[Genotype-environment interaction on arterial stiffness: A pedigree-based study].

OBJECTIVE: To utilized the baseline data of the Beijing Fangshan Family Cohort Study, and to estimate whether the association between a healthy lifestyle and arterial stiffness might be modified by genetic effects. METHODS: Probands and their relatives from 9 rural areas in Fangshan district, Beijing were included in this study. We developed a healthy lifestyle score based on five lifestyle behaviors: smoking, alcohol consumption, body mass index (BMI), dietary pattern, and physical activity. The measurements of arterial stiffness were brachial-ankle pulse wave velocity (baPWV) and ankle-brachial index (ABI). A variance component model was used to determine the heritability of arterial stiffness. Genotype-environment interaction effects were performed by the maximum likelihood methods. Subsequently, 45 candidate single nucleotide polymorphisms (SNPs) located in the glycolipid metabolism pathway were selected, and generalized estimated equations were used to assess the gene-environment interaction effects between particular genetic loci and healthy lifestyles. RESULTS: A total of 6 302 study subjects across 3 225 pedigrees were enrolled in this study, with a mean age of 56.9 years and 45.1% male. Heritability of baPWV and ABI was 0.360 (95%CI: 0.302-0.418) and 0.243 (95%CI: 0.175-0.311), respectively. Significant genotype-healthy diet interaction on baPWV and genotype-BMI interaction on ABI were observed. Following the findings of genotype-environment interaction analysis, we further identified two SNPs located in ADAMTS9-AS2 and CDH13 might modify the association between healthy dietary pattern and arterial stiffness, indicating that adherence to a healthy dietary pattern might attenuate the genetic risk on arterial stiffness. Three SNPs in CDKAL1, ATP8B2 and SLC30A8 were shown to interact with BMI, implying that maintaining BMI within a healthy range might decrease the genetic risk of arterial stiffness. CONCLUSION: The current study discovered that genotype-healthy dietary pattern and genotype-BMI interactions might affect the risk of arterial stiffness. Furthermore, we identified five genetic loci that might modify the relationship between healthy dietary pattern and BMI with arterial stiffness. Our findings suggested that a healthy lifestyle may reduce the genetic risk of arterial stiffness. This study has laid the groundwork for future research exploring mechanisms of arterial stiffness.

[The role of the high-level public health school in the development of the Center for Disease Control and Prevention].

The Ministry of Education and other four departments jointly issued the Notice on the Construction of high-level schools of public Health, proposing that "it will take ten years to build a number of high-level schools of public health, and form a high-quality education development system to adapt to the construction of modern public health system". At present, the construction of high-level public health schools in various universities in China is in full swing. The high-level School of Public Health and the CDC have played an important role in constructing the national public health system and the human health community. The high-level public health schools are of strategic significance and important value to the development of the CDC. The review presents reflections and insights on the role of high-level public health schools in the development of the CDC and the challenges they might face.

[Progress in research of risk prediction of non-syndromic oral clefts using genetic information].

Non-syndromic oral cleft (NSOC), a common birth defect, remains to be a critical public health problem in China. In the context of adjustment of childbearing policy for two times in China and the increase of pregnancy at older childbearing age, NSOC risk prediction will provide evidence for high-risk population identification and prenatal counseling. Genome-wide association study and second generation sequencing have identified multiple loci associated with NSOC, facilitating the development of genetic risk prediction of NSOC. Despite the marked progress, risk prediction models of NSOC still faces multiple challenges. This paper summarizes the recent progress in research of NSOC risk prediction models based on the results of extensive literature retrieval to provide some insights for the model development regarding research design, variable selection, model-build strategy and evaluation methods.

[Family-based association tests for rare variants].

Next-generation sequencing has revolutionized family-based association tests for rare variants. As the lower power of genome wide association study for detecting casual rare variants, methods aggregating effects of multiple variants have been proposed, such as burden tests and variance component tests. This paper summarizes the methods of rare variants association test that can be applied for family data, introduces their principles, characteristics and applicable conditions and discusses the shortcomings and the improvement of the present methods.

