Zmiz1 is a novel regulator of lymphatic endothelial cell gene expression and function.

Zinc Finger MIZ-Type Containing 1 (Zmiz1), also known as ZIMP10 or RAI17, is a transcription cofactor and member of the Protein Inhibitor of Activated STAT (PIAS) family of proteins. Zmiz1 is critical for a variety of biological processes including vascular development. However, its role in the lymphatic vasculature is unknown. In this study, we utilized human dermal lymphatic endothelial cells (HDLECs) and an inducible, lymphatic endothelial cell (LEC)-specific Zmiz1 knockout mouse model to investigate the role of Zmiz1 in LECs. Transcriptional profiling of Zmiz1-deficient HDLECs revealed downregulation of genes crucial for lymphatic vessel development. Additionally, our findings demonstrated that loss of Zmiz1 results in reduced expression of proliferation and migration genes in HDLECs and reduced proliferation and migration in vitro. We also presented evidence that Zmiz1 regulates Prox1 expression in vitro and in vivo by modulating chromatin accessibility at Prox1 regulatory regions. Furthermore, we observed that loss of Zmiz1 in mesenteric lymphatic vessels significantly reduced valve density. Collectively, our results highlight a novel role of Zmiz1 in LECs and as a transcriptional regulator of Prox1, shedding light on a previously unknown regulatory factor in lymphatic vascular biology.

Construction and Analysis of a Colorectal Cancer Prognostic Model Based on N6-Methyladenosine-Related lncRNAs.

Given the relatively poor understanding of the expression and functional effects of the N6-methyladenosine (m6A) RNA methylation on colorectal cancer (CRC), we attempted to measure its prognostic value and clinical significance. We comprehensively screened 37 m6A-related prognostic long non-coding RNAs (lncRNAs) with significant differences in expression based on 21 acknowledged regulators of m6A modification and data on 473 colorectal cancer tissues and 41 para-cancer tissues obtained from the TCGA database. Accordingly, we classified 473 CRC patients into two clusters by consensus clustering on the basis of significantly different survival outcomes. We also found a potential correlation between m6A-related prognostic lncRNAs and BRAF-KRAS expression, as well as immune cell infiltration. Then, we established a prognostic model by selecting 16 m6A-related prognostic lncRNAs via LASSO Cox analysis and grouped the CRC patients into low- and high-risk groups to calculate risk scores. Then, we performed stratified sampling to validate and confirm our model by categorising the 473 samples into a training group (N = 208) and a testing group (N = 205) in a 1:1 ratio. The survival curve showed a distinct clinical outcome in the low- and high-risk subgroups. We reconfirmed the reliability and independence of the prognostic model through various measures: risk curve, heat map and univariate and multivariate Cox analyses. To ensure that the outcomes were applicable to clinical settings, we performed stratified analyses on different clinical features, such as age, lymph node status and clinical stage. CRC patients with downregulated m6A-related gene expression, lower immune score, distant metastasis, lymph node metastasis or more advanced clinical staging had higher risk scores, indicating less-desirable outcomes. Moreover, we explored the immunology of colorectal cancer cells. The risk score showed positive correlations with eosinophils, M2 macrophages and neutrophils. In summary, our effort revealed the significance of m6A RNA methylation regulators in colorectal cancer, and the prognostic model we constructed may be used as an essential reference for predicting the outcome of CRC patients.

Thyroid function during a prolonged stay in Antarctica.

Adaptation of the thyroid gland to the Antarctic environment was studied in nine healthy euthyroid tropical men of the Sixth Indian Antarctic Expedition during 1 year of their residence at polar latitudes. Circulatory concentrations of thyroid hormones, total T4 (TT4), total T3 (TT3), free T4 (FT4), free T3 (FT3), reverse T3 (rT3), thyroxine binding globulin (TBG), T3 uptake and thyroid stimulating hormone (TSH) were estimated in New Delhi and during the first week of each month of the stay in Antarctica. At the end of the Austral summer in March, the TT3 concentrations were found to be significantly lower (P < 0.01) compared to values recorded in New Delhi and showed a significant increase (P < 0.05) during the Austral winter in August. The mean TT3 concentrations from May to December were found to be significantly higher than the March or April values. Plasma TT4 and rT3 concentrations tended to decline in March but remained unaltered during the entire period in Antarctica. The FT4, FT3, TBG and T3 uptake did not show any appreciable change. Though, the TT3:TT4 ratio tended to decline in March and April suggesting decreased peripheral conversion of T4 to T3 as the possible mechanism for a decline in TT3 in March. physical exertion and prolonged exposure to extreme cold appeared to be the major contributory factors. The TSH concentration in March, April, November and December were found to be significantly higher than the New Delhi values. The morning as well as evening cortisol concentrations during the Austral winter were higher than the March values suggesting that cortisol rhythmicity was well maintained in Antarctica, albeit at a higher level. These observations indicated that the subtle changes in thyroid hormones during a prolonged stay at polar latitudes are related not only to the extreme cold but also to other factors such as physical activity, polar days and polar nights.