Exploring the roles and potential therapeutic strategies of inflammation and metabolism in the pathogenesis of vitiligo: a mendelian randomization and bioinformatics-based investigation.

Introduction: Vitiligo, a common autoimmune acquired pigmentary skin disorder, poses challenges due to its unclear pathogenesis. Evidence suggests inflammation and metabolism's pivotal roles in its onset and progression. This study aims to elucidate the causal relationships between vitiligo and inflammatory proteins, immune cells, and metabolites, exploring bidirectional associations and potential drug targets. Methods: Mendelian Randomization (MR) analysis encompassed 4,907 plasma proteins, 91 inflammatory proteins, 731 immune cell features, and 1400 metabolites. Bioinformatics analysis included Protein-Protein Interaction (PPI) network construction, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Subnetwork discovery and hub protein identification utilized the Molecular Complex Detection (MCODE) plugin. Colocalization analysis and drug target exploration, including molecular docking validation, were performed. Results: MR analysis identified 49 proteins, 39 immune cell features, and 59 metabolites causally related to vitiligo. Bioinformatics analysis revealed significant involvement in PPI, GO enrichment, and KEGG pathways. Subnetwork analysis identified six central proteins, with Interferon Regulatory Factor 3 (IRF3) exhibiting strong colocalization evidence. Molecular docking validated Piceatannol's binding to IRF3, indicating a stable interaction. Conclusion: This study comprehensively elucidates inflammation, immune response, and metabolism's intricate involvement in vitiligo pathogenesis. Identified proteins and pathways offer potential therapeutic targets, with IRF3 emerging as a promising candidate. These findings deepen our understanding of vitiligo's etiology, informing future research and drug development endeavors.

Relationship between bullous pemphigoid and malignancy: A Mendelian randomization study.

Bullous pemphigoid (BP) is the most common autoimmune blistering disease, which primarily affects the elderly. However, the relationship between BP and malignancy remains controversial in traditional observational studies. The aim of this study, which included only European populations, was to assess the potential causative link between BP and 13 types of malignant tumors in a two-sample Mendelian randomization (MR) study. BP was not associated with an increased risk of developing 13 types of malignant tumors. This study did not find a causal relationship between BP and malignant tumors. However, further research is warranted to examine the generalizability of this conclusion in non-European populations.

Hypervalent Fluoro-iodane-Triggered Semipinacol Rearrangements: Synthesis of α-Fluoro Ketones.

Hypervalent fluoro-λ3-iodanes have emerged as versatile reagents that provide unusual fluorination selectivities under mild reaction conditions. Here, we report on adding a semipinacol rearrangement, fluorination, and aryl migration cascade reaction of styrene derivatives. Thus, various cyclopentanones became accessible in up to 96% yield, all bearing tertiary C,F-carbon centers adjacent to the ketone group. Such fluorinated structural motifs are difficult to build with previously established methods. Preliminary experiments on enantioselective processes validated that asymmetric transformations are likewise feasible.

Exosomal lncRNA HOTAIR induces PDL1+ B cells to impede anti-tumor immunity in colorectal cancer.

Regulatory B cells (Bregs) contribute to tumor immunosuppression. However, how B cells acquire their regulatory features in tumors remain unclear. Exosomes are important messengers that transmit tumor information to remodel tumor immunity. Here we revealed that tumor-derived exosomes drive Bregs to suppress anti-tumor immunity by delivering long non-coding RNAs (lncRNAs). HOTAIR was screened by lncRNA profiling in both colorectal cancer (CRC)-derived exosomes and infiltrating B cells. Tumor-derived HOTAIR polarized B cells toward a regulatory feature marked by programmed cell death-ligand 1 (PDL1) in CRC, and induced PDL1+ B cells to suppress CD8+ T cell activity. Exosomal HOTAIR bound to and protected pyruvate kinase M2 (PKM2) against ubiquitination degradation, resulting in STAT3 activation and PDL1 expression. Results from CRC patients showed a positive correlation between exosomal HOTAIR and tumor-infiltrating PDL1+ B cells. These findings reveal how B cells acquire PDL1-dominant regulatory feature in CRC, implying the clinical significance of exosomal therapy targeting HOTAIR.

Alveolar soft tissue sarcoma: a report of 50 cases at a single institution.