[Exploring the association between de novo mutations and non-syndromic cleft lip with or without palate based on whole exome sequencing of case-parent trios].

OBJECTIVE: To explore the association between de novo mutations (DNM) and non-syndromic cleft lip with or without palate (NSCL/P) using case-parent trio design. METHODS: Whole-exome sequencing was conducted for twenty-two NSCL/P trios and Genome Analysis ToolKit (GATK) was used to identify DNM by comparing the alleles of the cases and their parents. Information of predictable functions was annotated to the locus with SnpEff. Enrichment analysis for DNM was conducted to test the difference between the actual number and the expected number of DNM, and to explore whether there were genes with more DNM than expected. NSCL/P-related genes indicated by previous studies with solid evidence were selected by literature reviewing. Protein-protein interactions analysis was conducted among the genes with protein-altering DNM and NSCL/P-related genes. R package "denovolyzeR" was used for the enrichment analysis (Bonferroni correction: P=0.05/n, n is the number of genes in the whole genome range). Protein-protein interactions among genes with DNM and genes with solid evidence on the risk factors of NSCL/P were predicted depending on the information provided by STRING database. RESULTS: A total of 339 908 SNPs were qualified for the subsequent analysis after quality control. The number of high confident DNM identified by GATK was 345. Among those DNM, forty-four DNM were missense mutations, one DNM was nonsense mutation, two DNM were splicing site mutations, twenty DNM were synonymous mutations and others were located in intron or intergenic regions. The results of enrichment analysis showed that the number of protein-altering DNM on the exome regions was larger than expected (P < 0.05), and five genes (KRTCAP2, HMCN2, ANKRD36C, ADGRL2 and DIPK2A) had more DNM than expected (P < 0.05/(2×19 618)). Protein-protein interaction analysis was conducted among forty-six genes with protein-altering DNM and thirteen genes associated with NSCL/P selected by literature reviewing. Six pairs of interactions occurred between the genes with DNM and known NSCL/P-related genes. The score measuring the confidence level of the predicted interaction between RGPD4 and SUMO1 was 0.868, which was higher than the scores for other pairs of genes. CONCLUSION: Our study provided novel insights into the development of NSCL/P and demonstrated that functional analyses of genes carrying DNM were warranted to understand the genetic architecture of complex diseases.

[A descriptive analysis on body mass index distribution in adult twin pairs in China].

Objective: To describe the differences in body mass index (BMI) distribution in adult twins registered in Chinese National Twin Registry (CNTR), and provide evidence for the risk factor analysis and prevention and control of overweight or obesity. Methods: A total of 32 725 twin pairs aged 18 years and above who completed the questionnaire survey during 2010-2018 and had complete registered information in CNTR and normal body weight and length were included in the analysis on the population and region specific distributions of BMI of twin pairs and the difference in BMI in twin pairs. Results: The twin pairs included in the analysis were aged (34.6±12.4) years, the twin pairs of same gender accounted for 79.7%. The average BMI was 22.5 kg/m2. The overall prevalence of obesity and overweight was 4.9% and 23.7%, respectively. Participants who were men, 50-59 years old, married, had lower education level, and lived in northern China had higher overweight rate and obesity rate (P<0.001). The difference in overweight or obesity prevalence between monozygotic (MZ) twin pars and dizygotic (DZ) twin pairs was not significant, but firstborn twin pairs had slightly higher rates of overweight and obesity than later-born twin pairs (P<0.05). The analysis in same gender-twin pairs indicated that the difference in BMI was associated with age (trend test: P<0.001), and the difference was more obvious in DZ twin pair in MZ pair and this difference increased with age. The concordant rate of BMI was higher in MZ twin pairs than DZ twin pairs (P<0.05). Conclusion: The distribution of BMI of twin pairs varied with population and region and BMI varied with age due to its genetic nature.

[Silencing PBX1 expression induces apoptosis and ROS production of lung cancer cells].

