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For old pipes that have been in service for a long time in disrepair conditions, it is common to find internal and external defects in the pipelines. The repair technologies for internal defects inside the pipes are well-established, but these technologies for the defects around the pipe are still in the early stage. In this study, an innovative trenchless pretreatment technology for concrete pipes with corrosion and void defects, termed as the membrane bag pile polymer grouting pretreatment (MBP-PGP) technology, was developed in the field test. As a part of this study, the circumferential strains and bending moments in the concrete pipes with the dense, repaired, and void beddings were investigated under different wheel loads. The observed data from the field test were validated by a refined three-dimensional (3D) finite element (FE) model. Furthermore, the impacts of different corrosion depths, corrosion widths, void depths, and void widths on the behavior of corroded pipes were also discussed. The results show that the values and distributions of the circumferential strains predicted by the FE model are similar to those observed in the test. When the wheel load was 83kN, the maximum increase of the strains and bending moment in the pipe with the void bedding was 63.3% and 54.0%, and that of the pipe repaired using the MBP-PGP technology was only 14.6% and 17.3%, respectively, compared to the pipe with the dense bedding. It can be concluded that the circumferential strains in the pipes with void and repaired beddings are positively correlated with the corrosion depth, void depth, and void width, while they are negatively correlated with the corrosion width.

Mounting evidence suggests that copy number variations (CNVs) can contribute to cancer susceptibility. The main goal of this study was to evaluate the role of germline CNVs in melanoma predisposition in high-risk melanoma families. We used genome-wide tiling comparative genomic hybridization and single nucleotide polymorphism arrays to characterize CNVs in 335 individuals (240 melanoma cases) from American melanoma-prone families (22 with germline CDKN2A or CDK4 mutations). We found that the global burden of overall CNVs (or deletions or duplications separately) was not significantly associated with case-control or CDKN2A/CDK4 mutation status after accounting for the familial dependence. However, we identified several rare CNVs that either involved known melanoma genes (e.g., PARP1, CDKN2A) or cosegregated with melanoma (duplication on 10q23.23, 3p12.2 and deletions on 8q424.3, 2q22.1) in families without mutations in known melanoma high-risk genes. Some of these CNVs were correlated with expression changes in disrupted genes based on RNASeq data from a subset of melanoma cases included in the CNV study. These results suggest that rare cosegregating CNVs may influence melanoma susceptibility in some melanoma-prone families and genes found in our study warrant further evaluation in future genetic analyses of melanoma.

Background Pressure ulcers (PUs) prevalence has been considered as an index for patient safety and cure quality of hospital and community. Skin cellular oxidative response damage is existed in the development of PUs. Angelica polysaccharide (AP) has the anti-oxidation function. Therefore, our goal was to investigate the mechanism of AP in relieving cellular oxidative damage. Methods Transfected HaCaT cells with miR-126 inhibitor, pre-treated by AP, and then treated by H 2 O 2 . CCK-8 assay and flow cytometry detection were set to test viability and apoptosis of cells respectively. qRT-PCR and western blot tested levels of miR-126 and oxidative damage relative factors. ROS assay tested the production of ROS in cells. Results Cellular oxidative response damage was induced by H 2 O 2 at concentration of 300 μM. We found that AP could attenuate cellular oxidative response damage caused by H 2 O 2 that it elevated cell viability, attenuated cell apoptosis and production of ROS and promoted activation of PI3K/AKT and mTOR signal pathways. Further, miR-126 was up-regulated by AP. The up-regulation of miR-126 could activate the PI3K/AKT and mTOR signal pathways. Conclusion Our study demonstrated that AP attenuated cellular oxidative response damage in HaCaT cells by positively regulated miR-126.

Posttraumatic stress disorder is developed by exposure to a threatening and/or a horrifying event and characterized by the presence of anxiety, hyperarousal, avoidance, and sleep abnormality for a prolonged period of time. To elucidate the potential molecular mechanisms, we constructed a mouse model by electric foot shock followed by situational reminders and performed transcriptome analysis in brain tissues. The stressed mice acquired anxiety-like behavior after 2 weeks and exaggerated startle response after 4 weeks. Avoidance latency and freezing behavior were sustained up to 5 weeks post stress and abnormal static behavior was observed during the sleep period. RNA sequencing was performed in two of the emotional regulatory regions, anterior cingulate cortex and amygdala, at 2 and 5 weeks post stress. More than 1000 differentially expressed genes were identified at 2 weeks in both regions. The number of the regulated genes remained constant in amygdala at 5 weeks post stress, whereas those in anterior cingulate cortex were plummeted. Although synaptic remodeling and endocrine system were the most enriched signaling pathways in both anterior cingulate cortex and amygdala, the individual gene expression profile was regulated in a region- and time-dependent manner. In addition, several genes associated with PTSD involved in Hypothalamic-Pituitary-Adrenal axis were differentially regulated. These findings suggested that global gene expression profile was dynamically regulated in accordance with the disease development stage, and therefore targeting the distinct signaling molecules in different region and development stage might be critical for effective treatment to PTSD.

Posttraumatic stress disorder is developed by exposure to a threatening and/or a horrifying event and characterized by the presence of anxiety, hyperarousal, avoidance, and sleep abnormality for a prolonged period of time. To elucidate the potential molecular mechanisms, we constructed a mouse model by electric foot shock followed by situational reminders and performed transcriptome analysis in brain tissues. The stressed mice acquired anxiety-like behavior after 2 weeks and exaggerated startle response after 4 weeks. Avoidance latency and freezing behavior were sustained up to 5 weeks post stress and abnormal static behavior was observed during the sleep period. RNA sequencing was performed in two of the emotional regulatory regions, anterior cingulate cortex and amygdala, at 2 and 5 weeks post stress. More than 1000 differentially expressed genes were identified at 2 weeks in both regions. The number of the regulated genes remained constant in amygdala at 5 weeks post stress, whereas those in anterior cingulate cortex were plummeted. Although synaptic remodeling and endocrine system were the most enriched signaling pathways in both anterior cingulate cortex and amygdala, the individual gene expression profile was regulated in a region- and time-dependent manner. In addition, several genes associated with PTSD involved in Hypothalamic-Pituitary-Adrenal axis were differentially regulated. These findings suggested that global gene expression profile was dynamically regulated in accordance with the disease development stage, and therefore targeting the distinct signaling molecules in different region and development stage might be critical for effective treatment to PTSD. Electronic supplementary material The online version of this article (10.1186/s13041-019-0449-0) contains supplementary material, which is available to authorized users.

