Crosstalk of Genetic Variants, Allele-Specific DNA Methylation, and Environmental Factors for Complex Disease Risk

Over the past decades, genome-wide association studies (GWAS) have identified thousands of phenotype-associated DNA sequence variants for potential explanations of inter-individual phenotypic differences and disease susceptibility. However, it remains a challenge for translating the associations into causative mechanisms for complex diseases, partially due to the involved variants in the noncoding regions and the inconvenience of functional studies in human population samples. So far, accumulating evidence has suggested a complex crosstalk among genetic variants, allele-specific binding of transcription factors (ABTF), and allele-specific DNA methylation patterns (ASM), as well as environmental factors for disease risk. This review aims to summarize the current studies regarding the interactions of the aforementioned factors with a focus on epigenetic insights. We present two scenarios of single nucleotide polymorphisms (SNPs) in coding regions and non-coding regions for disease risk, via potentially impacting epigenetic patterns. While a SNP in a coding region may confer disease risk via altering protein functions, a SNP in non-coding region may cause diseases, via SNP-altering ABTF, ASM, and allele-specific gene expression (ASE). The allelic increases or decreases of gene expression are key for disease risk during development. Such ASE can be achieved via either a “SNP-introduced ABTF to ASM” or a “SNP-introduced ASM to ABTF.” Together with our additional in-depth review on insulator CTCF, we are convinced to propose a working model that the small effect of a SNP acts through altered ABTF and/or ASM, for ASE and eventual disease outcome (named as a “SNP intensifier” model). In summary, the significance of complex crosstalk among genetic factors, epigenetic patterns, and environmental factors requires further investigations for disease susceptibility

Liquefaction Risk Evaluation During Earthquakes

A simplified method is herein presented to evaluate liquefaction risk, where we modified the form of liquefaction potential index suggested by Iwasaki, Tokida and others (1980, 1982). Based upon the investigations of structure damage induced by soil liquefaction during Tangshan earthquake, four categories for evaluating liquefaction risk and the principles of engineering treatment are proposed. Several typical liquefaction sites are analyzed by this method

Impaired cardioprotective function of transplantation of mesenchymal stem cells from patients with diabetes mellitus to rats with experimentally induced myocardial infarction

BACKGROUND: Diabetes mellitus (DM) exacerbates coronary artery disease (CAD) morbidity and mortality. Mesenchymal stem cells (MSCs) play an important therapeutic role in myocardial ischemic injury. However, little is known about changes in the cardioprotective characteristics of MSCs from patients with DM. METHODS: Sternal bone marrow aspirates were taken at the time of coronary artery bypass graft surgery. The morphology and growth characteristics of hMSCs were observed in passage 3. Differences in gene expression profiling were measured by Affymetrix GeneChipHuman Genome U133 Plus 2.0 Arrays. Forty two adult male rats with experimentally CAD were randomized into three groups. MSCs from patients with CAD+DM or CAD were injected into the infarcted myocardium. Control animals received culture medium. Echocardiography, TUNEL, immunohistochemistry and Western-blot analysis were performed 4 weeks after transplantation. RESULTS: Growth curves showed that proliferation of hMSCs in the CAD+DM group was significantly lower than in the CAD group. Nine transcripts of genes related to apoptosis containing Bcl-2 were found to differentiate the two groups. Transplantation of hMSCs in the infarcted border zone improved cardiac function, but DM partly impaired this effect. Similar results were observed from TUNEL, immunohistochemistry and Western-blot analysis. CONCLUSIONS: hMSCs from patients with CAD+DM and CAD alone both have proliferative properties. Transplantation of hMSCs ameliorate heart function, but proliferative ability and myocardial protection decrease significantly in MSCs obtained from patients with CAD+DM compared with cultures from patients with CAD alone, possibly as a result of differences in Bcl-2 protein expression and reduced anti-apoptosis

The effect of chemotherapy combined with recombination mutant human tumor necrosis factor on advanced cancer

