Revealing microstructural evolutions, mechanical properties and wear performance of wire arc additive manufacturing homogeneous and heterogeneous NiTi alloy

Heterogeneous microstructure designs have attracted a great deal of attention, not only because they have the potential to achieve an ideal combination of two conflicting properties, but also because the processes involved in their fabrication are cost-effective and can be scaled up for industrial production. The process parameters in the preparation process have an important effect on the microstructure and properties of alloy members prepared by wire arc additive manufacturing (WAAM) technology. It was expected that the spatial heterogeneous microstructure with large microstructural heterogeneities in metals can be formed through changing the process parameters. In this work, homogeneous NiTi thin-walled component and heterogeneous NiTi thin-walled component were fabricated using WAAM technology by adjusting the heat input. The effects of deposition height and heat input on the microstructure, mechanical properties and wear properties of WAAM NiTi alloys were investigated. The results show that grains were gradually refined with the increase of deposition height in the homogeneous WAAM NiTi component. The ultimate tensile strength of homogeneous WAAM NiTi component increased from 606.87 MPa to 654.45 MPa and the elongation increased from 12.72% to 15.38%, as the increase of deposition height. Moreover, the homogeneous WAAM NiTi component exhibited excellent wear resistance, the coefficient of friction decreased from 0.760 to 0.715 with the increase of deposition height. Meanwhile, the grains in the heterogeneous WAAM NiTi component shows the finest grains in the central region. The ultimate tensile strength of the lower region, middle region and upper region of heterogeneous WAAM NiTi components were 556.12 MPa, 599.53 MPa and 739.79 MPa, and the elongations were 12.98%, 16.69%, 21.74%, respectively. The coefficient of friction for the lower region, middle region and upper region of heterogeneous WAAM NiTi components were 0.713, 0.720 and 0.710, respectively. The microhardness and cyclic compression properties of the homogeneous components with higher heat input were better than those of the heterogeneous components for the same deposition height. The tensile yield strength, elongation and wear resistance of the heterogeneous components were superior compared to the homogeneous components. These results can be used to optimize the WAAM process parameters to prepare NiTi components with excellent mechanical properties

Intragenic motifs regulate the transcriptional complexity of Pkhd1/PKHD1

Autosomal recessive polycystic kidney disease (ARPKD) results from mutations in the human PKHD1 gene. Both this gene, and its mouse ortholog, Pkhd1, are primarily expressed in renal and biliary ductal structures. The mouse protein product, fibrocystin/polyductin complex (FPC), is a 445-kDa protein encoded by a 67-exon transcript that spans >500 kb of genomic DNA. In the current study, we observed multiple alternatively spliced Pkhd1 transcripts that varied in size and exon composition in embryonic mouse kidney, liver, and placenta samples, as well as among adult mouse pancreas, brain, heart, lung, testes, liver, and kidney. Using reverse transcription PCR and RNASeq, we identified 22 novel Pkhd1 kidney transcripts with unique exon junctions. Various mechanisms of alternative splicing were observed, including exon skipping, use of alternate acceptor/donor splice sites, and inclusion of novel exons. Bioinformatic analyses identified, and exon-trapping minigene experiments validated, consensus binding sites for serine/arginine-rich proteins that modulate alternative splicing. Using site-directed mutagenesis, we examined the functional importance of selected splice enhancers. In addition, we demonstrated that many of the novel transcripts were polysome bound, thus likely translated. Finally, we determined that the human PKHD1 R760H missense variant alters a splice enhancer motif that disrupts exon splicing in vitro and is predicted to truncate the protein. Taken together, these data provide evidence of the complex transcriptional regulation of Pkhd1/PKHD1 and identified motifs that regulate its splicing. Our studies indicate that Pkhd1/PKHD1 transcription is modulated, in part by intragenic factors, suggesting that aberrant PKHD1 splicing represents an unappreciated pathogenic mechanism in ARPKD. Key messages: Multiple mRNA transcripts are generated for Pkhd1 in renal tissues Pkhd1 transcription is modulated by standard splice elements and effectors Mutations in splice motifs may alter splicing to generate nonfunctional peptides

American ginseng suppresses Western diet-promoted tumorigenesis in model of inflammation-associated colon cancer: role of EGFR