Expression levels of interleukin-17 (IL-17) and IL-34 was investigated to analyze the influencing factors for prognosis in patients with lupus nephritis (LN). Clinical data of 45 patients (LN group) treated and diagnosed with LN via renal biopsy in Yanan University Affiliated Hospital from October 2010 to October 2012 and 50 healthy subjects (control group) were analyzed retrospectively. Levels of serum IL-17 and IL-34 were detected via enzyme-linked immunosorbent assay. Correlations of serum IL-17 and IL-34 with urinary protein in LN patients were analyzed via Pearson correlation analysis. Univariate survival analysis was performed using the Kaplan-Meier method, and multivariate analysis was performed for LN prognosis using the Cox proportional hazards model. Levels of serum IL-34 and IL-17 in patients in LN group were significantly higher than those in control group (P

Table S1. Enriched molecular functions of regulated genes in AMY and ACC at 2 and 5â weeks post stress. (PPTX 44 kb)

Figure S1. RNAseq analysis in Anterior Cingulate Cortex (ACC) of stressed mice. Total RNA was isolated from ACC by punching brain slice and applied for RNA sequence. Heatmaps of DEGs were shown for 2â weeks (A) and 5â weeks (B) PS. Green bars and orange bars indicated control and stressed animals, respectively. Venn diagram of overlapped DEGs between the two time points was shown in (C). (PPTX 496 kb)

Figure S2. RNAseq analysis in Amygdala (AMY) of stressed mice. Total RNA was isolated from AMY by punching brain slice and applied for RNA sequence. Heatmaps of DEGs were shown for 2â weeks (A) and 5â weeks (B) PS. Green bars and orange bars indicated control and stressed animals, respectively. Venn diagram between the two conditions was shown in (C). (PPTX 491 kb)

Figure S4. Heatmap of enriched GOs involved in neuronal development, neurogenesis, and differentiation, and non-neuronal cell differentiation. Color index represents level of significance (p-values). (PPTX 53 kb)

Figure S3. Heatmap of enriched GOs related to transcriptional regulation. Color index represents level of significance (p-values). (PPTX 54 kb)

Table S3. Enriched pathways of regulated genes in AMY and ACC at 2 and 5â weeks post stress. (PPTX 45 kb)

With the rapid growth of transportation, all kinds of traffic data show explosive growth, and accurate and timely traffic forecasting is also particularly important. Among them, traffic flow prediction is the basis for realizing reasonable traffic guidance and control, and it is also a prerequisite for intelligent transportation. Traffic flow data belongs to a typical chaotic time series with strong non-linearity. In the application of neural network, a two-layer neural network can theoretically approach any continuous function infinitely, so as to achieve very accurate prediction. This paper proposes a predictive traffic flow model based on the combination of GRU network and BP neural network, and uses the US Twin Cities traffic data experiment to verify that the model is feasible in traffic flow prediction. The experimental results show that the combined model has high prediction accuracy and can capture the volatility of traffic flow at rush hour. At the same time, the model has strong robustness.

Corrosion commonly affects buried concrete drainage pipelines, causing pipe leaks, pipe explosions and even road collapses. To assess the mechanical properties of corroded concrete pipes, a series of pipeline mechanical performance test were performed. The failure process, carrying capacity and circumferential strains of corroded concrete pipes were analyzed under various loading speeds, corrosion depths, corrosion widths and corrosion locations. The results showed that cracks first appeared on the inside of the pipe crown and pipe invert, and as the load continued to increase, the cracks rapidly expanded. When cracks penetrated the entire section of the pipe, the pipe was crushed. The deformation of the pipe was small, and there was no plastic development stage in the pipe failure process, indicating that the concrete pipe exhibited brittle failure. The loading speed had a small effect on the carrying capacity of the pipe and a large effect on the circumferential strain of the pipe. Corrosion had a greater impact on the stress and strain in the corroded area of the pipe and a smaller impact on other locations. With increasing corrosion depth and corrosion width, the carrying capacity of the pipe decreased, whereas the circumferential strain of the pipe increased. The research results provide a theoretical basis for the prediction of the safety performance of concrete pipes.

Hodgkin lymphoma shows strong familial aggregation but no major susceptibility genes have been identified to date. The goal of this study was to identify high-penetrance variants using whole exome sequencing in 17 Hodgkin lymphoma prone families with three or more affected cases or obligate carriers (69 individuals), followed by targeted sequencing in an additional 48 smaller HL families (80 individuals). Alignment and variant calling were performed using standard methods. Dominantly segregating, rare, coding or potentially functional variants were further prioritized based on predicted deleteriousness, conservation, and potential importance in lymphoid malignancy pathways. We selected 23 genes for targeted sequencing. Only the p.A1065T variant in KDR (kinase insert domain receptor) also known as VEGFR2 (vascular endothelial growth factor receptor 2) was replicated in two independent Hodgkin lymphoma families. KDR is a type III receptor tyrosine kinase, the main mediator of vascular endothelial growth factor induced proliferation, survival, and migration. Its activity is associated with several diseases including lymphoma. Functional experiments have shown that p.A1065T, located in the activation loop, can promote constitutive autophosphorylation on tyrosine in the absence of vascular endothelial growth factor and that the kinase activity was abrogated after exposure to kinase inhibitors. A few other promising mutations were identified but appear to be "private". In conclusion, in the largest sequenced cohort of Hodgkin lymphoma families to date, we identified a causal mutation in the KDR gene. While independent validation is needed, this mutation may increase downstream tumor cell proliferation activity and might be a candidate for targeted therapy.

