Breast cancer malignancy is governed by regulation of the macroH2A2/TM4SF1 axis, the AKT/NF-κB pathway, and elevated MMP13 expression.

The histone variant, macroH2A (mH2A) influences gene expression through epigenetic regulation. Tumor suppressive function of mH2A isoforms has been reported in various cancer types, but few studies have investigated the functional role of mH2A2 in breast cancer pathophysiology. This study aimed to determine the significance of mH2A2 in breast cancer development and progression by exploring its downstream regulatory mechanisms. Knockdown of mH2A2 facilitated the migration and invasion of breast cancer cells, whereas its overexpression exhibited the opposite effect. In vivo experiments revealed that augmenting mH2A2 expression reduced tumor growth and lung metastasis. Microarray analysis showed that TM4SF1 emerged as a likely target linked to mH2A2 owing to its significant suppression in breast cancer cell lines where mH2A2 was overexpressed among the genes that exhibited over twofold upregulation upon mH2A2 knockdown. Suppressing TM4SF1 reduced the migration, invasion, tumor growth, and metastasis of breast cancer cells in vitro and in vivo. TM4SF1 depletion reversed the increased aggressiveness triggered by mH2A2 knockdown, suggesting a close interplay between mH2A2 and TM4SF1. Our findings also highlight the role of the mH2A2/TM4SF1 axis in activating the AKT/NF-κB pathway. Consequently, activated NF-κB signaling leads to increased expression and secretion of MMP13, a potent promoter of metastasis. In summary, we propose that the orchestrated regulation of the mH2A2/TM4SF1 axis in conjunction with the AKT/NF-κB pathway and the subsequent elevation in MMP13 expression constitute pivotal factors governing the malignancy of breast cancer.

Investigating the safety profiles of exogenous melatonin and associated adverse events: A pharmacovigilance study using WHO-VigiBase.

Melatonin, a pineal hormone that modulates circadian rhythms, sleep, and neurotransmitters, is widely used to treat sleep disorders. However, there are limited studies on the safety of melatonin. Therefore, we aimed to present the overall patterns of adverse events (AEs) following melatonin administration and identify potential safety signals associated with melatonin. Using VigiBase, a global individual case safety report (ICSRs) database managed by the World Health Organization (WHO), we conducted a retrospective, observational, pharmacovigilance study of melatonin between January 1996 and September 2022. Disproportionality analysis was conducted using two comparator settings: all other drugs and other sleep medications. We used multivariable logistic regression to estimate reporting odds ratios (RORs) with 95% confidence intervals (CIs) to compare the frequencies of AEs reporting between melatonin and each comparator setting. Furthermore, we assessed adverse events of special interests (AESIs) that could potentially be associated with melatonin. Signals were identified when the following criteria were met: cases ≥3, x2 ≥ 4, IC025 ≥ 0, and the lower end of the 95% CI of ROR > 2. These signals were then compared with the AE information on the drug labels provided by regulatory bodies. A total of 35 479 AE reports associated with melatonin were identified, with a higher proportion of reports from females (57.1%) and individuals aged 45-64 years (20.8%). We identified 21 AEs that were commonly detected as safety signals in the disproportionality analyses, including tic, educational problems, disturbance in social behavior, body temperature fluctuation, and growth retardation. In AESI analyses, accidents and injuries (adjusted ROR 2.97; 95% CI, 2.80-3.16), fall (2.24; 2.12-2.37), nightmare (4.90; 4.37-5.49), and abnormal dreams (3.68; 3.19-4.25) were detected as a signal of melatonin when compared to all other drugs, whereas those signals were not detected when compared to other sleep medications. In this pharmacovigilance study, exogenous melatonin showed safety profiles comparable to other sleep medications. However, several unexpected potential safety signals were identified, underscoring the need for further investigation at the population level.

The discovery of an anti-inflammatory monoterpenoid, neoroseoside from the Zea mays.