<p>Abstract</p> <p>Background</p> <p>Western diets increase colon cancer risk. Epidemiological evidence and experimental studies suggest that ginseng can inhibit colon cancer development. In this study we asked if ginseng could inhibit Western diet (20% fat) promoted colonic tumorigenesis and if compound K, a microbial metabolite of ginseng could suppress colon cancer xenograft growth.</p> <p>Methods</p> <p>Mice were initiated with azoxymethane (AOM) and, two weeks later fed a Western diet (WD, 20% fat) alone, or WD supplemented with 250-ppm ginseng. After 1 wk, mice received 2.5% dextran sulfate sodium (DSS) for 5 days and were sacrificed 12 wks after AOM. Tumors were harvested and cell proliferation measured by Ki67 staining and apoptosis by TUNEL assay. Levels of EGF-related signaling molecules and apoptosis regulators were determined by Western blotting. Anti-tumor effects of intraperitoneal compound K were examined using a tumor xenograft model and compound K absorption measured following oral ginseng gavage by UPLC-mass spectrometry. Effects of dietary ginseng on microbial diversity were measured by analysis of bacterial 16S rRNA.</p> <p>Results</p> <p>Ginseng significantly inhibited colonic inflammation and tumorigenesis and concomitantly reduced proliferation and increased apoptosis. The EGFR cascade was up-regulated in colonic tumors and ginseng significantly reduced EGFR and ErbB2 activation and Cox-2 expression. Dietary ginseng altered colonic microbial diversity, and bacterial suppression with metronidazole reduced serum compound K following ginseng gavage. Furthermore, compound K significantly inhibited tumor xenograft growth.</p> <p>Conclusions</p> <p>Ginseng inhibited colonic inflammation and tumorigenesis promoted by Western diet. We speculate that the ginseng metabolite compound K contributes to the chemopreventive effects of this agent in colonic tumorigenesis.</p

Identification of Mouse Serum miRNA Endogenous References by Global Gene Expression Profiles

MicroRNAs (miRNAs) are recently discovered small non-coding RNAs and can serve as serum biomarkers for disease diagnosis and prognoses. Lack of reliable serum miRNA endogenous references for normalization in miRNA gene expression makes single miRNA assays inaccurate. Using TaqMan® real-time PCR miRNA arrays with a global gene expression normalization strategy, we have analyzed serum miRNA expression profiles of 20 female mice of NOD/ShiLtJ (n = 8), NOR/LtJ (n = 6), and C57BL/6J (n = 6) at different ages and disease conditions. We identified five miRNAs, miR-146a, miR-16, miR-195, miR-30e and miR-744, to be stably expressed in all strains, which could serve as mouse serum miRNA endogenous references for single assay experiments

Hostility, Physical Aggression and Trait Anger as Predictors for Suicidal Behavior in Chinese Adolescents: A School-Based Study

Purpose: This study explored the extent to which trait aggression is associated with suicidal behavior in a nationwide school-based sample of adolescents. Methods: A nationwide sample of 14,537 high school students in urban areas of China was recruited. Information concerning suicide ideation, plans, attempts, trait aggression and other risk factors was collected by a self-reported questionnaire. Multivariate regression analyses were employed to predict suicidal behavior. Results: Approximately 18.5 % of students reported suicide ideation, 8.7 % reported suicide plans, and 4.1 % reported attempts during the past one year. Hostility and trait anger had a significant positive association with suicidal ideation. Hostility and physical aggression were positively related to suicide plans. Hostility had a positive correlation with suicide attempts, while trait anger was inversely associated with suicide attempts. Conclusions: This study suggests that hostility, physical aggression and trait anger may be able to be used to predict suicidal behavior among adolescents. Suicide prevention programs should target at attenuating the severity of hostility, anger and physical aggression. But teachers and parents should also give close attention to students with low trait anger

Plasma miRNA as Biomarkers for Assessment of Total-Body Radiation Exposure Dosimetry

The risk of radiation exposure, due to accidental or malicious release of ionizing radiation, is a major public health concern. Biomarkers that can rapidly identify severely-irradiated individuals requiring prompt medical treatment in mass-casualty incidents are urgently needed. Stable blood or plasma-based biomarkers are attractive because of the ease for sample collection. We tested the hypothesis that plasma miRNA expression profiles can accurately reflect prior radiation exposure. We demonstrated using a murine model that plasma miRNA expression signatures could distinguish mice that received total body irradiation doses of 0.5 Gy, 2 Gy, and 10 Gy (at 6 h or 24 h post radiation) with accuracy, sensitivity, and specificity of above 90%. Taken together, these data demonstrate that plasma miRNA profiles can be highly predictive of different levels of radiation exposure. Thus, plasma-based biomarkers can be used to assess radiation exposure after mass-casualty incidents, and it may provide a valuable tool in developing and implementing effective countermeasures