For unknown reasons, there is huge variability in risk conferred by different HPV types and, remarkably, strong differences even between closely related variant lineages within each type. HPV16 is a uniquely powerful carcinogenic type, causing approximately half of cervical cancer and most other HPV-related cancers. To permit the large-scale study of HPV genome variability and precancer/cancer, starting with HPV16 and cervical cancer, we developed a high-throughput next-generation sequencing (NGS) whole-genome method. We designed a custom HPV16 AmpliSeq™ panel that generated 47 overlapping amplicons covering 99% of the genome sequenced on the Ion Torrent Proton platform. After validating with Sanger, the current “gold standard” of sequencing, in 89 specimens with concordance of 99.9%, we used our NGS method and custom annotation pipeline to sequence 796 HPV16-positive exfoliated cervical cell specimens. The median completion rate per sample was 98.0%.Our method enabled us to discover novel SNPs, large contiguous deletions suggestive of viral integration (OR of 27.3, 95% CI 3.3–222, P=0.002), and the sensitive detection of variant lineage coinfections. This method represents an innovative high-throughput, ultra-deep coverage technique for HPV genomic sequencing, which, in turn, enables the investigation of the role of genetic variation in HPV epidemiology and carcinogenesis. Keywords: HPV16, HPV epidemiology, HPV genomics

Lung adenocarcinoma is a highly lethal tumor that displays extensive molecular heterogeneity of which deep characterization may drive therapeutic development and improve clinical outcomes. Through the Applied Proteogenomics Organizational Learning and Outcomes (APOLLO) research network, we utilized five molecular profiling technologies (DNA whole genome sequencing, RNA sequencing, total and phospho-proteomics by mass spectrometry, and reverse phase protein arrays [RPPA]) to characterize a longitudinally-annotated cohort of 87 lung adenocarcinomas. Through whole genome sequencing, we identified molecular signatures from patterns of somatic SNVs, indels, and large structural alterations that stratified tumors into three groups associated with patient smoke exposures. We also identified TP53, EGFR, KRAS, and STK11 as recurrently mutated genes, which together represent 80% of the cohort, in addition to genes mutated in smaller cohort subsets (e.g. RBM10), fusion genes, and pathogenic germline variants. To characterize tumor proteomes, we quantified >7,000 proteins and >10,000 phosphopeptides by mass spectrometry and >300 species by RPPA. Matched RNAs and proteins were typically positively correlated across samples (median ρ = 0.49). Through quantitative trait loci analyses, we identified genes whose RNA and protein expression levels were significantly modified by somatic mutations. We then classified tumors into RNA expression subtypes and found coordinated proteogenomic alterations and distinct clinical associations: terminal respiratory unit subtype – EGFR mutations and RNA/protein overexpression, acinar histology, non-smokers; proximal-proliferative subtype – STK11 mutations and RNA/protein underexpression, high smoking signature; proximal-inflammatory subtype – high tumor mutational burden. We also identified phospho-peptide signatures associated with these subtypes, including downregulation of CDK1/2 targets in terminal respiratory unit tumors. Protein co-expression network analysis discovered biologically-diverse pathway activities of the RNA expression subtypes. To interrogate somatic mutations in the context of molecular pathways, we projected DNA alterations onto known interaction networks and identified four subtypes with markedly distinct proteomic and microenvironment characteristics. Finally, several molecular characteristics were found to significantly predict patient outcomes, including RNA expression subtype classification against metastasis-free survival. Thus, our integrative, proteogenomic characterization of lung adenocarcinoma uncovered novel tumor biology and identified potential molecular markers for predicting patient outcomes. The views expressed in this abstract are solely of the authors and do not reflect the official policy of the Departments of Army/Navy/Air Force, Department of Defense, USUHS, HJF, or U.S. Government. Citation Format: Anthony R. Soltis, Nicholas W. Bateman, Thomas P. Conrads, Clifton L. Dalgard, Hai Hu, Teri J. Franks, Jianfang Liu, Daoud Meerzaman, Emanuel F. Petricoin, Qingrong Chen, Chunhua Yan, Xijun Zhang, Clesson E. Turner, The APOLLO Research Network, Craig D. Shriver, Christopher A. Moskaluk, Robert F. Browning, Matthew D. Wilkerson. Comprehensive proteogenomic analysis and classification of lung adenocarcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5893.

Background: DNA damage repair genes (DDRGs) play a critical role in protecting genome integrity and have been implicated in several cancer types. In the context of prostate cancer (CaP) emerging data provide potential role of this pathway in aggressive disease. It has also been recently demonstrated that PARP inhibitors can extend overall survival in metastatic patients with DDRG mutations. However, the association and therapeutic stratification based on inherited mutations of DDRGs remains to be defined in African American (AA) CaP patients. Our objective was to assess the frequency and association with disease aggressiveness of all known DDRGs in blood derived genomic DNAs of AA and Caucasian American (CA) CaP patients archived at the DOD Center for Prostate Disease Research and assess how this information can refine patient stratification for specific targeted therapeutic options. Method: Germline mutations in all DDRGs was evaluated by whole genome sequence (WGS) analysis of archived blood DNA samples from 600 CaP patients (300 AA and 300 CA) who underwent primary treatment at Walter Reed National Military Medical Center (WRNMMC) over the past 20 years. These patients had equal access Department of Defense healthcare system with up to 20 years of follow-up time. Following quality control steps to assess DNA quantity by Qubit assay and DNA quality by Bioanalyzer assay, DNA samples were used to generate PCR-free libraries for WGS using the NovaSeq (Illumina) platform. Out of the 600 libraries we generated, 14 dropped out, achieving a success rate of 97.6%. The successful libraries had an excellent quality based on DNA library metrics (yield and fragment length). Whole genome sequencing depth of the samples exceeded 37x on average and about 4 million SNPs were identified in the samples. Patient genotypes were projected onto principal components from reference populations. Sample ancestries were predicted by using the “Peddy” program, which uses a machine learning model trained on individuals of diverse ancestries from the 1000 Genomes Project reference panel. Due to mismatched ancestry, 33 samples were excluded from further analyses. An additional 17 samples were excluded due to higher than minimal noise level based on analyses using “ContEst” tool from Broad GATK package and Illumina noise percent values. Results: Interrogation of an inclusive DDRG set of 180 genes predicted to have non-silent effects on the protein sequence (e.g. missense, nonsense, frameshift) for germline mutations in this cohort revealed several known and novel mutations. The analysis has not been finalized yet. Mutation data will be assessed for association with the extensive available clinical and pathological data, including disease progression (metastasis), family history and African ancestry. Novel mutations, anticipated especially in the understudied AA context, will be analyzed for functional impact. Citation Format: Kevin Babcock, Xijun Zhang, Matthew Wilkerson, Clifton L. Dalgard, Shyh-Han Tan, Lakshmi Ravindranath, Yongmei Chen, Jennifer Cullen, Shiv Srivastava, Inger L. Rosner, Gyorgy Petrovics. Defining germline mutations of DNA damage repair genes in African American prostate cancer patients [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr B075.