A new monoterpenoid, neoroseoside (1), along with two previously reported compounds, 2″-O-α-l-rhamnosyl-6-C-fucosylluteolin (2) and farobin A (3) were isolated from the Zea mays. The structure of compound 1 was determined through the analysis spectroscopic data, including mass spectrometry (MS), infrared (IR) spectroscopy, and nuclear magnetic resonance (NMR) data. The absolute configurations of 1 were deduced from the comparing the values of optical rotations and from the interpretation of electronic circular dichroism (ECD) spectra. Compounds 2 and 3 displayed moderate antibacterial activity against Streptococcus mutans ATCC 25175 (inhibition rates 24 % and 28 %, respectively) and Streptococcus sobrinus ATCC 33478 (inhibition rate of 26 %), at a concentration of 100 µg/mL, whereas compound 1 did not have any significant antibacterial activities. The compounds 1-3 also showed anti-inflammatory activity on cytokine IL-6 and TNF-α.

Bi-Allelic UQCRFS1 Variants Are Associated with Mitochondrial Complex III Deficiency, Cardiomyopathy, and Alopecia Totalis.

Isolated complex III (CIII) deficiencies are among the least frequently diagnosed mitochondrial disorders. Clinical symptoms range from isolated myopathy to severe multi-systemic disorders with early death and disability. To date, we know of pathogenic variants in genes encoding five out of 10 subunits and five out of 13 assembly factors of CIII. Here we describe rare bi-allelic variants in the gene of a catalytic subunit of CIII, UQCRFS1, which encodes the Rieske iron-sulfur protein, in two unrelated individuals. Affected children presented with low CIII activity in fibroblasts, lactic acidosis, fetal bradycardia, hypertrophic cardiomyopathy, and alopecia totalis. Studies in proband-derived fibroblasts showed a deleterious effect of the variants on UQCRFS1 protein abundance, mitochondrial import, CIII assembly, and cellular respiration. Complementation studies via lentiviral transduction and overexpression of wild-type UQCRFS1 restored mitochondrial function and rescued the cellular phenotype, confirming UQCRFS1 variants as causative for CIII deficiency. We demonstrate that mutations in UQCRFS1 can cause mitochondrial disease, and our results thereby expand the clinical and mutational spectrum of CIII deficiencies.

Health-promoting behavior among undergraduate students in the COVID-19 era: Its association with problematic use of social media, social isolation, and online health information-seeking behavior.

OBJECTIVE: To examine the association between problematic use of social media, online health information-seeking, social isolation, and health-promoting behaviors among Korean undergraduate students. METHODS: In total, 178 undergraduate students participated in this study. A multiple linear regression analysis was performed. RESULTS: Predictors of health-promoting behaviors included overall time spent on social media, problematic social media use, social isolation, and online information-seeking, explaining 33.5 % of the variance in health-promoting behaviors. CONCLUSION: Prolonged social media use and social isolation negatively affected undergraduate students' health-promoting behaviors, while online information-seeking positively affected them. Nurses should assist young adults in improving health-promoting behaviors by preventing problematic social media uses, reducing social isolation, and strengthening their online health information-seeking ability.

Role of senescent tumor cells in building a cytokine shield in the tumor microenvironment: mathematical modeling.

Cellular senescence can induce dual effects (promotion or inhibition) on cancer progression. While immune cells naturally respond and migrate toward various chemotactic sources from the tumor mass, various factors including senescent tumor cells (STCs) in the tumor microenvironment may affect this chemotactic movement. In this work, we investigate the mutual interactions between the tumor cells and the immune cells that either inhibit or facilitate tumor growth by developing a mathematical model that consists of taxis-reaction-diffusion equations and receptor kinetics for the key players in the interaction network. We apply a mathematical model to a transwell Boyden chamber invasion assay used in the experiments to illustrate that STCs can play a pivotal role in negating immune attack through tight regulation of intra- and extra-cellular signaling molecules. In particular, we show that senescent tumor cells in cell cycle arrest can block intratumoral infiltration of CD8+ T cells by secreting a high level of CXCL12, which leads to significant reduction its receptors, CXCR4, on T cells, and thus impaired chemotaxis. The predictions of nonlinear responses to CXCL12 were in good agreement with experimental data. We tested several hypotheses on immune-tumor interactions under various biochemical conditions in the tumor microenvironment and developed new concepts for anti-tumor strategies targeting senescence induced immune impairment.

