Testing Gene-Gene Interactions Based on a Neighborhood Perspective in Genome-wide Association Studies.

Unexplained genetic variation that causes complex diseases is often induced by gene-gene interactions (GGIs). Gene-based methods are one of the current statistical methodologies for discovering GGIs in case-control genome-wide association studies that are not only powerful statistically, but also interpretable biologically. However, most approaches include assumptions about the form of GGIs, which results in poor statistical performance. As a result, we propose gene-based testing based on the maximal neighborhood coefficient (MNC) called gene-based gene-gene interaction through a maximal neighborhood coefficient (GBMNC). MNC is a metric for capturing a wide range of relationships between two random vectors with arbitrary, but not necessarily equal, dimensions. We established a statistic that leverages the difference in MNC in case and in control samples as an indication of the existence of GGIs, based on the assumption that the joint distribution of two genes in cases and controls should not be substantially different if there is no interaction between them. We then used a permutation-based statistical test to evaluate this statistic and calculate a statistical p-value to represent the significance of the interaction. Experimental results using both simulation and real data showed that our approach outperformed earlier methods for detecting GGIs.

Involvement of SIRT1 in amelioration of schistosomiasis-induced hepatic fibrosis by genistein.

Previous study revealed that genistein alleviate the extent of hepatic fibrosis in schistosomiasis-infected mice, however, the potential mechanism is still incomplete. Present study was, therefore, carried out to investigate the underlying mechanism of ameliorating schistosomiasis-induced hepatic fibrosis by genistein. α-smooth muscle actin (α-SMA) expression, as a critical fibrotic marker, was markedly upregulated in Schistosoma japonicum (S. japonicum) egg-induced liver fibrosis, and gradually inhibited by genistein administration in infected mice. Contrary to the changes of α-SMA expression, hepatic SIRT1 expression and activity was greatly inhibited in mice upon S. japonicum infection, and the repression was reversed in liver tissues after receiving 25 mg/kg genistein. 50 mg/kg genistein treatment gave rise to the higher SIRT1 expression and activity than that of the control group. In hepatic stellate cells (HSCs), genistein (5, 10, 20 µM) treatment resulted in the increases of SIRT1 expression and activity in concentration-dependent manner. Moreover, to mimic the fibrogenesis in vivo, macrophage was treated with soluble egg antigen (SEA) to obtain macrophage-conditioned medium (MφCM), which was used to stimulate HSCs. Intriguingly, SIRT1 overexpression decreased fibrosis associated gene expression in HSCs exposed to MφCM or not. Additionally, MφCM gave rise to high levels of α-SMA and p-Smad3 and the increments were reversed upon genistein treatment in HSCs. Furthermore, EX527, SIRT1 specific inhibitor, abrogated the inhibitory effects of genistein on HSCs activation. Together, the results support the notion that the strong elevation of SIRT1 expression and activity may represent a potential mechanism of protection against schistosomiasis-induced hepatic fibrosis by genistein.

Development and validation of a simple-to-use nomogram to predict the deterioration and survival of patients with COVID-19.

BACKGROUND: COVID-19 pandemic has forced physicians to quickly determine the patient's condition and choose treatment strategies. This study aimed to build and validate a simple tool that can quickly predict the deterioration and survival of COVID-19 patients. METHODS: A total of 351 COVID-19 patients admitted to the Third People's Hospital of Yichang between 9 January to 25 March 2020 were retrospectively analyzed. Patients were randomly grouped into training (n = 246) or a validation (n = 105) dataset. Risk factors associated with deterioration were identified using univariate logistic regression and least absolute shrinkage and selection operator (LASSO) regression. The factors were then incorporated into the nomogram. Kaplan-Meier analysis was used to compare the survival of patients between the low- and high-risk groups divided by the cut-off point. RESULTS: The least absolute shrinkage and selection operator (LASSO) regression was used to construct the nomogram via four parameters (white blood cells, C-reactive protein, lymphocyte≥0.8 × 109/L, and lactate dehydrogenase ≥400 U/L). The nomogram showed good discriminative performance with the area under the receiver operating characteristic (AUROC) of 0.945 (95% confidence interval: 0.91-0.98), and good calibration (P = 0.539). Besides, the nomogram showed good discrimination performance and good calibration in the validation and total cohorts (AUROC = 0.979 and AUROC = 0.954, respectively). Decision curve analysis demonstrated that the model had clinical application value. Kaplan-Meier analysis illustrated that low-risk patients had a significantly higher 8-week survival rate than those in the high-risk group (100% vs 71.41% and P < 0.0001). CONCLUSION: A simple-to-use nomogram with excellent performance in predicting deterioration risk and survival of COVID-19 patients was developed and validated. However, it is necessary to verify this nomogram using a large-scale multicenter study.