Objective This in vitro study calculated longitudinal strain (LS) from different ultrasound systems (GE Vivid E9 and Philips IE 33) before and after myocardial infarct (MI) using a vendor-independent analysis software package (TomTec's 4D LV Analysis) to validate the variation of two ultrasound systems. Methods Ten freshly harvested porcine hearts were passively driven by a pulsatile pump apparatus at stroke volumes (SV) 30-70 mL. Full-volume three-dimensional echocardiography (3DE) data were acquired before and after MI using two different ultrasound systems. LS was derived from TomTec and validated against sonomicrometry data. Results Linear regression analyses showed excellent correlations between TomTec-calculated LS values and sonomicrometry data for both normal and simulated MI groups (GE: R2 = 0.72/0.68, Philip: R2 = 0.71/0.66). Bland-Altman analyses demonstrated overestimation of echo-derived strain values for all groups. Both ultrasound system-derived strain values demonstrated decreased LS after MI, and the average change in strain after infarct was roughly 30% in GE images and 25% in Philips images. Conclusions Both GE and Philips echocardiographic systems can be analyzed with TomTec's program, and these images correlated well with sonomicrometry with acceptable variations.

ObjectiveTo elucidate the genetic architecture of gene expression in pancreatic tissues.DesignWe performed expression quantitative trait locus (eQTL) analysis in histologically normal pancreatic tissue samples (n=95) using RNA sequencing and the corresponding 1000 genomes imputed germline genotypes. Data from pancreatic tumour-derived tissue samples (n=115) from The Cancer Genome Atlas were included for comparison.ResultsWe identified 38 615 cis-eQTLs (in 484 genes) in histologically normal tissues and 39 713 cis-eQTL (in 237 genes) in tumour-derived tissues (false discovery rate cis-eQTLs appeared to be specific for tumour-derived and normal-derived tissues, respectively. Significant enrichment of cis-eQTL variants was noted in non-coding regulatory regions, in particular for pancreatic tissues (1.53-fold to 3.12-fold, p≤0.0001), indicating tissue-specific functional relevance. A common pancreatic cancer risk locus on 9q34.2 (rs687289) was associated with ABO expression in histologically normal (p=5.8×10−8) and tumour-derived (p=8.3×10−5) tissues. The high linkage disequilibrium between this variant and the O blood group generating deletion variant in ABO (exon 6) suggested that nonsense-mediated decay (NMD) of the ‘O’ mRNA might explain this finding. However, knockdown of crucial NMD regulators did not influence decay of the ABO ‘O’ mRNA, indicating that a gene regulatory element influenced by pancreatic cancer risk alleles may underlie the eQTL.ConclusionsWe have identified cis-eQTLs representing potential functional regulatory variants in the pancreas and generated a rich data set for further studies on gene expression and its regulation in pancreatic tissues.

Juvenile myelomonocytic leukemia (JMML) is a pediatric myeloproliferative neoplasm that arises from malignant transformation of the stem cell compartment and results in increased production of myeloid cells. Somatic and germline variants in CBL (Casitas B-lineage lymphoma proto-oncogene) have been associated with JMML. We report an incompletely penetrant CBL Y371C mutation discovered by whole-exome sequencing in three individuals with JMML in a large pedigree with 35 years of follow-up. The Y371 residue is highly evolutionarily conserved among CBL orthologs and paralogs. In silico bioinformatics prediction programs suggested that the Y371C mutation is highly deleterious. Protein structural modeling revealed that the Y371C mutation abrogated the ability of the CBL protein to adopt a conformation that is required for ubiquitination. Clinically, the three mutation-positive JMML individuals exhibited variable clinical courses; in two out of three, primary hematologic abnormalities persisted into adulthood with minimal clinical symptoms. The penetrance of the CBL Y371C mutation was 30 % for JMML and 40 % for all leukemia. Of the 8 mutation carriers in the family with available photographs, only one had significant dysmorphic features; we found no evidence of a clinical phenotype consistent with a “CBL syndrome”. Although CBL Y371C has been previously reported in familial JMML, we are the first group to follow a complete pedigree harboring this mutation for an extended period, revealing additional information about this variant’s penetrance, function and natural history.

Although CDKN2A is the most frequent high-risk melanoma susceptibility gene, the underlying genetic factors for most melanoma-prone families remain unknown. Using whole-exome sequencing, we identified a rare variant that arose as a founder mutation in the telomere shelterin gene POT1 (chromosome 7, g.124493086C>T; p.Ser270Asn) in five unrelated melanoma-prone families from Romagna, Italy. Carriers of this variant had increased telomere lengths and numbers of fragile telomeres, suggesting that this variant perturbs telomere maintenance. Two additional rare POT1 variants were identified in all cases sequenced in two separate Italian families, one variant per family, yielding a frequency for POT1 variants comparable to that for CDKN2A mutations in this population. These variants were not found in public databases or in 2,038 genotyped Italian controls. We also identified two rare recurrent POT1 variants in US and French familial melanoma cases. Our findings suggest that POT1 is a major susceptibility gene for familial melanoma in several populations.

