Trideuteromethylthiolation through Reaction of Arynes, S-Methyl-d3 Sulfonothioate with Sulfonamides or Amides: Access to Trideuteromethylated Sulfilimines.

A direct and practical three-component tandem reaction of arynes, S-methyl-d3 sulfonothioate with sulfonamides or amides is developed. The reaction is highly efficient and chemoselective, which allows mild synthesis of trideuteromethylated sulfilimines with broad substrate scope and good functional group compatibility, giving the products in good to excellent yields with 92%-99% deuterium incorporation. Mechanism studies disclosed sulfenamide that generated in situ is the key intermediate for the reaction. This protocol provides potential method for introduction of -SCD3 moiety for deuteration of marked drugs and drug candidates containing sulfilimine skeleton.

What the SARS-CoV-2 Pandemic Has Taught Us About Immunosuppression, Vaccinations, and Immune Dysregulation: The Rheumatology Experience.

PURPOSE OF REVIEW: This review reflects on the impact of the COVID-19 pandemic on the field of rheumatology, emphasizing resulting insights related to the risks of viral infections in immunosuppressed patients, vaccine immunogenicity in immunocompromised patients, and immune dysregulation in the setting of viral infection. RECENT FINDINGS: During the pandemic, global patient registries provided real-time insights into the risk factors associated with severe COVID-19 outcomes in rheumatology patients. Updated evidence-based recommendations from the American College of Rheumatology (ACR) guided rheumatology practice during a time of considerable uncertainty. Studies on COVID-19 vaccines in immunocompromised populations enhanced our understanding of specific immunosuppressive therapies on vaccine efficacy. The immune dysregulation seen in severe COVID-19 underscored a role for immunomodulation in this and other severe infections. Furthermore, novel post-infectious conditions, namely multisystem inflammatory syndrome in children (MIS-C) and Long COVID, reshaped our understanding of post-viral syndromes and revealed novel pathological mechanisms. Lessons from the COVID-19 pandemic demonstrate the power of collaborative research. The scientific revelations from this dreadful time will, nonetheless, benefit the practice of rheumatology for years to come.

Development of Detection Antibody Targeting the Linear Epitope in SARS-CoV-2 Nucleocapsid Protein with Ultra-High Sensitivity.

The COVID-19 pandemic caused by SARS-CoV-2 highlighted the importance of reliable detection methods for disease control and surveillance. Optimizing detection antibodies by rational screening antigens would improve the sensitivity and specificity of antibody-based detection methods such as colloidal gold immunochromatography. In this study, we screened three peptide antigens with conserved sequences in the N protein of SARS-CoV-2 using bioinformatical and structural biological analyses. Antibodies that specifically recognize these peptides were prepared. The epitope of the peptide that had the highest binding affinity with its antibody was located on the surface of the N protein, which was favorable for antibody binding. Using the optimal antibody that can recognize this epitope, we developed colloidal gold immunochromatography, which can detect the N protein at 10 pg/mL. Importantly, this antibody could effectively recognize both the natural peptide antigen and mutated peptide antigen in the N protein, showing the feasibility of being applied in the large-scale population testing of SARS-CoV-2. Our study provides a platform with reference significance for the rational screening of detection antibodies with high sensitivity, specificity, and reliability for SARS-CoV-2 and other pathogens.

PVALB Was Identified as an Independent Prognostic Factor for HCC Closely Related to Immunity, and Its Absence Accelerates Tumor Progression by Regulating NK Cell Infiltration.