[Changes of different cell subsets in thymus and spleen of mice at different growth stages and the facilitating effect of ROCK inhibitor on thymus regeneration in aged mice].

Objective To investigate the changes of subsets of thymocytes, thymic epithelial cells (TECs) and T lymphocytes in the spleen of mice at different growth stages, and to explore the effect of Rho-associated coiled-coil protein kinase (ROCK) inhibitor on thymus regeneration in aged mice. Methods The thymus and spleens were harvested from female C57BL/6 mice at juvenile, mature adult, middle-aged and aged phases. The subsets of thymocytes, TECs and T cells in the spleen were analyzed by flow cytometry (FCM). TECs of aging mice were treated with ROCK inhibitor in vitro. Cell proliferation was observed using fluorescence immune-linked spot analyzer. Aged mice of 20-month old were treated with ROCK inhibitor in vivo. The changes of thymocytes, TECs and T cell subgroups in the spleen were detected with FCM. Results The total numbers of thymocytes and TECs as well as the number of each cell subpopulation decreased significantly with aging. The proportions of CD4+ naive T cells, CD8+ naive T cells and CD4+ recent thymus emigrant cells (RTEs) in the spleen showed significant decreasing trends although there were not obvious changes in the proportions of CD4+ T cells and CD8+ T cells in the spleen of mice during aging. ROCK inhibitor facilitated the proliferation of TECs in aging mice in vitro. ROCK inhibitor also increased the numbers of the subsets of thymocytes, TECs and T cells in the spleen of aged mice significantly. Conclusion The mouse thymus undergoes progressing degeneration with aging. ROCK inhibitor has potential of relieving the atrophy of thymus, facilitating thymus regeneration in aged mice.

Alterations of the Gut Microbiota in Patients With Severe Chronic Heart Failure.

Chronic heart failure (CHF) is the final outcome of almost all forms of cardiovascular diseases, remaining the main cause of mortality worldwide. Accumulating evidence is focused on the roles of gut microbial community in cardiovascular disease, but few studies have unveiled the alterations and further directions of gut microbiota in severe CHF patients. Aimed to investigate this deficiency, fecal samples from 29 CHF patients diagnosed with NYHA Class III-IV and 30 healthy controls were collected and then analyzed using bacterial 16S rRNA gene sequencing. As a result, there were many significant differences between the two groups. Firstly, the phylum Firmicutes was found to be remarkably decreased in severe CHF patients, and the phylum Proteobacteria was the second most abundant phyla in severe CHF patients instead of phylum Bacteroides strangely. Secondly, the α diversity indices such as chao1, PD-whole-tree and Shannon indices were significantly decreased in the severe CHF versus the control group, as well as the notable difference in ß-diversity between the two groups. Thirdly, our result revealed a remarkable decrease in the abundance of the short-chain fatty acids (SCFA)-producing bacteria including genera Ruminococcaceae UCG-004, Ruminococcaceae UCG-002, Lachnospiraceae FCS020 group, Dialister and the increased abundance of the genera in Enterococcus and Enterococcaceae with an increased production of lactic acid. Finally, the alternation of the gut microbiota was presumably associated with the function including Cell cycle control, cell division, chromosome partitioning, Amino acid transport and metabolism and Carbohydrate transport and metabolism through SCFA pathway. Our findings provide the direction and theoretical knowledge for the regulation of gut flora in the treatment of severe CHF.