Tire force can be divided into normal force and tangential force when the vehicle is in tilting condition, the general load cell can't differentiate these two signals accurately. This paper introduces a portable wheel load measuring plate which is characterized by integrating the strain gauge with the upper platform and can be used in tilting condition. In order to decoupling these signals from component of forces, the structure of the upper platform is optimized and analyzed by commercial FEA software. Experimental results show that the maximal measuring error cause by eccentric load is 1.49 % and the maximal measuring error caused by tilting error is 2.49 %.

As a nation with early R&D activities and significant achievements in papers and patents on nanotech, China noticeably lags behind in the industrialization of the field, and has not yet formed a nanotech “industry” consensus. Suzhou is the first city in China taking nanotech industry as its strategic emerging industry to lead the transforming and upgrading of regional economy. This strategy is highly supported by central government, Chinese Academy of Sciences and Jiangsu Province. The development of strategic emerging industry relies on top-level design and systematic planning. With international experiences, national conditions and regional realities in mind, Suzhou proposed to build nanotech industry ecosystem to layout and integrate industry resources and eventually to establish an effective interactive model in accordance with the need of industrial development. This model has been well recognized and accepted by nanotech related academia, industry and government agencies both domestically and internationally.

Objective The objective of this study was to fine-map common pancreatic cancer susceptibility regions. Methods We conducted targeted Roche-454 resequencing across 428 kb in 3 genomic regions identified in genome-wide association studies (GWAS) of pancreatic cancer, on chromosomes 1q32.1, 5p15.33, and 13q22.1. Results An analytical pipeline for calling genotypes was developed using HapMap samples sequenced on chr5p15.33. Concordance to 1000 Genomes data for chr5p15.33 was greater than 96%. The concordance for chr1q32.1 and chr13q22.1 with pancreatic cancer GWAS data was greater than 99%. Between 9.2% and 19.0% of variants detected were not present in 1000 Genomes for the respective continental population. The majority of completely novel single-nucleotide polymorphisms (SNPs) were less common (minor allele frequency [MAF], ≤5%) or rare (MAF, ≤2%), illustrating the value of enlarging test sets for discovery of less common variants. Using the data set, we examined haplotype blocks across each region using a tag SNP analysis (r2 > 0.8 for MAF of ≥5%) and determined that at least 196, 243, and 63 SNPs are required for fine-mapping chr1q32.1, chr5p15.33, and chr13q22.1, respectively, in European populations. Conclusions We have characterized germline variation in 3 regions associated with pancreatic cancer risk and show that targeted resequencing leads to the discovery of novel variants and improves the completeness of germline sequence variants for fine-mapping GWAS susceptibility loci.

The impact of major lung resections on myocardial function has not been well-investigated. We aimed to identify this impact through the use of speckle tracking echocardiography (STE) to evaluate the right and left ventricular myocardial function in patients who underwent lung resections. Thirty patients who had lung resections were recruited for this study. Ten patients who underwent pneumonectomies were matched by age and sex, with 20 patients who underwent lobectomies. STE was performed on both right and left ventricle (RV and LV). Strain values of pre and postlung resections were compared in both the pneumonectomy group and the lobectomy group. Comparison between the pneumonectomy group and the lobectomy group was also studied. Left ventricular ejection fraction remained normal (>55%), but significantly decreased after lung resection in both the pneumonectomy group and the lobectomy group. An accelerated heart rate was observed in both groups after lung resection, with the pneumonectomy group demonstrating extra rapid heart rate (P

Learning Freedom is the core concept of modern university education. Learning culture of freedom and creative talents there is an inherent association. Learn the students as the main liberal education, giving students freedom of choice, is to foster an innovative spirit, innovation and the ability to create high-quality talent rich soil. Learning achievement of freedom required to meet the appropriate conditions, which the students have a sense of responsibility and self-realization of the spirit of freedom of the internal conditions of learning, school teaching and flexible management of the implementation of flexible learning is to achieve the freedom of external protection.

Germline inactivating mutations of isoform 4 of phosphodiesterase (PDE) 11A (coded by the PDE11A gene) have been associated with familial adrenocortical tumors and familial testicular cancer. Testicular tissue is unique in expressing all four isoforms of PDE11A. In a prior candidate gene study of 94 familial testicular germ cell tumor (TGCT) subjects, we identified a significant association between the presence of functionally abnormal variants in PDE11A and familial TGCT risk. To validate this novel observation, we sequenced the PDE11A coding region in 259 additional TGCT patients (both familial and sporadic) and 363 controls. We identified 55 PDE11A variants: 20 missense, four splice-site, two nonsense, seven synonymous, and 22 intronic. Ten missense variants were novel; nine occurred in transcript variant 4 and one in transcript variant 3. Five rare mutations (p.F258Y, p.G291R, p.V820M, p.R545X, and p.K568R) were present only in cases and were significantly more common in cases vs controls (P=0.0037). The latter two novel variants were functionally characterized and shown to be functionally inactivating, resulting in reduced PDE activity and increased cAMP levels. In further analysis of this cohort, we focused on white participants only to minimize confounding due to population stratification. This study builds upon our prior reports implicating PDE11A variants in familial TGCT, provides the first independent validation of those findings, extends that work to sporadic testicular cancer, demonstrates that these variants are uncommonly but reproducibly associated with TGCT, and refines our understanding regarding which specific inactivating PDE11A variants are most likely to be associated with TGCT risk.