G9a Knockdown Suppresses Cancer Aggressiveness by Facilitating Smad Protein Phosphorylation through Increasing BMP5 Expression in Luminal A Type Breast Cancer.

Epigenetic abnormalities affect tumor progression, as well as gene expression and function. Among the diverse epigenetic modulators, the histone methyltransferase G9a has been focused on due to its role in accelerating tumorigenesis and metastasis. Although epigenetic dysregulation is closely related to tumor progression, reports regarding the relationship between G9a and its possible downstream factors regulating breast tumor growth are scarce. Therefore, we aimed to verify the role of G9a and its presumable downstream regulators during malignant progression of breast cancer. G9a-depleted MCF7 and T47D breast cancer cells exhibited suppressed motility, including migration and invasion, and an improved response to ionizing radiation. To identify the possible key factors underlying these effects, microarray analysis was performed, and a TGF-ß superfamily member, BMP5, was selected as a prominent target gene. It was found that BMP5 expression was markedly increased by G9a knockdown. Moreover, reduction in the migration/invasion ability of MCF7 and T47D breast cancer cells was induced by BMP5. Interestingly, a G9a-depletion-mediated increase in BMP5 expression induced the phosphorylation of Smad proteins, which are the intracellular signaling mediators of BMP5. Accordingly, we concluded that the observed antitumor effects may be based on the G9a-depletion-mediated increase in BMP5 expression and the consequent facilitation of Smad protein phosphorylation.

Androsamide, a Cyclic Tetrapeptide from a Marine Nocardiopsis sp., Suppresses Motility of Colorectal Cancer Cells.

A cyclic tetrapeptide, androsamide (1), was isolated from a marine actinomycete of the genus Nocardiopsis, strain CNT-189. The planar structure of 1 was assigned by the interpretation of 1D and 2D NMR spectroscopic data. The absolute configurations of constituent amino acids of 1 were determined by application of the Marfey's and advanced Marfey's methods. Androsamide (1) strongly suppressed the motility of Caco2 cells caused by epithelial-mesenchymal transition.

The susceptible-unidentified infected-confirmed (SUC) epidemic model for estimating unidentified infected population for COVID-19.

In this article, we propose the Susceptible-Unidentified infected-Confirmed (SUC) epidemic model for estimating the unidentified infected population for coronavirus disease 2019 (COVID-19) in China. The unidentified infected population means the infected but not identified people. They are not yet hospitalized and still can spread the disease to the susceptible. To estimate the unidentified infected population, we find the optimal model parameters which best fit the confirmed case data in the least-squares sense. Here, we use the time series data of the confirmed cases in China reported by World Health Organization. In addition, we perform the practical identifiability analysis of the proposed model using the Monte Carlo simulation. The proposed model is simple but potentially useful in estimating the unidentified infected population to monitor the effectiveness of interventions and to prepare the quantity of protective masks or COVID-19 diagnostic kit to supply, hospital beds, medical staffs, and so on. Therefore, to control the spread of the infectious disease, it is essential to estimate the number of the unidentified infected population. The proposed SUC model can be used as a basic building block mathematical equation for estimating unidentified infected population.

Discrimination of Lycium chinense and L. barbarum Based on Metabolite Analysis and Hepatoprotective Activity.