BACKGROUND: Alveolar soft-part sarcoma (ASPS) is a rare soft tissue sarcoma subtype, occurring mainly in young people, with poor prognosis. MATERIALS AND METHODS: We conducted a retrospective analysis of localized or metastatic ASPS patients admitted to the First Affiliated Hospital of Zhengzhou University (China) from 2012 to 2020, focusing on treatment and prognosis. RESULTS: The median age at diagnosis was 24 years (range: 1.4-78 years). Women (n = 29, 58%), especially those aged <30 years, dominated this series. The most common metastasis site was lung. Thirty-one (62%) patients developed lung metastasis (localized: n = 9 [18%]; metastatic: n = 22 [44%]). Only a tumor maximum diameter ≥ 5 cm was associated with a high lung metastasis rate (p = 0.039). The mean follow-up time was 37.5 months (1-108 months), and the 5-year overall survival (OS) rate was 84.7%. Univariate analysis indicated that distant metastasis observed at the initial visit and incomplete resection of the primary tumor were associated with poor OS. For localized cases, neither surgery plus radiotherapy (p = 0.486) nor surgery plus chemotherapy (p = 0.536) improved progression-free survival compared to surgery alone. Among the metastatic cases, the disease control rate (PR + SD) was higher for targeted therapy (60%) and combined immunosuppressive therapy (100%) than for conventional cytotoxic chemotherapy (26%). CONCLUSIONS: Postoperative adjuvant radiotherapy and chemotherapy do not provide good local control for patients with localized disease. Although there is no standard treatment strategy for patients with advanced or metastatic disease, they can benefit from targeted therapy and/or immunosuppressive therapy.

Leucine-tRNA-synthase-2-expressing B cells contribute to colorectal cancer immunoevasion.

Immunoregulatory B cells impede antitumor immunity through unknown features and mechanisms. We report the existence of leucine-tRNA-synthase-2 (LARS2)-expressing B cell (LARS B) subset with a transforming growth factor-ß1 (TGF-ß1)-dominant regulatory feature in both mouse and human progressive colorectal cancer (CRC). Of note, LARS B cells exhibited a leucine nutrient preference and displayed active mitochondrial aminoacyl-tRNA biosynthesis. They were located outside the tertiary lymphoid structure and correlated with colorectal hyperplasia and shortened survival in CRC patients. A leucine diet induced LARS B cell generation, whereas LARS B cell deletion by Lars2 gene ablation or leucine blockage repressed CRC immunoevasion. Mechanistically, LARS2 programmed mitochondrial nicotinamide adenine dinucleotide (NAD+) regeneration and oxidative metabolism, thus determining the regulatory feature of LARS B cells in which the NAD-dependent protein deacetylase sirtuin-1 (SIRT1) was involved. We propose a leucine-dieting scheme to inhibit LARS B cells, which is safe and useful for CRC therapy.

Dechlorane Plus Biomagnification and Transmission through Prairie Food Webs in Inner Mongolia, China.

Dechlorane Plus (DP) is found widely in the environment. It is important to study DP enrichment and biomagnification in terrestrial ecosystems to improve our understanding of the possible effects of DP on the environment and human health. A total of 90 samples, including plant and animal tissues, were collected from Xilingol Prairie in Inner Mongolia, China. The DP concentrations in different species were assessed, and transmission of DP through food webs containing ectotherms and endotherms was assessed. The compound was detected in the biotic samples (plant; range 0.133-0.422 ng/g dry wt), in animal muscle (range: not dected-5.70 ng/g lipid wt), and in animal hair (range: not dected-2.03 ng/g dry wt), indicating that DP is present in remote environments such as Xilingol Prairie. These findings suggest that DP can undergo long-distance transport in the environment. Biomagnification factors (ectotherms: range 0.146-88.0, endotherms: range 0.866-17.2) and anti-DP/total DP concentration ratios (fanti values of 0.412-0.787) for the prairie animals were calculated. Ectotherms were found to selectively enrich syn-DP, and stereoselective enrichment increased moving up the food web. Lower-trophic-level endotherms strongly stereoselectively enriched syn-DP, and higher-trophic-level endotherms stereoselectively enriched anti-DP. Environ Toxicol Chem 2021;40:413-421. © 2020 SETAC.

Complete chloroplast genome sequence of Peganum harmala, an important medicinal plant.