BACKGROUND Genome-wide association studies of prostate cancer have identified single nucleotide polymorphism (SNP) markers in a region of chromosome 11q13.3 in men of European decent. A fine-mapping analysis with tag SNPs in the cancer genetic markers of susceptibility study identified three independent loci, marked by rs10896438, rs12793759, and rs10896449. This study further annotates common and uncommon variation across this region. METHODS A next generation resequence analysis of a 122.9-kb region of 11q13.3 (68,642,755-68,765,690) was conducted in 78 unrelated individuals of European background, 1 CEPH trio, and 1 YRI trio. RESULTS In total, 644 polymorphic loci were identified by our sequence analysis. Of these, 166 variants—118 SNPs and 48 insertion-deletion polymorphisms (indels)—were novel, namely not present in the 1000 Genomes or International HapMap Projects. We identified 22, 25, 6, and 4 variants strongly correlated (r2 ≥ 0.8) with rs10896438, rs10896449, rs12793759, and rs11228565, respectively. HapMap SNPs were in linkage disequilibrium (r2 ≥ 0.8) with 48%, 69%, 14%, and 60% of SNPs marking bins by rs10896438, rs10896449, rs12793759, and rs11228565, respectively. CONCLUSIONS Our next generation resequence analysis compliments publicly available datasets of European descent (HapMap, build 28 and 1000 Genome, Pilot 1, October 2010), underscoring the value of targeted resequence analysis prior to initiating functional studies based on public databases alone. Increasing the number of common variants enables investigators to better prioritize variants for functional studies designed to uncover the biological basis of the direct association(s) in the region. Prostate 72:476–486, 2012. © 2011 Wiley Periodicals, Inc.

In this paper, a new electrostatic discharge (ESD) testing system is designed and the influence of the approach speed and charge voltage on ESD parameters, e.g., discharge current, rise time, and induced voltage in a semicircular loop antenna, and also the reproducibility of experimental results are analyzed. It is concluded that, as the charge voltage is constant, ESD parameters are linearly proportional to the approach speed, the reproducibility increases with growth of the approach speed, especially at 0.8 m/s. As the approach speed is constant, the field strength generated at low charge voltage is stronger than that at high charge voltage; better reproducibility can be also reached at low charge voltage. These important conclusions provide the foundation for developing standard method for air ESD immunity tests.

Background: Lung squamous cell carcinoma (SqCC) arises in the epithelial layer of the bronchial airway and is often preceded by the development of premalignant lesions. However, not all premalignant lesions progress to lung SqCC and many will regress spontaneously. Understanding the somatic alterations and molecular subtypes associated with progression will allow us to identify biomarkers for early detection and develop therapeutic strategies for disease prevention and interception. Methods: Biopsies were obtained from high-risk smokers undergoing lung cancer screening by auto-fluorescence bronchoscopy and CT at the Roswell Park Cancer Institute. For each subject, multiple sites were sampled repeatedly over time. One biopsy from each region was sent for pathological review while another biopsy was taken for molecular studies. Whole-exome sequencing (WES) was performed at Uniform Services University to 120x coverage and RNA-seq was performed at Boston University School of Medicine. Results: The median number of somatic mutations across all premalignant lesions that underwent DNA-seq (150 biopsies from 20 subjects) was 0.45 per megabase and displayed a modest association with histological grade (p=0.05). The most frequently mutated known lung cancer genes included NOTCH1 (14%), TP53 (6%), FAT1 (3%), PIK3CA (2%), KRAS ( Citation Format: Joshua D. Campbell, Xijun Zhang, Catalina Perdomo, Sarah Mazzilli, Yaron Geshalter, Samjot S. Dhillon, Gang Liu, Sherry Zhang, Hanqiao Liu, Jessica Vick, Christopher Moy, Stefano Monti, Evan Johnson, Matthew Meyerson, Matthew Wilkerson, Clifton Dalgard, Suso Platero, Chris Stevenson, Marc Lenburg, Mary Reid, Jennifer Beane, Avrum Spira. Genomic characterization of premalignant lung squamous cell carcinoma lesions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3248.

The etiologic contribution of germline genetic variation to sporadic osteosarcoma is not well understood. Osteosarcoma is a sentinel cancer of Li-Fraumeni syndrome (LFS), in which approximately 70% of families meeting the classic criteria have germline TP53 mutations. We sequenced TP53 exons in 765 osteosarcoma cases. Data were analyzed with χ(2) tests, logistic regression, and Cox proportional hazards regression models. We observed a high frequency of young osteosarcoma cases (age

The relationship between chromosomal instability and integration of the human papillomavirus (HPV) DNA into the host genome is not well understood. We found that chromosomal instability increases with HPV integration and diagnosis. However, chromosomal instability could occur without HPV integration.

The shelterin complex protects chromosomal ends by regulating how the telomerase complex interacts with telomeres. Following the recent finding in familial melanoma of inactivating germline mutations in POT1, encoding a member of the shelterin complex, we searched for mutations in the other five components of the shelterin complex in melanoma families.Next-generation sequencing techniques were used to screen 510 melanoma families (with unknown genetic etiology) and control cohorts for mutations in shelterin complex encoding genes: ACD, TERF2IP, TERF1, TERF2, and TINF 2. Maximum likelihood and LOD [logarithm (base 10) of odds] analyses were used. Mutation clustering was assessed with χ(2) and Fisher's exact tests. P values under .05 were considered statistically significant (one-tailed with Yates' correction).Six families had mutations in ACD and four families carried TERF2IP variants, which included nonsense mutations in both genes (p.Q320X and p.R364X, respectively) and point mutations that cosegregated with melanoma. Of five distinct mutations in ACD, four clustered in the POT1 binding domain, including p.Q320X. This clustering of novel mutations in the POT1 binding domain of ACD was statistically higher (P = .005) in melanoma probands compared with population control individuals (n = 6785), as were all novel and rare variants in both ACD (P = .040) and TERF2IP (P = .022). Families carrying ACD and TERF2IP mutations were also enriched with other cancer types, suggesting that these variants also predispose to a broader spectrum of cancers than just melanoma. Novel mutations were also observed in TERF1, TERF2, and TINF2, but these were not convincingly associated with melanoma.Our findings add to the growing support for telomere dysregulation as a key process associated with melanoma susceptibility.