Objective: To investigate the effects of pre-B lymphocytic leukemia transcription factor (PBX1) expression on the apoptosis, reactive oxygen species (ROS) content and transcriptional activation factor 3 (STAT3) signaling pathway of lung cancer cells. Methods: Real-time quantitative polymerase chain reaction was used to detect the expression level of PBX1 in lung cancer tissues and adjacent tissues. The correlation between PBX1 expression level and clinical pathological parameters of patients were analyzed. Western blot was used to detect the protein expression level of PBX1 in human lung cancer cell lines, including A549, SPC-A1, SK-MES-1 and H1299. A549 cells were transfected with blank control (blank group), negative control (NC group) or PBX1 small interfering RNA (siRNA group), respectively. The cells apoptosis and ROS content were detected by flow cytometry. The protein expression levels of PBX1, STAT3, phosphorylated STAT3 (p-STAT3), B cell lymphoma/leukemia-2 (Bcl-2) and survivin in each group were detected by western blot. Results: The expression level of PBX1 mRNA in lung cancer was (2.36±0.23), significantly higher than (1.02±0.15) in paracancerous tissues (P<0.05). The expression level of PBX1 was correlated with lung cancer differentiation, lymph node metastasis and TNM stage (P<0.05). The expression levels of PBX1 in human lung cancer cells A549, SPC-A1, SK-MES-1 and H1299 were (0.454±0.038), (0.403±0.034), (0.311±0.028) and (0.377±0.035), respectively, significantly higher than (0.041±0.007) of human normal lung cells MRC-5 (P<0.05). The expression level of PBX1 protein in A549 cells transfected with PBX1 siRNA was (0.082±0.010), significantly lower than (0.704±0.065) of the blank group (P<0.05). The apoptosis rate and ROS content of siPBX1 group were (30.78±3.64)% and (51.55±5.03), respectively, significantly higher than (3.92±0.27)% and (22.36±1.31) of blank group (P<0.05). The protein expressions of p-STAT3, Bcl-2 and survivin were (0.051±0.006), (0.202±0.018) and (0.068±0.008), respectively, significantly lower than (0.172±0.010), (0.425±0.041) and (0.196±0.021) of blank group (P<0.05). Conclusion: Inhibition of PBX1 expression can induce the apoptosis of lung cancer cell, the mechanism may be related to ROS production and down-regulation of STAT3 signal.

Magnetic graphene enabled tunable microwave absorber via thermal control.

By synthesizing nitrogen-doped graphene (NG) via a facile thermal annealing method, a fine control of the amount and location of doped nitrogen as well as the oxygen-containing functional groups is achieved with varying annealing temperature. The favorable magnetic properties have been achieved for N-doped rGO samples obtained at two temperatures of all NG samples, i.e., 500 °C and 900 °C with saturation magnetization of 0.63 emu g-1 and 0.67 emu g-1 at 2 K, respectively. This is attributed to the optimized competition of the N-doping and reduction process at 500 °C and the dominated reduction process at 900 °C. NG obtained at 300 °C affords the best overall absorbing performance: when the absorber thickness is 3.0 mm, the maximum absorption was -24.6 dB at 8.51 GHz, and the absorption bandwidth was 4.89 GHz (7.55-12.44 GHz) below -10 dB. It owes its large absorbing intensity to the good impedance match and significant dielectric loss. The broad absorption bandwidth benefits from local fluctuations of dielectric responses contributed by competing mechanisms. Despite the significant contribution from materials loss to the absorption, the one quarter-wavelength model is found to be responsible for the reflection loss peak positions. Of particular significance is that an appropriate set of electromagnetic parameters associated with reasonable reduction is readily accessible by convenient control of annealing temperature to modulate the microwave absorbing features of graphene. Thus, NG prepared by thermal annealing promises to be a highly efficient microwave absorbent.

Significantly enhanced creep resistance of low volume fraction in-situ TiBw/Ti6Al4V composites by architectured network reinforcements.

