural FFAR4 agonists, ω3 PUFAs may be considered for the treatment of PD-associated peritoneal fibrosis.