This article focuses on the design of intelligent transportation systems in the construction of the smart urban. Learning from the wisdom of traffic building programs, the paper is given the overall design of intelligent transportation process based on location big data. Lanzhou City was analyzed and designed using this method. The collected GPS big data was deeply excavated and analyzed through the mathematical model. Thus the clear city traffic analysis chart was got to predict the traffic flow. In the end the intelligent transportation was realized in the smart city. The arrival of the "smart city" is not only changing the quality of life of personal information, but also can be applied to urban public safety, manufacturing production, environmental monitoring, intelligent traffic, intelligent home, environmental monitoring and other fields. It can make full use of the social resources. It can greatly promote the enterprise to reduce the cost. It can make the government improve public service ability and city management efficiency.(1-3) From the point of the architecture of the smart city the wisdom of the city is based on the technology of the Internet of things, so the architecture of the smart city is similar to the internet of things. It is divided into four layers which are the perception layer, transport layer, system layer and application layer. The goal of the intelligent transportation system (ITS) is using the communication system to closely combine the transport system of people, vehicles and road. Advanced traffic control system and advanced traffic management system are required to provide real-time traffic flow information. Traffic flow analysis is an important research content in the transportation system. The traditional traffic flow model is described the traffic flow state variables (velocity, density and flow) with the change of time and space.(4-5) From the research of traffic flow, the research method of traffic flow is developed from the empirical method to the research method based on physical model and the mathematical model. Finally it returns to the initial empirical method.The Fig.1 is shown the platform of the location big data.(6-8) All study is based on the data. The location big data is studied through this platform. There are four steps which are data acquisition, data analysis, data calculation and data visualization. The intelligent transportation on business analysis can be got through those

The completion of the 5,373,180-bp genome sequence of the marine psychrophilic bacterium Colwellia psychrerythraea 34H, a model for the study of life in permanently cold environments, reveals capabilities important to carbon and nutrient cycling, bioremediation, production of secondary metabolites, and cold-adapted enzymes. From a genomic perspective, cold adaptation is suggested in several broad categories involving changes to the cell membrane fluidity, uptake and synthesis of compounds conferring cryotolerance, and strategies to overcome temperature-dependent barriers to carbon uptake. Modeling of three-dimensional protein homology from bacteria representing a range of optimal growth temperatures suggests changes to proteome composition that may enhance enzyme effectiveness at low temperatures. Comparative genome analyses suggest that the psychrophilic lifestyle is most likely conferred not by a unique set of genes but by a collection of synergistic changes in overall genome content and amino acid composition.

Background: Accurate detection of somatic mutations is critical for informing targeted therapy options. Prevalent non-cancer cell admixture complicates this detection in breast cancer. Conventional mutation detection relies on DNA sequencing; however in prior work, we demonstrated that combining RNA and DNA sequencing increases mutation signal strength, or mutant allele fraction (MAF). The ratio of RNA MAF versus DNA MAF (RNA:DNA MAF) was greatest in low purity breast tumors. We hypothesized that this elevation is biologically driven and would be conserved in a second, distinct tissue specimen of the same tumors. Here, we compare mutation characteristics between two tissue blocks in a cohort of breast tumors (n = 8) to evaluate possible preservation of RNA versus DNA mutation signal throughout the tumor. Methods: We selected four high purity and four low purity breast tumors (“Block1”) from The Cancer Genome Atlas (TCGA) cohort and associated ABSOLUTE purity analysis. For these tumors, we acquired a second tissue block (“Block2”) not analyzed by TCGA, cut sections, analyzed sections by H&E stains, and extracted nucleic acids. Whole genome DNA sequencing and mRNA sequencing was performed for Block2 specimens using Illumina X and NextSeq 500 sequencers, respectively. Somatic mutations in Block2 were detected using UNCeqR and compared to published UNCeqR somatic mutations from TCGA. We then evaluate MAF characteristics in the entire TCGA breast tumor cohort (n = 695). Results: Tumor purity estimates, determined by histology and by sequencing, were reduced in Block2 of the low purity tumor set versus the high purity tumor set, consistent with Block1 analysis. Molecular properties of genome-wide gene expression and somatic DNA copy number were highly similar between block-mated specimens (p < 0.01). We then identified expressed mutations present in Block1 and Block2 of the same tumor and compared the MAFs on these common mutations. DNA MAF and RNA MAF were each significantly correlated between Block1 and Block2 (p < 1e-12 in both cases). The average RNA:DNA MAF was 2.5 for the cohort, indicating that RNA mutation signal is greater than DNA in general. In Block2 specimens, the RNA:DNA MAFs were significantly greater in the low purity tumor set than the high purity tumor set (mean 2.7 versus 2.1, p < 6e-5), reflecting the same trend observed in Block1 specimens. Analyzing the entire TCGA cohort, RNA:DNA MAF was positively correlated with proliferation pathway gene expression (p < 3e-16 ) and was greatest in the Basal subtype versus other subtypes (p < 2e-9). Conclusion: Mutant allele fraction both of DNA and of RNA was conserved across breast tumor subsections. Low purity and basal subtype breast tumors had elevated RNA:DNA MAF supporting a relationship to underlying biology and identifying classes of tumors with pronounced benefit for DNA and RNA integrated mutation analysis. Citation Format: Jerez Te, Coralie Viollet, Xijun Zhang, Jatinder Singh, Jeffrey A. Hooke, Harvey B. Pollard, Hai Hu, Craig D. Shriver, Clifton L. Dalgard, Matthew D. Wilkerson. Reproducible elevation of RNA versus DNA mutation signal in low purity breast tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5403. doi:10.1158/1538-7445.AM2017-5403