Purpose: Hepatocellular carcinoma is the most common primary liver cancer, with poor prognosis. Complex immune microenvironment of the liver is linked to the development of HCC. PVALB is a calcium-binding protein which has been described as a cancer suppressor gene in thyroid cancer and glioma. Nevertheless, the role of PVALB in HCC is unknown. Materials and Methods: We obtained data from TCGA and GSE54236 datasets. MCP-counter, WGCNA and LASSO model were applied to identify PVALB. With UALCAN, MethSurv, and other websites, we probed the expression, methylation and survival of PVALB. LinkedOmics and GSEA were adopted for functional analysis, while TIMER, TISIDB, Kaplan-Meier plotter, TIDE databases were utilized to evaluate the relevance of PVALB to the tumor immune microenvironment and predict immunotherapy efficacy. TargetScan, DIANA, LncRNASNP2 databases and relevant experiments were employed to construct ceRNA network. Finally, molecular docking and drug sensitivity of PVALB were characterized by GeneMANIA, CTD, and so on. Results: PVALB was recognized as a gene associated with HCC and NK cell. Its expression was down-regulated in HCC tissue, which lead to adverse prognosis. Besides, the hypomethylation of PVALB was related to its reduced expression. Notably, PVALB was tightly linked to immune, and its reduced expression attenuated the anticancer effect of NK cells via the Fas/FasL pathway, leading to a adverse outcome. The lnc-YY1AP1-3/hsa-miR-6735-5p/PVALB axis may regulate the PVALB expression. Finally, we found immunotherapy might be a viable treatment option. Conclusion: In a word, PVALB is a prognostic indicator, whose low expression facilitates HCC progression by impacting NK cell infiltration.

An immune biomarker associated with EMT serves as a predictor for prognosis and drug response in bladder cancer.

BACKGROUND: Bladder cancer (BLCA), which develops from the upper endometrial of the bladder, is the sixth most prevalent cancer across the globe. WDHD1 (WD repeat and HMG-box DNA binding protein 1 gene) directly affects signaling, the cell cycle, and the development of the cell skeleton. Uncertainty surrounds WDHD1's function in BLCA immunity and prognosis, though. MATERIALS AND METHODS: Using weighed gene co-expression network analysis (WGCNA), initially, we first identified 32 risk factors in genes with differential expression for this investigation. Then, using a variety of bioinformatic techniques and experimental validation, we examined the connections between WDHD1 and BLCA expression, clinical pathological traits, WDHD1-related proteins, upper-skin-intermediate conversion (EMT), immune cell immersion, convergence factors, immune markers, and drug sensitivity. RESULT: The findings demonstrated that we constructed a 32-gene risk-predicting model where WDHD1 was elevated as a representative gene expression in BLCA and related to a range of clinical traits. Furthermore, high WDHD1 expression was a standalone predictor associated with a worse survival rate. The most commonly recruited cells and their evolutionary patterns were highlighted to better comprehend WDHD1's function in cancer. High WDHD1 expression was associated with many aspects of immunology. Finally, the study found that individuals with high expression of WDHD1 were drug-sensitive to four different broad-spectrum anti-cancer drugs. CONCLUSION: These results describe dynamic changes in the tumor microenvironment in BLCA and provide evidence for the hypothesis that WDHD1 is a novel biomarker of tumor development. WDHD1 may therefore be a useful target for the detection and management of BLCA.

LAMP3 is a potent uterine corpus endometrial carcinoma prognostic biomarker associated with immune behavior.

BACKGROUND: Uterine corpus endometrial carcinoma (UCEC) is one of the most common gynecological malignancies and its incidence and mortality continue apace. Lysosome-associated membrane protein 3 (LAMP3) is the third member of the LAMP family and its overexpression has been described to be involved in the progression of breast, ovarian and cervical cancers, but there has been an absence of research focusing on its role in UCEC. METHODS: WGCNA, TIMER, LinkedOmics, GSEA, Cytoscape, Kaplan-Meier plotter, GDC, GeneMANIA, cBioPortal, PDB, RNAinter, miRNet were applied in this research. RESULTS: Our study uncovers that LAMP3 possesses higher expression levels in UCEC compared to normal tissues, and this differential expression profile is tightly aligned with clinical and pathological features, and patients demonstrating high LAMP3 expression tend to have a shorter survival expectancy. The high expression of LAMP3 is modulated by the designated ceRNA network. LAMP3 is engaged in UCEC progression by functioning in a variety of biological roles of relevance to immunity. Furthermore, we predicted several prospering drugs based on drug sensitivity. Finally, we also constructed possible docking patterns of LAMP3 with ABCA3, RAB9A, and SGTB. CONCLUSIONS: LAMP3 is a formidable biomarker for UCEC and could be a prospective candidate for the diagnosis, treatment and prognostic assessment of UCEC.