We present a new class of TiBw/Ti6Al4V composites with a network reinforcement architecture that exhibits a significant creep resistance compared to monolithic Ti6Al4V alloys. Creep tests performed at temperatures between 773 K and 923 K and stress range of 100 MPa-300 MPa indicate both a significant improvement of the composites creep resistance due to the network architecture made by the TiB whiskers (TiBw), and a decrease of the steady-state creep rates by augmenting the local volume fractions of TiBw in the network region. The deformation behavior is driven by a diffusion-controlled dislocation climb process. Moreover, the activation energies of these composites are significantly higher than that of Ti6Al4V alloys, indicating a higher creep resistance. The increase of the activation energy can be attributed to the TiBw architecture that severely impedes the movements of dislocation and grain boundary sliding and provides a tailoring of the stress transfer. These micromechanical mechanisms lead to a remarkable improvement of the creep resistance of these networked TiBw/Ti6Al4V composites featuring the special networked architecture.

Molecular analysis of MLH1 variants in Chinese sporadic colorectal cancer patients.

Single nucleotide polymorphisms (SNPs) in mismatch repair genes, especially in the MLH1 gene, are closely associated with susceptibility to hereditary nonpolyposis colorectal cancer. However, few relevant findings are available regarding the association between sporadic colorectal cancer (SCRC) and SNPs of MLH1 in Chinese patients. Therefore, the present study aimed to describe the pathogenic association between three important MLH1 polymorphisms and SCRC in the Chinese population. Peripheral blood samples from 156 SCRC patients and 311 healthy controls were collected. DNA was purified from peripheral blood, and the V384D, R217C, and I219V polymorphisms were evaluated using high-resolution melting analysis and direct sequencing. The association between the three important MLH1 polymorphisms and clinical pathological features of the SCRC patients was analyzed. In addition, PMS2-MLH1 protein interactions were determined by co-immunoprecipitation (Co-IP) to determine the protein functional alteration induced by these SNPs. Among the three polymorphisms, V384D was significantly associated with the risk of SCRC (OR = 31.36, P < 0.0001). The allele frequencies were 4.81 and 0.16% in the SCRC group. No association was found between SCRC and R217C, or between SCRC and I219V. Moreover, the allele frequency of R217C was significantly higher in the SCRC patients younger than 60 years than in those older than 60 years. Co-IP showed that the MLH1 R217C, V384D, and I219V variants had relative binding abilities with PMS2 of 0.59, 0.70, and 0.80, respectively, compared with the wild-type. These findings suggest that MLH1 V384D could be a promising genetic marker for susceptibility to SCRC.

Management of Valsa Canker on Apple with Adjustments to Potassium Nutrition.

Valsa canker, caused by the fungus Valsa mali, is one of the most destructive diseases of apple in the primary production areas of China and other East Asian countries. Currently, there are no effective control methods for this disease. We investigated the occurrence of Valsa canker in 24 apple orchards in Shaanxi Province in concert with foliar nutrient analysis, and found that there was a significant negative correlation of leaf potassium (K) content with incidence and severity of Valsa canker. Fertilization experiments showed that increasing tree K content enhanced resistance to pathogen colonization and establishment. Apple trees with leaf K content greater than 1.30% exhibited almost complete resistance to Valsa mali. Field trials demonstrated that increasing K fertilization could significantly reduce disease incidence. Improved management of tree nutrition, especially K content, could effectively control the occurrence and development of Valsa canker.

Self-Assemblies of Acicular Hollow Fe/C Nanostructures.

Self-assemblies of acicular hollow Fe/C structures were synthesized using D-glucose monohydrate and ferric chloride as precursors by a simple hydrothermal process followed by carbonization at 800 °C. The self-assembled structures with an overall diameter of 15~20 µm composed of radially formed hollow needles from a central core with an average diameter of ca. 1 µm and a length up to 10 µm. The end of the needles was revealed to be a awl shape with a hollow structure formed during the self-assembly process and the subsequent heat treatment. The hollow structure was probably caused by the Kirkendall effect at 800 °C. The materials exhibit ferromagnetic characteristic with saturation magnetization (Ms), remanent magnetization (Mr), and coercivity (Hc) of 22.2 emu/g, 3 emu/g, and 151.22 Oe, respectively, with Ms much lower than that of Fe3O4.

JNK phosphorylation promotes natural degeneration of cervical endplate chondrocytes by down-regulating expression of ANK.