Background: Lung squamous cell carcinoma (SqCC) arises in the epithelial layer of the bronchial airway and is often preceded by the development of premalignant lesions. However, not all premalignant lesions progress to lung SqCC and many regress without therapeutic intervention. Understanding the somatic alterations that contribute to progression of premalignant lesions in the airway will allow us to identify biomarkers for early detection and develop therapeutic strategies for early intervention. Methods: Airway biopsies were obtained from high-risk smokers undergoing lung cancer screening by auto-fluorescence bronchoscopy and chest CT at the Roswell Park Cancer Institute. For each subject (n=30), multiple premalignant lesions were sampled repeatedly over time (n=144 samples). One biopsy from each region was sent for pathological review while another biopsy was taken for molecular studies. DNA was also isolated from the blood or cytologically normal bronchial brushings to serve as a matched normal control. Exome capture was performed using the Illumina TruSeq Rapid Exome kit and sequenced to a mean depth of coverage of 120x at Uniform Services University and Walter Reed National Military Medical Center. Results: The median number of somatic mutations across all premalignant lesions was 0.73 per megabase (range: 0.10 - 9.8 per Mb) and displayed a modest association with histological grade (p=0.07). The most frequently mutated lung cancer genes included KMT2C (12%), NOTCH1 (11%), FAT1 (6%), TP53 (5%), and CDKN2A (7/Mb) were taken from adjacent sites over two time points in the same individual with a prior history of lung squamous cell carcinoma. These lesions had a significantly overlapping set of mutations including FAT1 indicating a common evolutionary ancestor. Conclusions: The somatic alterations observed in known cancer genes such as TP53, KMT2C, NOTCH1, and FAT1 may be among the earliest driver events in lung SqCC development and may be useful as biomarkers for early detection as well as targets for lung cancer interception. Citation Format: Joshua Campbell, Xijun Zhang, Samjot S. Dhillon, Catalina Perdomo, Sarah Mazzilli, Yaron Geshalter, Gang Liu, Sherry Zhang, Hanqiao Lin, Jessica Vick, Christopher Moy, Stefano Monti, Evan Johnson, Matthew Meyerson, Steven Dubinett, Suso Platero, Matthew Wilkerson, Clifton Dalgard, Marc Lenburg, Mary Reid, Jennifer Beane, Avrum Spira. The genomic landscape of premalignant lung squamous cell carcinoma lesions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3259. doi:10.1158/1538-7445.AM2017-3259

Purpose: Cervical cancer is one of the most common causes of cancer mortality for women living in poverty, causing more than 28,000 deaths annually in Latin America and 266,000 worldwide. To better understand the molecular basis of the disease, we ascertained blood and tumor samples from Guatemala and Venezuela and performed genomic characterization. Experimental Design: We performed human papillomavirus (HPV) typing and identified somatically mutated genes using exome and ultra-deep targeted sequencing with confirmation in samples from Mexico. Copy number changes were also assessed in the exome sequence. Results: Cervical cancer cases in Guatemala and Venezuela have an average age of diagnosis of 50 years and 5.6 children. Analysis of 675 tumors revealed activation of PIK3CA and other PI3K/AKT pathway genes in 31% of squamous carcinomas and 24% of adeno- and adenosquamous tumors, predominantly at two sites (E542K, E545K) in the helical domain of the PIK3CA gene. This distribution of PIK3CA mutations is distinct from most other cancer types and does not result in the in vitro phosphorylation of AKT. Somatic mutations were more frequent in squamous carcinomas diagnosed after the age of 50 years. Frequent gain of chromosome 3q was found, and low PIK3CA mutation fractions in many tumors suggest that PI3K mutation can be a late event in tumor progression. Conclusions: PI3K pathway mutation is important to cervical carcinogenesis in Latin America. Therapeutic agents that directly target PI3K could play a role in the therapy of this common malignancy. Clin Cancer Res; 21(23); 5360–70. ©2015 AACR.

We assessed the performance of the new Life Technologies Proton sequencer by comparing whole-exome sequence data in a Centre d’Etude du Polymorphisme Humain trio (family 1463) to the Illumina HiSeq instrument. To simulate a typical user’s results, we utilized the standard capture, alignment and variant calling methods specific to each platform. We restricted data analysis to include the capture region common to both methods. The Proton produced high quality data at a comparable average depth and read length, and the Ion Reporter variant caller identified 96 % of single nucleotide polymorphisms (SNPs) detected by the HiSeq and GATK pipeline. However, only 40 % of small insertion and deletion variants (indels) were identified by both methods. Usage of the trio structure and segregation of platform-specific alleles supported this result. Further comparison of the trio data with Complete Genomics sequence data and Illumina SNP microarray genotypes documented high concordance and accurate SNP genotyping of both Proton and Illumina platforms. However, our study underscored the problem of accurate detection of indels for both the Proton and HiSeq platforms.

BACKGROUND HPV16 is a common sexually transmitted infection although few infections lead to cervical precancer/cancer; we cannot distinguish nor mechanistically explain why only certain infections progress. HPV16 can be classified into four main evolutionary-derived variant lineages (A, B, C, D) that have been previously suggested to have varying disease risks. METHODS We used a high-throughput HPV16 whole-genome sequencing assay to investigate variant lineage risk among 3215 HPV16-infected women. Using sublineages A1/A2 as the reference, we assessed all variant lineage associations with infection outcome over three or more years of follow-up: 1107 control subjects (

Background Hoyeraal-Hreidarsson syndrome is a dyskeratosis congenita–related telomere biology disorder that presents in infancy with intrauterine growth retardation, immunodeficiency, and cerebellar hypoplasia in addition to the triad of nail dysplasia, skin pigmentation, and oral leukoplakia. Individuals with Hoyeraal-Hreidarsson syndrome often develop bone marrow failure in early childhood. Germline mutations in DKC1, TERT, TINF2, RTEL1, ACD, or PARN cause about 60% of individuals with Hoyeraal-Hreidarsson syndrome. Patient Description We describe 14 years of follow-up of an individual with Hoyeraal-Hreidarsson syndrome who initially presented as an infant with intrauterine growth retardation, microcephaly, and central nervous system calcifications. He was diagnosed with Hoyeraal-Hreidarsson syndrome at age 6 years and had a complicated medical history including severe developmental delay, cerebellar hypoplasia, esophageal and urethral stenosis, hip avascular necrosis, immunodeficiency, and bone marrow failure evolving to myelodysplastic syndrome requiring hematopoietic cell transplantation at age 14 years. He had progressive skin pigmentation, oral leukoplakia, and nail dysplasia leading to anonychia. Whole exome sequencing identified novel biallelic variants in PARN . Conclusions This patient illustrates that the constellation of intrauterine growth retardation, central nervous system calcifications, and cerebellar hypoplasia, esophageal or urethral stenosis, and cytopenias, in the absence of congenital infection, may be due to Hoyeraal-Hreidarsson syndrome. Early diagnosis of Hoyeraal-Hreidarsson syndrome is important to optimize medical management and provide genetic counseling.