Heterocyclic diamidines are strong DNA minor‐groove binders and have excellent antiparasitic activity. To extend the biological activity of these compounds, a series of arylimidamides (AIAs) analogues, which have better uptake properties in Leishmania and Trypanosoma cruizi than diamidines, was prepared. The binding of the AIAs to DNA was investigated by T_m, fluorescence displacement titration, circular dichroism, DNase I footprinting, biosensor surface plasmon resonance, X‐ray crystallography and molecular modeling. These compounds form 1:1 complexes with AT sequences in the DNA minor groove, and the binding strength varies with substituent size, charge and polarity. These substituent‐dependent structure and properties provide a SAR that can be used to estimate K values for binding to DNA in this series. The structural results and molecular modeling studies provide an explanation for the differences in binding affinities for AIAs.

Oxeiptosis is a recently discovered caspase-independent, non-inflammatory programmed cell death modality. Current studies suggest that oxeiptosis has crucial effects on biological processes in a variety of diseases. However, the mechanism of oxeiptosis in hepatocellular carcinoma (HCC) remains unclear and no relevant studies have been published. Therefore, this study is intended to investigate the mechanism and prognostic role of oxeiptosis-related genes in HCC. We explored the mechanisms and molecular phenotypes underlying the role of oxeiptosis in HCC through multi-omics analysis. Firstly, we obtained RNA-sequencing and clinical data from public database and divided the samples into trial and validation cohorts in subsequent analyses. We then screened oxeiptosis core genes (OCGs) and screened prognosis-related genes. Based on different molecular markers, we identified the molecular phenotypes of HCC, and the potential OCGs molecular mechanisms were explored. Subsequently, we construct a prognostic prediction system for HCC. Finally, we analyzed the tumor microenvironment and the immune escape phenomenon. We screened a total of 69 OCGs, most of which were prognostic risk factors for HCC. A majority of OCGs were enriched in cell cycle regulation and mitotic processes, which were related to both tumor cell proliferation and death. We identified 2 different molecular typing options with significant differences in prognosis, function, and signaling pathway enrichment between different molecular subtypes. The prognostic prediction model combined with molecular phenotypes and had a good predictive effect. Finally, we found CD4 + T-cell exhaustion in samples with specific molecular phenotypes. Through multi-omics analysis of OCGs, we not only revealed the possible molecular mechanisms of OCGs in HCC but also provided a prognostic prediction system for clinical application through molecular typing and risk scoring model. Meanwhile, we found immune escape mechanisms in HCC.

Thyroid hormones profoundly modulate hepatic fatty acid and cholesterol synthesis and turnover. Although nonalcoholic fatty liver disease (NAFLD) shows epidemiological links to hypothyroidism, the genetic substrates of this relationship remain unresolved. Integrating large-scale genome-wide association studies with single-cell transcriptomics, spatial transcriptomics, and single-cell chromatin accessibility via state-of-the-art computational approaches, we interrogated the association between NAFLD and hypothyroidism across organ systems, cellular expression landscapes, and molecular–genetic strata. We uncovered pronounced spatial specificity in genetic risk within the liver, prioritized hepatocytes as the principal shared cell type affected, and, leveraging spatial transcriptomics, advanced a dynamic spatiotemporal two-hit model. We further nominated MAGI3, RRNAD1, and PRCC as high-confidence candidate genes and pinpointed a key risk locus, rs926103. These findings deliver a dynamic, testable framework for the full pathophysiological continuum linking NAFLD and hypothyroidism and yield new targets and leads for precision intervention.

Hepatic viral infections and breast cancer (BC) constitute major global health challenges, yet the interconnection between these hepatic infections and BC continues to be ambiguous. Conducting a comprehensive evaluation of the link between hepatitis virus infection and the incidence of BC and leveraging data from the National Health and Nutrition Examination Survey covering the period from 1999 to March 2022, we utilized logistic regression and subgroup analysis, among other methodologies, to execute a cross-sectional investigation. The univariate logistic regression analysis elucidates that individuals classified as non-Hispanic White exhibit a markedly higher incidence of BC at 2.620 (95% confidence interval [CI], 1.117–7.676; P = .045); moreover, advanced age at 1.063 (95% CI, 1.036–1.093; P < .001), elevated educational attainment at 1.962 (95% CI, 1.17–3.366; P = .012), and higher income levels at 2.835 (95% CI, 1.303–7.439; P = .017) emerge as significant predisposing factors for BC. In contrast, a greater number of live births significantly diminishes the risk of BC, reducing the incidence to 81.1% with each additional birth. Pertaining to hepatitis and vaccination status, our analysis distinctly demonstrates that only hepatitis B at 0.110 (95% CI, 0.018–0.353; P = .002) bears a significant inverse relationship with BC risk, suggesting a protective effect. The multivariate logistic regression analysis further reveals a negative association between hepatitis B infection and BC incidence, whereas hepatitis B vaccination shows a positive correlation with the disease incidence. After adjusting for all covariates, model 3 delineates odds ratios (95% CI) as follows: 0.14 (0.02–0.50; P = .009) and 1.92 (0.99–3.62; P = .046). Our investigation uncovers that within the general populace, there exists an inverse correlation between hepatitis B infection and BC incidence; in addition, the administration of the hepatitis B virus vaccine is potentially positively associated with the prevalence of BC.

The skin microbiome has been linked to the etiology and progression of skin cancer, but the causal relationship remains unclear. This study employs two-sample Mendelian randomization (TSMR) and meta-analysis techniques to elucidate the putative genetic causal relationships between skin microbiota and skin cancer. Genetic variant data for the skin microbiome and skin cancer, drawn from large-scale genome-wide association studies, were extracted from European populations. TSMR analysis, heterogeneity tests, horizontal pleiotropy assessments, sensitivity analysis, and directional tests were conducted, followed by a meta-analysis to enhance the reliability of the findings. The TSMR and meta-analysis results indicate a significant association between the Proteobacteria phylum, including Gammaproteobacteria, and an increased risk of melanoma. Conversely, the Staphylococcus genus is significantly associated with a reduced risk of melanoma. Additionally, the Bacteroidetes phylum exhibits a statistically significant association with an elevated risk of basal cell carcinoma. This study furnishes genetic evidence substantiating the causal nexus between the skin microbiome and skin cancer. Further research is warranted to elucidate the underlying mechanisms and explore skin microbiome-centric prophylactic and therapeutic strategies for skin cancer.