BACKGROUND: Past studies suggested that tumor necrosis factor (TNF) assisted anti-tumor treatment and intensified the sensitivity of chemotherapy. However its clinical application has been curbed because of its low purity, high dosage, and strong toxicity. This research, through perspective random clinical control experiment, observed the therapeutic effect of the treatment of late malignant tumor through the injection of recombinant mutant human tumor necrosis factor (rmhTNF) combined with general chemotherapy and its adverse reactions. METHODS: 105 patients with advanced malignant tumor were randomly divided into trial group, 69 patients, and control group, 36 patients. Injection of rmhTNF 4 × 10(6)u/m(2 )was given to the trial group, from the 1(st )to 7(th )days, the 11(th )to 17(th )days combined with chemotherapy course. The chemotherapy plan was as follows: CAP for patients with the NSCLC; FAM for patients with gastric cancer; FC for patients with colorectal cancer. One treatment cycle lasted for 21 days and two cycles were scheduled. The control group was given only the same chemotherapy as the trial group. RESULTS: In the trial group there was 1 CR case and 12 PR cases, and the response rate is 13/69 (18.84%); in the control group 1 PR case, the response rate 1/36 (2.78%). The response rate of the trial group was significantly higher than that of the control group (P = 0.022). The response rate for NSCLC in the trial group was 8/17 (47.06%), and 1/6 (16.67%) in the control group. The response rates for gastric cancer and colorectal cancer in the trial groups also were higher than those of the control groups. After the treatment the KPS is 89.00 ± 9.92 in the trial group, and 84.17 ± 8.84 in the control group, with a significant difference between the two groups (P = 0.028). The adverse reactions of rmhTNF injection included: pain in the injection area, chill, hardening and swelling and redness in the injection area, fever, ostealgia and myosalgia, and cold-like symptoms. All these adverse reactions were mild and bearable. CONCLUSIONS: The administration of rmhTNF injection in combination with general chemotherapy is an effective and secure means in treating advanced malignant tumor

Polydatin Protects Diabetic Heart against Ischemia-Reperfusion Injury via Notch1/Hes1-Mediated Activation of Pten/Akt Signaling

Diabetes exacerbates oxidative/nitrative stress during myocardial ischemia-reperfusion (MI/R) injury. Recent studies highlighted the cardioprotective actions of polydatin. However, its effect on diabetic MI/R injury and the underlying mechanisms remain unknown. This work was undertaken to evaluate the effect of polydatin on diabetic MI/R injury with a focus on Notch1/Hes1 signaling and myocardial oxidative/nitrative stress. Streptozotocin- (STZ-) induced diabetic rats were administered with polydatin (20 mg/kg/d) in the absence or presence of DAPT (a γ-secretase inhibitor) or LY294002 (a PI3K/Akt inhibitor) and then subjected to MI/R injury. Polydatin administration preserved cardiac function and reduced myocardial infarct size. Moreover, polydatin ameliorated myocardial oxidative/nitrative stress damage as evidenced by decreased myocardial superoxide generation, malondialdehyde, gp91phox expression, iNOS expression, NO metabolite level, and nitrotyrosine content and increased eNOS phosphorylation. However, these effects were blocked by DAPT administration. DAPT also inhibited the stimulatory effect of polydatin on the Notch1/Hes1-Pten/Akt signaling pathway in a diabetic myocardium. Additionally, LY294002 not only abolished polydatin’s antiapoptotic effect but also reversed its inhibitory effect on myocardial oxidative/nitrative stress. Polydatin effectively reduced MI/R injury and improved left ventricular functional recovery under diabetic condition by ameliorating oxidative/nitrative stress damage. Importantly, Notch1/Hes1-mediated activation of Pten/Akt signaling played a crucial role in this process

Survival and risk factors associated with surgical repair of ventricular septal rupture after acute myocardial infarction: A single-center experience

ObjectiveTo analyze the survival and risk factors associated with the surgical treatment of ventricular septal rupture (VSR) after acute myocardial infarction (AMI).MethodsWe retrospectively analyzed 45 consecutive patients with VSR after AMI whose procedures were performed in the Department of Cardiovascular Surgery at the General Hospital of Northern Theater Command between January 2012 and December 2021. Relevant clinical data, surgery-related conditions, and follow-up data of all patients were summarized. Patients were divided into the survival group and the death group. The Kaplan–Meier method and log-rank test were used to determine the cumulative incidence of all-cause mortality. Multivariate logistic regression was used to evaluate the independent risk factors for all-cause mortality.ResultsThe average postoperative follow-up time was 42.1 ± 34.1 months. The overall mortality rate was 20% (9/45 patients) and the operative mortality rate was 8.9% (4/45 patients). Logistic analysis showed that the death group had higher serum creatinine (127.32 ± 47.82 vs. 82.61 ± 27.80 μmol/L, respectively; P = 0.0238) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) [8,654.00 pg/mL (6,197.00–11,949.00 pg/mL) vs. 4,268.96 pg/mL (1,800.00–7,894.00 pg/mL), respectively; P = 0.0134] levels than the survival group. The cardiopulmonary bypass time (CPB) was longer in the death group than in the survival group [131.00 min (121.00–184.00 min) vs. 119.00 min (103.00–151.50 min), respectively; P = 0.0454]. Significantly more red blood cells were transfused in the death group than in the survival group [11.60 units (6.10–16.50) vs. 3.75 units (0.00–7.00 units), respectively; P = 0.0025]. Intra-aortic balloon pump (IABP) implantation (P = 0.016) and ventilation time (P = 0.0022) were risk factors for mortality. A 1-month landmark analysis showed that compared with patients with VSR to surgical time >14 days, patients who underwent surgery within 14 days had a higher rate of all-cause mortality (25.00 vs. 3.33%; log-rank P = 0.023). Patients with VSR within 14 days also had a higher rate of residual shunts that were higher than moderate. Multivariate analysis showed that transfusion of red blood cells and NT-proBNP level were risk factors for all-cause mortality, as well as major adverse cardiovascular and cerebrovascular events.ConclusionsSurgical repair resulted in good outcomes for patients with VSR after AMI. Patients with VSR to surgical time >14 days had a lower rate of all-cause mortality. Treatment strategies for VSR should be based on the patient's condition and comprehensively determined through real-time evaluation and monitoring