Lycii Fructus is a traditional medicine used to prevent liver and kidney diseases, which commonly derives from Lycium chinense and Lycium barbarum. Here, the extracts and ethyl acetate-soluble fractions of L. chinense fruits exhibited better hepatoprotective effects than those of L. barbarum, which was likely due to differences in their composition. Therefore, GC-MS and HPLC analyses were conducted to characterize the metabolite differences between L. chinense and L. barbarum. Based on amino acid (AA) and phenolic acid (PA) profiling, 24 AAs and 9 PAs were identified in the two species. Moreover, each species exhibited unique and readily distinguishable AA and PA star graphic patterns. HPLC analysis elucidated composition differences between the ethyl acetate-soluble layers of the two compounds. Further, NMR analysis identified their chemical structures as 4-(2-formyl-5-(hydroxymethyl)-1H-pyrrol-1-yl)butanoic acid and p-coumaric acid. The higher content of 4-(2-formyl-5-(hydroxymethyl)-1H-pyrrol-1-yl)butanoic acid was detected in L. chinense, whereas the content of p-coumaric acid was higher in L. barbarum. Therefore, the differences in the relative contents of these two secondary metabolites in the ethyl acetate-soluble layer of Lycii Fructus could be a good marker to discriminate between L. chinense and L. barbarum.

Electroactive microorganisms enriched from activated sludge remove nitrogen in bioelectrochemical reactor.

The bioelectrochemical anaerobic nitrogen removal was demonstrated in an anaerobic batch reactor equipped with a pair of polarized bioelectrodes. The bioelectrochemical reactor was operated in sequential batch mode after inoculating activated sludge and polarizing the electrode to 0.6 V. The medium contains ammonium, nitrite, alkalinity and trace minerals, but no organic carbon source. By the repetitive sequential operation, simultaneous removals of ammonium, nitrite and alkalinity were improved, and the electrochemical activity of the bulk sludge was confirmed from the redox peaks of the cyclic voltammogram. This indicates that ammonia oxidizing exoelectrogens (AOE) and denitritating electrotrophs (DNE) were enriched more in the bulk solution. Biogas production that mainly consisted of nitrogen was observed from the bioelectrochemical reactor, and the minor components in the biogas were methane and carbon dioxide. This demonstrates that AOE use nitrite as an electron acceptor to oxidize ammonia. The requirements of nitrite and alkalinity for the removal of ammonia nitrogen are around 0.72 mg NO2-N/mg NH4-N and 1.73 mg as CaCO3/mg NH4-N, respectively, and nitrate was not produced as a by-product. The bacterial groups involved in the bioelectrochemical nitrogen removal are electroactive autotrophs and can be enriched from activated sludge by polarized electrode. This bioelectrochemical ammonia oxidation is a novel approach recommended for treatment of nitrogen-rich wastewater.

Polymorphisms of MTHFR, eNOS, ACE, AGT, ApoE, PON1, PDE4D, and Ischemic Stroke: Meta-Analysis.

INTRODUCTION: The association between ischemic stroke and genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR; 677C>T and 1298A>C), endothelial nitric oxide synthase (eNOS; -786T>C, +894G>T, and variable number tandem repeat [VNTR]), phosphodiesterase 4D (PDE4D; SNPs 83 and 87), angiotensin-converting enzyme (ACE) I/D, angiotensinogen (AGT) 235M>T, paraoxonase 1 (PON1) 192Q>R, and apolipoprotein E (ApoE) ε2ε3ε4 remains inconclusive. Therefore, this updated meta-analysis aimed to clarify the presumed influence of genetic polymorphisms on ischemic stroke by meta-analyzing the comprehensive coverage of all individual association studies. METHODS: All case-control studies published in different languages such as English, Japanese, Korean, Spanish, Chinese, Hungarian, Ukrainian, or Russian were identified from databases. The pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated via fixed- and random-effect models. Sensitivity analysis, heterogeneity test, Hardy Weinberg Equilibrium, and Egger's regression analyses were performed in this study. RESULTS: A total of 490 case-control studies with 138,592 cases and 159,314 controls were included in this meta-analysis. Pooled ORs from all the genetic models indicated that MTHFR 677TT and 1298CC, eNOS +894TT and VNTR, PDE4D SNP 83, ACE DD, AGT 235TT, PON1 192RR, and ApoE ε4 polymorphisms were increasing the risks of ischemic stroke. Nevertheless, PDE4D SNP 87 and eNOS -786T>C polymorphisms are not associated with ischemic stroke risks. CONCLUSIONS: Hence, the evidence from this meta-analysis concluded that MTHFR (677C>T and 1298A>C), eNOS (+894G>T and VNTR), PDE4D SNP 83, ACE I/D, AGT 235M>T, PON1 192Q>R, and ApoE ε2ε3ε4 polymorphisms predispose individuals to ischemic stroke.