Peganum harmala is a perennial herbaceous plant belonging to the genus Peganum, Nitrariaceae and is mainly distributed in dry areas in the Mediterranean and many Asia countries. This plant species has high medicinal value and considerable ecological value. This article reports the first chloroplast genome of species in Peganum. The size of the P. harmala chloroplast genome is 160,070 bp, including a large single-copy (LSC) region (88,279 bp), a small single-copy (SSC) region (26,468 bp), and two reverse (IR) regions (18,856 bp). The P. harmala chloroplast genome consists of 132 genes, including 83 protein-coding genes, 38 transfer RNA (tRNA) genes, and 8 ribosomal RNA (rRNA) genes. The GC content of P. harmala chloroplast genome is 36.44%. Phylogenetic analysis showed that P. harmala and another Nitrariaceaeis species formed a single blade in the phylogenetic tree.

Distributions and biomagnification of polybrominated diphenyl ethers in a grassland ecosystem food chain.

The concentrations, distributions, and biomagnification of polybrominated diphenyl ethers (PBDEs) in environmental and biological media in a terrestrial grass ecosystem were studied, The total PBDE concentrations in grasses were 4.00 × 10-2 to 4.28 ng·g-1. The total PBDE concentration in weasel muscle (23.2 ng·g-1 l.w.) was the highest concentrations of all animal tissue samples, and the total PBDE concentration in hair from local herdsmen (22.2 ng·g-1 l.w.) was second highest. Less-brominated PBDEs were found to be more strongly biomagnified than more-brominated PBDEs in the grassland food web. PBDEs were found to be much more strongly biomagnified in the food chains of homothermic animals than heterothermic animals. More-brominated PBDEs were not markedly biomagnified in the grassland food web. For example, BDE-153 was not biomagnified in the grassland wildlife food chain but was clearly biomagnified through the sheep, cattle, or horse hair to human hair route. The biomagnification factors and log Kows negatively correlated for the toad-snake, lizard-snake, and mouse-weasel food chains. The ability of PBDE congeners to become enriched generally decreased as the log Kow increased, and this decrease occurred 100-1000 times more strongly for homothermic animals than heterothermic animals.

TRAF4, a new substrate of SIAH1, participates in chemotherapy resistance of breast cancer cell by counteracting SIAH1-mediated downregulation of ß-catenin.

PURPOSE: TRAF4 plays an important role in the development and progression of breast cancer, but its impact on chemotherapy resistance is as yet, however, poorly understood. METHODS: Western blotting, immunoprecipitation, and immunofluorescence staining were used to identify and verify that TRAF4 was a novel substrate of SIAH1 and prevented SIAH1-mediated ß-catenin degradation. Cell proliferation analysis and Flow cytometry analysis were utilized to detect TRAF4's function on the growth-inhibitory effect of etoposide. Immunohistochemistry was used to detect the expression of TRAF4, SIAH1, and ß-catenin. Statistical analysis was used to analyze the relationships between them with clinical parameters and curative effect of chemotherapy pathologically. RESULTS: Our results suggested that TRAF4 prevents SIAH1-mediated ß-catenin degradation. TRAF4 was a novel substrate of SIAH1 and the TRAF domain of TRAF4 was critical for binding to SIAH1. TRAF4 reduced the growth-inhibitory effect of etoposide via reducing the number of S-phase cells and suppressing cell apoptosis. Concordantly, we found that breast cancer patients with a low-TRAF4 expression benefited most from chemotherapy, who had higher tumor volume reduction rate and better pathological response, while, the high-TRAF4 expression group had lower tumor volume reduction rate and poor pathological response. CONCLUSIONS: TRAF4 was a novel substrate of SIAH1 and prevented SIAH1-mediated ß-catenin degradation, which explains the protective effect of TRAF4 on ß-catenin during cell stress and links TRAF4 to chemotherapy resistance in tumors. These findings implicated a novel pathway for the oncogenic function of TRAF4.

Competitive Adsorption as a Route to Area-Selective Deposition.

In this work, we have explored the use of a third species during chemical vapor deposition (CVD) to direct thin-film growth to occur exclusively on one surface in the presence of another. Using a combination of density functional theory (DFT) calculations and experiments, including in situ surface analysis, we have examined the use of 4-octyne as a coadsorbate in the CVD of ZrO2 thin films on SiO2 and Cu surfaces. At sufficiently high partial pressures of the coadsorbate and sufficiently low substrate temperatures, we find that 4-octyne can effectively compete for adsorption sites, blocking chemisorption of the thin-film precursor, Zr[N(CH3C2H5)]4, and preventing growth on Cu, while leaving growth unimpeded on SiO2. The selective dielectric-on-dielectric (DoD) process developed herein is fast, totally vapor phase, and does not negatively alter the composition or morphology of the deposited thin film. We argue that this approach to area-selective deposition (ASD) should be widely applicable, provided that suitable candidates for preferential binding can be identified.