MicroRNA 494 increases chemosensitivity to doxorubicin in gastric cancer cells by targeting phosphodiesterases 4D.

Acquired drug resistance is one of the main limitations in pharmacological therapy of malignancies including gastric cancer. MicroRNAs (miRNAs) are a class of small noncoding RNAs that suppress their targets by binding to the 3'UTR region of genes. In this study, we explored investigate the target gene of miR-494 and its roles in chemoresistance of gastric cancer. We found that miR-494 was significantly down-regulated in gastric cancer cells lines compared to the normal gastric epithelial cell line. Exogenous overexpression of miR-494 increased the chemosensitivity of gastric cancer cells to doxorubicin. Moreover, miR-494 expression was reduced in a doxorubicin-resistant gastric cancer cells (AGS/dox) compared with the parental cells. MTT assay showed that AGS/dox cells exhibited an elevated viability compared with the parental cells. Enforced expression of miR-494 inhibited AGS/dox cell viability and colony formation ability. In addition, we demonstrated that elevated expression of miR-494 inhibited the mRNA and protein expression of phosphodiesterases 4D (PDE4D) in gastric cancer cell. Luciferase assay showed that miR-494 directly targeted the 3'UTR region of PDE4D. Furthermore, restoration of PDE4D recovered the chemoresistance in miR-494-overexpressed gastric cancer cells. Taken together, this study demonstrated that miR-494 enhanced doxorubicin sensitivity via regulation of PDE4D expression, suggesting a novel therapeutic strategy for anti-chemoresistance in gastric cancer.

Fully integrated InGaAs/InP single-photon detector module with gigahertz sine wave gating.

InGaAs/InP single-photon avalanche diodes (SPADs) working in the regime of GHz clock rates are crucial components for the high-speed quantum key distribution (QKD). We have developed for the first time a compact, stable, and user-friendly tabletop InGaAs/InP single-photon detector system operating at a 1.25 GHz gate rate that fully integrates functions for controlling and optimizing SPAD performance. We characterize the key parameters of the detector system and test the long-term stability of the system for continuous operation of 75 h. The detector system can substantially enhance QKD performance and our present work paves the way for practical high-speed QKD applications.

[Inhibitory effects of Salvia miltiorrhiza injection coordinated with dexamethasone on interleukin-13 and eotaxin expression in lung of asthmatic rats].

OBJECTIVE: To investigate the molecular mechanism of inhibitory effect of Salvia miltiorrhiza Injection (SMI) coordinated with dexamethasone (DXM) on allergic airway inflammation in asthmatic rats. METHODS: Forty SD rats were randomly divided into 5 groups equally: the normal group, the asthma model group, the DXM group, the SMI group and the DXM + SMI group, they were treated with correspondant herbal medicines. Pathologic changes of lung tissue were obseved with HE stain, count of WBC and eosinophil (Eos) in bronchoalveolar lavage fluid (BALF) were estimated and the expressions of interleukin-13 (IL-13) and Eotaxin in lung tissue were measured by RT-PCR and SP method of immunohistochemistry assay. RESULTS: There was moderate inflammation in lung tissue in the SMI group, and mild inflammation in the DXM + SMI and the DXM group, which was similar to that in the normal group. Compared with the asthma model group, Eos and WBC count in BALF and the expression of IL-13 and Eotaxin in the lung tissue were significantly lower in the three treated groups (P < 0.05), particularly in the DXM + SMI group, showing a significant difference as compared with the other two groups (P < 0.05 or P < 0.01). Additionally, IL-13 expression was positively correlated with Eotaxin expression (r = 0.92, P < 0.01). CONCLUSION: SMI could inhibit the expression of IL-13 and Eotaxin in the lung of asthmatic rats, showing inhibitory effects synergistic with DXM on airway inflammation.