Genome-wide association study reveals sex-specific selection signals against autosomal nucleotide variants.

A genome-wide association study (GWAS) was conducted to examine genetic associations of common autosomal nucleotide variants with sex in a Korean population with 4183 males and 4659 females. Nine genetic association signals were identified in four intragenic and five intergenic regions (P<5 × 10(-8)). Further analysis with an independent data set confirmed two intragenic association signals in the genes encoding protein phosphatase 1, regulatory subunit 12B (PPP1R12B, intron 12, rs1819043) and dynein, axonemal, heavy chain 11 (DNAH11, intron 61, rs10255013), which are directly involved in the reproductive system. This study revealed autosomal genetic variants associated with sex ratio by GWAS for the first time. This implies that genetic variants in proximity to the association signals may influence sex-specific selection and contribute to sex ratio variation. Further studies are required to reveal the mechanisms underlying sex-specific selection.

Statistical power for identifying nucleotide markers associated with quantitative traits in genome-wide association analysis using a mixed model.

Use of mixed models is in the spotlight as an emerging method for genome-wide association studies (GWASs). This study investigated the statistical power for identifying nucleotide variants associated with quantitative traits using the mixed model methodology. Quantitative traits were simulated through design of heritability, the number of causal variants (NCV), the number of polygenic variants, and genetic variance ratio of causal to polygenic variants (VRCTP). Statistical power estimates were influenced not only by individual factors of heritability, NCV, and VRCTP, but also by their interactions (P < 0.05). As the genetic variance ratio decreased, the difference in power between heritabilities of 0.3 and 0.5 increased with the use of 20 causal variants, but decreased when there were 100 causal variants (P < 0.05). The power empirically estimated from the simulation study would be applicable to the design of GWAS for quantitative traits with known genetic parameters by predicting the degree of false negative associations.

A mixed model reduces spurious genetic associations produced by population stratification in genome-wide association studies.

Population stratification can produce spurious genetic associations in genome-wide association studies (GWASs). Mixed model methodology has been regarded useful for correcting population stratification. This study explored statistical power and false discovery rate (FDR) with the data simulated for dichotomous traits. Empirical FDRs and powers were estimated using fixed models with and without genomic control and using mixed models with and without reflecting loci linked to the candidate marker in genetic relationships. Population stratification with admixture degree ranged from 1% to 10% resulted in inflated FDRs from the fixed model analysis without genomic control and decreased power from the fixed model analysis with genomic control (P<0.05). Meanwhile, population stratification could not change FDR and power estimates from the mixed model analyses (P>0.05). We suggest that the mixed model methodology was useful to reduce spurious genetic associations produced by population stratification in GWAS, even with a high degree of admixture (10%).

Analytical Models For Genetics of Human Traits Influenced By Sex.

Analytical models usually assume an additive sex effect by treating it as a covariate to identify genetic associations with sex-influenced traits. Their underlying assumptions are violated by ignoring interactions of sex with genetic factors and heterogeneous genetic effects by sex. Methods to deal with the problems are compared and discussed in this article. Especially, heterogeneity of genetic variance by sex can be assessed employing a mixed model with genetic relationship matrix constructed from genome-wide nucleotide variant information. Estimating genetic architecture of each sex would help understand different prevalence, course, and severity of complex diseases between women and men in the era of personalized medicine.

Transcriptional Downregulation by Nucleotide Substitution with the Minor Allele of rs3760776 Located in the Promoter of FUT6 Gene.

