Interpretation of personal genome sequencing data in terms of disease ranks based on mutual information

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Abstract Background The rapid advances in genome sequencing technologies have resulted in an unprecedented number of genome variations being discovered in humans. However, there has been very limited coverage of interpretation of the personal genome sequencing data in terms of diseases. Methods In this paper we present the first computational analysis scheme for interpreting personal genome data by simultaneously considering the functional impact of damaging variants and curated disease-gene association data. This method is based on mutual information as a measure of the relative closeness between the personal genome and diseases. We hypothesize that a higher mutual information score implies that the personal genome is more susceptible to a particular disease than other diseases. Results The method was applied to the sequencing data of 50 acute myeloid leukemia (AML) patients in The Cancer Genome Atlas. The utility of associations between a disease and the personal genome was explored using data of healthy (control) people obtained from the 1000 Genomes Project. The ranks of the disease terms in the AML patient group were compared with those in the healthy control group using "Leukemia, Myeloid, Acute" (C04.557.337.539.550) as the corresponding MeSH disease term. The mutual information rank of the disease term was substantially higher in the AML patient group than in the healthy control group, which demonstrates that the proposed methodology can be successfully applied to infer associations between the personal genome and diseases. Conclusions Overall, the area under the receiver operating characteristics curve was significantly larger for the AML patient data than for the healthy controls. This methodology could contribute to consequential discoveries and explanations for mining personal genome sequencing data in terms of diseases, and have versatility with respect to genomic-based knowledge such as drug-gene and environmental-factor-gene interactions

Resveratrol suppresses gastric cancer cell proliferation and survival through inhibition of PIM-1 kinase activity

The proviral integration site for Moloney murine leukemia virus (PIM) family of serine/threonine-specific kinases consist of three isoforms, that regulate proliferation, apoptosis, metabolism, invasion, and metastasis of cancer cells. Among these, abnormally elevated kinase activity of PIM-1 contributes to the progression of gastric cancer and predicts poor prognosis and a low survival rate in gastric cancer patients. In the present study, we found that resveratrol, one of the representative chemopreventive and anticarcinogenic phytochemicals, directly binds to PIM-1 and thereby inhibits its catalytic activity in human gastric cancer SNU-601 cells. This resulted in suppression of phosphorylation of the proapoptotic Bad, a known substrate of PIM-1. Resveratrol, by inactivating PIM-1, also inhibited anchorage-independent growth and proliferation of SNU-601 cells. To understand the molecular interaction between resveratrol and PIM-1, we conducted docking simulation and found that resveratrol directly binds to the PIM-1 at the ATP-binding pocket. In conclusion, the proapototic and anti-proliferative effects of resveratrol in gastric cancer cells are likely to be mediated through suppression of PIM-1 kinase activity, which may represent a novel mechanism underlying its chemopreventive and anticarcinogenic actions.

Helicobacter pylori infection induces STAT3 phosphorylation on Ser727 and autophagy in human gastric epithelial cells and mouse stomach

© 2020, The Author(s).Helicobacter pylori (H. pylori) infection is considered as one of the principal risk factors of gastric cancer. Constitutive activation of the signal transducer and activator of transcription 3 (STAT3) plays an important role in inflammation-associated gastric carcinogenesis. In the canonical STAT3 pathway, phosphorylation of STAT3 on Tyr705 is a major event of STAT3 activation. However, recent studies have demonstrated that STAT3 phosphorylated on Ser727 has an independent function in mitochondria. In the present study, we found that human gastric epithelial AGS cells infected with H. pylori resulted in localization of STAT3 phosphorylated on Ser727 (P-STAT3Ser727), predominantly in the mitochondria. Notably, H. pylori-infected AGS cells exhibited the loss of mitochondrial integrity and increased expression of the microtubule-associated protein light chain 3 (LC3), the autophagosomal membrane-associated protein. Treatment of AGS cells with a mitophagy inducer, carbonyl cyanide 3-chlorophenylhydrazone (CCCP), resulted in accumulation of P-STAT3Ser727 in mitochondria. In addition, the elevated expression and mitochondrial localization of LC3 induced by H. pylori infection were attenuated in AGS cells harboring STAT3 mutation defective in Ser727 phosphorylation (S727A). We also observed that both P-STAT3Ser727 expression and LC3 accumulation were increased in the mitochondria of H. pylori-inoculated mouse stomach.

Decadal variability of the upper ocean heat content in the East/Japan Sea and its possible relationship to northwestern Pacific variability

Author Posting. © American Geophysical Union, 2012. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Journal of Geophysical Research 117 (2012): C02017, doi:10.1029/2011JC007369.The upper ocean heat content variability in the East/Japan Sea was investigated using a 40 year temperature and salinity data set from 1968 to 2007. Decadal variability was identified as the dominant mode of variability in the upper ocean (0–300 m) aside from the seasonal cycle. The decadal variability is strong to the west of northern Honshu, west of the Tsugaru Strait, and west of southern Hokkaido. Temperature anomalies at 50–125 m exhibit a large contribution to the decadal variability, particularly in the eastern part of the East/Japan Sea. The vertical structure of regressed temperature anomalies and the spatial patterns of regressed 10°C isotherms in the East/Japan Sea suggest that the decadal variability is related to upper ocean circulation in the East/Japan Sea. The decadal variability also exhibits an increasing trend, which indicates that the regions showing large decadal variations experienced warming on decadal time scales. Further analysis shows that the decadal variability in the East/Japan Sea is not locally isolated but is related to variability in the northwestern Pacific.This work was supported by grants from the Ministry of Land, Transport, and Maritime Affairs, Korea (Ocean Climate Variability Program and EAST-I Project).2012-08-0

Impact of mental disorders on the risk of atrial fibrillation in patients with diabetes mellitus:a nationwide population-based study

BACKGROUND: It is unclear whether mental disorders are an independent risk factor for atrial fibrillation (AF) in patients with diabetes. We aimed to investigate whether patients with diabetes who have mental disorders have an increased risk for AF. METHODS: Using the Korea National Health Insurance Service database, we enrolled 2,512,690 patients diagnosed with diabetes without AF between 2009 and 2012. We assessed five mental disorders: depression, insomnia, anxiety, bipolar disorder, and schizophrenia. Newly diagnosed AF was identified during the follow-up period, and multivariate Cox regression analysis was performed. RESULTS: Among the 2,512,690 patients (mean age 57.2 ± 12.3 years; 60.1% men), 828,929 (33.0%) had mental disorders. Among the five mental disorders, anxiety (68.1%) was the most common, followed by insomnia (40.0%). During a median follow-up duration of 7.1 years, new-onset AF was diagnosed in 79,525 patients (4.66 per 1,000 person-years). Patients with diabetes who had mental disorders showed a higher risk for AF (adjusted hazard ratio [HR] 1.19; 95% confidence interval [CI] 1.17–1.21; p-value < 0.001). Depression, insomnia, and anxiety were significantly associated with higher risk for AF (adjusted HR [95% CI]: 1.15 [1.12–1.17], 1.15 [1.13–1.18], and 1.19 [1.67–1.21], respectively; all p-values < 0.001), whereas bipolar disorder and schizophrenia were not. CONCLUSIONS: Mental disorders, especially depression, insomnia, and anxiety, were associated with an increased risk for AF in patients with diabetes. Greater awareness with a prompt diagnosis of AF should be considered for patients with both DM and mental disorders. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12933-022-01682-7