Favorable prognostic value of SOCS2 and IGF-I in breast cancer

<p>Abstract</p> <p>Background</p> <p>Suppressor of cytokine signaling (SOCS) proteins comprise a protein family, which has initially been described as STAT induced inhibitors of the Jak/Stat pathway. Recent in vivo and in vitro studies suggest that SOCS proteins are also implicated in cancer. The STAT5 induced IGF-I acts as an endocrine and para/autocrine growth and differentiation factor in mammary gland development. Whereas high levels of circulating IGF-I have been associated with increased cancer risk, the role of autocrine acting IGF-I is less clear. The present study is aimed to elucidate the clinicopathological features associated with SOCS1, SOCS2, SOCS3, CIS and IGF-I expression in breast cancer.</p> <p>Methods</p> <p>We determined the mRNA expression levels of SOCS1, SOCS2, SOCS3, CIS and IGF-I in 89 primary breast cancers by reverse transcriptase PCR. SOCS2 protein expression was further evaluated by immuno-blot and immunohistochemistry.</p> <p>Results</p> <p>SOCS2 expression inversely correlated with histopathological grade and ER positive tumors exhibited higher SOCS2 levels. Patients with high SOCS2 expression lived significantly longer (108.7 vs. 77.7 months; P = 0.015) and high SOCS2 expression proved to be an independent predictor for good prognosis (HR = 0.45, 95% CI 0.23 – 0.91, P = 0.026). In analogy to SOCS2, high IGF-I expression was an independent predictor for good prognosis in the entire patient cohort. In the subgroup of patients with lymph-node negative disease, high IGF-I was a strong predictor for favorable outcome in terms of overall survival and relapse free survival (HR = 0.075, 95% CI 0.014 – 0.388, P = 0.002).</p> <p>Conclusion</p> <p>This is the first report on the favorable prognostic value of high SOCS2 expression in primary mammary carcinomas. Furthermore a strong association of high IGF-I expression levels with good prognosis was observed especially in lymph-node negative patients. Our results suggest that high expression of the STAT5 target genes SOCS2 and IGF-I is a feature of differentiated and less malignant tumors.</p

Network Modeling Identifies Molecular Functions Targeted by miR-204 to Suppress Head and Neck Tumor Metastasis

Due to the large number of putative microRNA gene targets predicted by sequence-alignment databases and the relative low accuracy of such predictions which are conducted independently of biological context by design, systematic experimental identification and validation of every functional microRNA target is currently challenging. Consequently, biological studies have yet to identify, on a genome scale, key regulatory networks perturbed by altered microRNA functions in the context of cancer. In this report, we demonstrate for the first time how phenotypic knowledge of inheritable cancer traits and of risk factor loci can be utilized jointly with gene expression analysis to efficiently prioritize deregulated microRNAs for biological characterization. Using this approach we characterize miR-204 as a tumor suppressor microRNA and uncover previously unknown connections between microRNA regulation, network topology, and expression dynamics. Specifically, we validate 18 gene targets of miR-204 that show elevated mRNA expression and are enriched in biological processes associated with tumor progression in squamous cell carcinoma of the head and neck (HNSCC). We further demonstrate the enrichment of bottleneckness, a key molecular network topology, among miR-204 gene targets. Restoration of miR-204 function in HNSCC cell lines inhibits the expression of its functionally related gene targets, leads to the reduced adhesion, migration and invasion in vitro and attenuates experimental lung metastasis in vivo. As importantly, our investigation also provides experimental evidence linking the function of microRNAs that are located in the cancer-associated genomic regions (CAGRs) to the observed predisposition to human cancers. Specifically, we show miR-204 may serve as a tumor suppressor gene at the 9q21.1–22.3 CAGR locus, a well established risk factor locus in head and neck cancers for which tumor suppressor genes have not been identified. This new strategy that integrates expression profiling, genetics and novel computational biology approaches provides for improved efficiency in characterization and modeling of microRNA functions in cancer as compared to the state of art and is applicable to the investigation of microRNA functions in other biological processes and diseases

Identification and Characterization of Alternative Promoters, Transcripts and Protein Isoforms of Zebrafish R2 Gene

Ribonucleotide reductase (RNR) is the rate-limiting enzyme in the de novo synthesis of deoxyribonucleoside triphosphates. Expression of RNR subunits is closely associated with DNA replication and repair. Mammalian RNR M2 subunit (R2) functions exclusively in DNA replication of normal cells due to its S phase-specific expression and late mitotic degradation. Herein, we demonstrate the control of R2 expression through alternative promoters, splicing and polyadenylation sites in zebrafish. Three functional R2 promoters were identified to generate six transcript variants with distinct 5′ termini. The proximal promoter contains a conserved E2F binding site and two CCAAT boxes, which are crucial for the transcription of R2 gene during cell cycle. Activity of the distal promoter can be induced by DNA damage to generate four transcript variants through alternative splicing. In addition, two novel splice variants were found to encode distinct N-truncated R2 isoforms containing residues for enzymatic activity but no KEN box essential for its proteolysis. These two N-truncated R2 isoforms remained in the cytoplasm and were able to interact with RNR M1 subunit (R1). Thus, our results suggest that multilayered mechanisms control the differential expression and function of zebrafish R2 gene during cell cycle and under genotoxic stress