We examined the promoter activity of an association signal in an upstream region of the gene encoding fucosyltransferae 6 (FUT6) identified from a recent genomewide association study for the N-glycan level. The luciferase assay using reporter constructs with T and C alleles at rs3760776 revealed differential promoter activity. The amount of luciferin expressed with the C allele corresponded to that without the reporter construct (P > 0.05). On the other hand, the expression was dramatically reduced with the T allele (P < 0.05). The difference in transcriptional activity between the two alleles was confirmed by an electrophoretic mobility shift assay. It demonstrated that the promoter with a T allele had a stronger binding affinity to nuclear factors than that with the C allele. We concluded that the T allele of rs3760776 might repress the transcription of the FUT6 gene. Further studies are warranted to understand its underlying mechanism and its influence on susceptibility to potential diseases.

Functional investigation of a venous thromboembolism GWAS signal in a promoter region of coagulation factor XI gene.

Coagulation factor XI (FXI) is essential for normal function of the intrinsic pathway of blood coagulation. A nucleotide variant (rs3756008) in the promoter region of the FXI gene was recently reported for association with venous thromboembolism. This study aimed to examine promoter activity of the rs3756008 or other variants linked with it. Luciferase assay was analyzed with minigenes including haplotypes (AA with frequency of 0.62 and TG with frequency of 0.38) of 2 completely linked nucleotide variants (rs3756008 and rs3756009) in 5'-upstream region of the FXI gene. While their expression did not differ in hepatic cell (P > 0.05), the major haplotype (AA) made a significantly more expression (P < 0.05) than the minor haplotype (TG) in human embryonic kidney 293 cells. Further luciferase analysis with additional haplotypes (artificial; TA, AG) revealed that the large expression was caused by the major allele of rs3756008 (P < 0.05), but not by that of rs3756009 (P > 0.05). We suggested that the minor allele of rs3756008 in the promoter of FXI gene could reduce its expression in kidney.

Identification of contemporary selection signatures using composite log likelihood and their associations with marbling score in Korean cattle.

Positive selection not only increases beneficial allele frequency but also causes augmentation of allele frequencies of sequence variants in close proximity. Signals for positive selection were detected by the statistical differences in subsequent allele frequencies. To identify selection signatures in Korean cattle, we applied a composite log-likelihood (CLL)-based method, which calculates a composite likelihood of the allelic frequencies observed across sliding windows of five adjacent loci and compares the value with the critical statistic estimated by 50,000 permutations. Data for a total of 11,799 nucleotide polymorphisms were used with 71 Korean cattle and 209 foreign beef cattle. As a result, 147 signals were identified for Korean cattle based on CLL estimates (P < 0.01). The signals might be candidate genetic factors for meat quality by which the Korean cattle have been selected. Further genetic association analysis with 41 intragenic variants in the selection signatures with the greatest CLL for each chromosome revealed that marbling score was associated with five variants. Intensive association studies with all the selection signatures identified in this study are required to exclude signals associated with other phenotypes or signals falsely detected and thus to identify genetic markers for meat quality.

Identification of functional haplotypes in the promoter region of the LST1 gene.

Psoriasis, an inflammatory skin disease, was associated with a promoter variant (rs9267502; P = 3.786 × 10(-19)) of LST1 that may regulate immune response and cellular morphogenesis. Promoter activity was examined to identify functional variants in the proximity of the associated variant. Five natural haplotypes (H1-H5) of four variants (rs7758790, rs9267502, rs41268884, rs17200775) in strong linkage disequilibrium were investigated. The most common haplotype (H1) was TGAG (frequency 0.78), and the second most frequent haplotype (H2) was CGGG (0.09). Luciferase assay was conducted using reporter constructs including each haplotype and firefly luciferase gene. As a result, promoter activity of H1 was smaller than the construct without the promoter region (P < 0.05). The promoter activities of H3, H4, and H5 corresponded to that of H1 (P > 0.05), and H2 promoter activity was larger than that of H1, H3, H4, and H5 (P < 0.05). This might result from changes in binding affinity to transcription factors by nucleotide substitutions of the promoter variants of the LST1 gene.