Heat shock protein 27 is a potential indicator for response to YangZheng XiaoJi and chemotherapy agents in cancer cells

Heat shock protein 27 (HSP27) is a member of the heat shock protein family which has been linked to tumour progression and, most interestingly, to chemotherapy resistance in cancer patients. The present study examined the potential interplay between HSP27 and YangZheng XiaoJi, a traditional Chinese medicine used in cancer treatment. A range of cell lines from different tumour types including pancreatic, lung, gastric, colorectal, breast, prostate and ovarian cancer (both wild-type and resistant) were used. Levels and activation of HSP27 and its potential associated signalling pathways were evaluated by protein array and western blotting. Knockdown of HSP27 in cancer cells was achieved using siRNA. Localisation and co-localisation of HSP27 and other proteins were carried out by immunofluorescence. Cell growth and migration were evaluated in their response to a range of chemotherapeutic agents. The present study first identified, by way of protein array, that YangZheng XiaoJi was able to inhibit the phosphorylation of HSP27 protein in cancer cells. We further demonstrated that HSP27, which is co-localised with caspase-9, can be blocked from localising in focal adhesions and co-localising with caspase-9 by YangZheng XiaoJi. The study also demonstrated that YangZheng XiaoJi was able to sensitise cancer cells including those cells that were resistant to chemotherapy, to chemotherapeutic agents. Finally, knocking down HSP27 markedly reduced the migration of cancer cells and increased the sensitivity of cancer cells to the inhibitory effect on cellular migration by YangZheng XiaoJi. YangZheng XiaoJi can act as an agent in first sensitising cancer cells to chemotherapy and secondly to overcome, to some degree, chemoresistance when used in an appropriate fashion in patients who have active HSP2

Minimizing the programming power of phase change memory by using graphene nanoribbon edge-contact

Nonvolatile phase change random access memory (PCRAM) is regarded as one of promising candidates for emerging mass storage in the era of Big Data. However, relatively high programming energy hurdles the further reduction of power consumption in PCRAM. Utilizing narrow edge-contact of graphene can effectively reduce the active volume of phase change material in each cell, and therefore realize low-power operation. Here, we demonstrate that a write energy can be reduced to about ~53.7 fJ in a cell with ~3 nm-wide graphene nanoribbon (GNR) as edge-contact, whose cross-sectional area is only ~1 nm2. It is found that the cycle endurance exhibits an obvious dependence on the bias polarity in the cell with structure asymmetry. If a positive bias was applied to graphene electrode, the endurance can be extended at least one order longer than the case with reversal of polarity. The work represents a great technological advance for the low power PCRAM and could benefit for in-memory computing in future.Comment: 14 pages, 4 figure

Isolating hydrogen in hexagonal boron nitride bubbles by a plasma treatment

Atomically thin hexagonal boron nitride (h-BN) is often regarded as an elastic film that is impermeable to gases. The high stabilities in thermal and chemical properties allow h-BN to serve as a gas barrier under extreme conditions.In this work, we demonstrate the isolation of hydrogen in bubbles of h-BN via plasma treatment.Detailed characterizations reveal that the substrates do not show chemical change after treatment. The bubbles are found to withstand thermal treatment in air,even at 800 degree celsius. Scanning transmission electron microscopy investigation shows that the h-BN multilayer has a unique aligned porous stacking nature, which is essential for the character of being transparent to atomic hydrogen but impermeable to hydrogen molecules. We successfully demonstrated the extraction of hydrogen gases from gaseous compounds or mixtures containing hydrogen element. The successful production of hydrogen bubbles on h-BN flakes has potential for further application in nano/micro-electromechanical systems and hydrogen storage.Comment: 55 pages, 33figure