BACKGROUND: Endplate degeneration leads to accelerated degeneration of the intervertebral disc. The importance of endplate chondrocytes in this process is unclear. Many cellular processes in chondrocytes are controlled by activated c-Jun N-terminal kinases (JNK) and protein kinase B (AKT). However, the involvement of their pathways in the degeneration process needs to be elucidated. AIM: To study activation of JNK and AKT signaling pathways and their significance for degeneration of endplate chondrocytes, as well as involvement of progressive ankylosis protein (ANK) in this process. MATERIALS AND METHODS: Rat primary chondrocytes were grown to confluence and subcultured until passage 4. Morphological appearances (microscope, hematoxylin & eosin staining, toluidine blue staining) and proliferation rates of cells (MTT test) were observed. Further, levels of type II collagen, aggrecan, phosphorylated JNK and AKT, total JNK, AKT and ANK were evaluated by qPCR, flow cytometry and Western blot assays. Furthermore, inhibition experiments with SP600125, the JNK inhibitor, were carried out in the passage 4 cells to assess the effects of the JNK pathway on natural degeneration of endplate chondrocytes. RESULTS: The proliferative speed of endplate chondrocytes progressively decreased during passaging. Expressions of type II collagen and aggrecan were significantly decreased with cells at higher passages. Furthermore, phosphorylation of JNK, but not AKT, was significantly up-regulated and accompanied by reduced ANK expression. Inhibition of the JNK pathway increased expression of type II collagen, aggrecan and ANK and facilitated proliferation rates. CONCLUSIONS: Phosphorylation of JNK promotes natural degeneration of cervical endplate chondrocytes, likely by down-regulating ANK expression.

High-resolution electron microscope observation of interface microstructure of a cast Al-Mg-Si-Bi-Pb(6262)/Al2O3p composite.

High-resolution electron microscopy was employed to characterize the interface structure of a cast Al-Mg-Si-Bi-Pb aluminium(6262)-based composite reinforced by alpha alumina particles with a trace of beta alumina in order to investigate the behaviour of alloying elements in cast composites. Except for a few primary Mg2Si particles, few reaction products were detected at the interface of Al/alpha-Al2O3 due to the unfavourable reaction kinetics during the squeeze-casting process. The Mg2Si particle has an orientation relationship with alpha-Al2O3 of [011]Mg2Si//[1210]alpha-Al2O3 (111)Mg2Si//(0006)alpha-Al2O3. A significant amount of MgAl2O4 was found on the surface of the beta-Al2O3 particles, which is in contrast to the small degree of reaction found on alpha-Al2O3 particles. MgAl2O4 and beta-Al2O3 particles have the following orientation relationship: [011]MgAl2O4//[1210]beta-Al2O3 (111) MgAl2O4//(0006)beta-Al2O3. The similar crystal structure of beta-Al2O3 to MgAl2O4 favours MgAl2O4 nucleation and growth on the surface of beta-Al2O3. Interfacial energy minimization dominates the atomic structure of the interface with the result that close packed planes and directions in the Al2O3 reinforcement and reaction products are parallel to the interfaces. Bi and Pb were found in the form of metallic nanometre particles between Al2O3 particles, or between the MgAl2O4 and Al2O3 particles, or in the open channels of beta-Al2O3 filled by the Al matrix.

Novel MMC microstructure with tailored distribution of the reinforcing phase.

Saffil short fibre agglomerates with diameters of 0.4 mm to 1 mm have been prepared using a tumbling technique. These were packed and infiltrated with molten 6061 Al alloy to make a metal matrix composite (MMC) with a novel microstructure in which the composite spheres are randomly distributed in the fibre-free aluminium matrix. In parallel, a commercial preform made of identical Saffil alumina short fibres and having the same fibre volume faction was used to prepare a conventional MMC by the same technique. Microstructural observation indicates that, within the composite spheres, the local volume fraction of fibre decreases from the outer layer to the centre region. The energy absorption during fracture was estimated by using a three point loading test on notched samples and was compared with that for conventional MMCs. Preliminary results suggest that this novel MMC possesses higher energy absorption capability and hence better damage tolerance. The fracture surfaces were examined by scanning electron microscopy in order to inform these experimental results.