Identification of a robust biomarker LAPTM4A for glioma based on comprehensive computational biology and experimental verification.

BACKGROUND: Glioma, a highly invasive and deadly form of human neoplasm, presents a pressing need for the exploration of potential therapeutic targets. While the lysosomal protein transmembrane 4A (LATPM4A) has been identified as a risk factor in pancreatic cancer patients, its role in glioma remains unexplored. METHODS: The analysis of differentially expressed genes (DEG) was conducted from The Cancer Genome Atlas (TCGA) glioma dataset and the Genotype Tissue Expression (GTEx) dataset. Through weighted gene co-expression network analysis (WGCNA), the key glioma-related genes were identified. Among these, by using Kaplan-Meier (KM) analysis and univariate/multivariate COX methods, LAPTM4A emerged as the most influential gene. Moreover, the bioinformatics methods and experimental verification were employed to analyze its relationships with diagnosis, clinical parameters, epithelial-mesenchymal transition (EMT), metastasis, immune cell infiltration, immunotherapy, drug sensitivity, and ceRNA network. RESULTS: Our findings revealed that LAPTM4A was up-regulated in gliomas and was associated with clinicopathological features, leading to poor prognosis. Furthermore, functional enrichment analysis demonstrated that LATPM4A played a role in the immune system and cancer progression. In vitro experiments indicated that LAPTM4A may influence metastasis through the EMT pathway in glioma. Additionally, we found that LAPTM4A was associated with the tumor microenvironment (TME) and immunotherapy. Notably, drug sensitivity analysis revealed that patients with high LAPTM4A expression were sensitive to doxorubicin, which contributed to a reduction in LAPTM4A expression. Finally, we uncovered the FGD5-AS1-hsa-miR-103a-3p-LAPTM4A axis as a facilitator of glioma progression. CONCLUSIONS: In conclusion, our study identifies LATPM4A as a promising biomarker for prognosis and immune characteristics in glioma.

Isolated Psychiatric Symptoms in Children With Anti-N-Methyl-d Aspartate Receptor Encephalitis.

BACKGROUND: Isolated psychiatric symptoms can be the initial symptom of pediatric anti-N-methyl-d-aspartate (NMDA) receptor autoimmune encephalitis (pNMDARE). Here we report on the prevalence of isolated psychiatric symptoms in pNMDARE. We also assess whether initial neurodiagnostic tests (brain magnetic resonance imaging [MRI], electroencephalography [EEG], and/or cerebrospinal fluid [CSF] white blood cell count) are abnormal in children with isolated psychiatric symptoms and pNMDARE. METHODS: This multicenter retrospective cohort study from CONNECT (Conquering Neuroinflammation and Epilepsies Consortium) from 14 institutions included children under age 18 years who were diagnosed with pNMDARE. Descriptive statistics using means, medians, and comparisons for continuous versus discrete data was performed. RESULTS: Of 249 children included, 12 (5%) had only psychiatric symptoms without other typical clinical features of autoimmune encephalitis at presentation. All but one (11 of 12 = 92%) had at least one abnormal finding on initial ancillary testing: eight of 12 (67%) had an abnormal EEG, six of 12 (50%) had an abnormal MRI, and five of 12 (42%) demonstrated CSF pleocytosis. The single patient with a normal MRI, EEG, and CSF profile had low positive CSF NMDA antibody (titer of 1:1), and symptoms improved without immunotherapy. CONCLUSIONS: Isolated first-episode psychiatric symptoms in pNMDARE are uncommon, and the majority of children will exhibit additional neurodiagnostic abnormalities. Delaying immunotherapy in a child with isolated psychiatric symptoms and normal neurodiagnostic testing may be warranted while awaiting confirmatory antibody testing.