Gas nitriding and subsequent oxidation of Ti-6Al-4V alloys

Ti-6Al-4V alloys consisting of α-Ti grains and intergranular β-Ti islands were nitrided at 850°C for 1 to 12 h under a nitrogen pressure of 1 Pa. With increasing nitriding time, the Ti-N compound layer became thicker, and the α-Ti diffusion zone containing dissolved nitrogen became wider. In the Ti-N compound layer, the initially formed Ti2N became TiN as the nitriding progressed. The nitride layers were oxidized to rutile-TiO2 after oxidation at 700°C for 10 h in air

Signal Peptide-Dependent Inhibition of MHC Class I Heavy Chain Translation by Rhesus Cytomegalovirus

The US2-11 region of human and rhesus cytomegalovirus encodes a conserved family of glycoproteins that inhibit MHC-I assembly with viral peptides, thus preventing cytotoxic T cell recognition. Since HCMV lacking US2-11 is no longer able to block assembly and transport of MHC-I, we examined whether this is also observed for RhCMV lacking the corresponding region. Unexpectedly, recombinant RhCMV lacking US2-11 was still able to inhibit MHC-I expression in infected fibroblasts, suggesting the presence of an additional MHC-I evasion mechanism. Progressive deletion analysis of RhCMV-specific genomic regions revealed that MHC-I expression is fully restored upon additional deletion of rh178. The protein encoded by this RhCMV-specific open reading frame is anchored in the endoplasmic reticulum membrane. In the presence of rh178, RhCMV prevented MHC-I heavy chain (HC) expression, but did not inhibit mRNA transcription or association of HC mRNA with translating ribosomes. Proteasome inhibitors stabilized a HC degradation intermediate in the absence of rh178, but not in its presence, suggesting that rh178 prevents completion of HC translation. This interference was signal sequence-dependent since replacing the signal peptide with that of CD4 or murine HC rendered human HCs resistant to rh178. We have identified an inhibitor of antigen presentation encoded by rhesus cytomegalovirus unique in both its lack of homology to any other known protein and in its mechanism of action. By preventing signal sequence-dependent HC translocation, rh178 acts prior to US2, US3 and US11 which attack MHC-I proteins after protein synthesis is completed. Rh178 is the first viral protein known to interfere at this step of the MHC-I pathway, thus taking advantage of the conserved nature of HC leader peptides, and represents a new mechanism of translational interference

TTF-1 Action on the Transcriptional Regulation of Cyclooxygenase-2 Gene in the Rat Brain

We have recently found that thyroid transcription factor-1 (TTF-1), a homeodomain-containing transcription factor, is postnatally expressed in discrete areas of the hypothalamus and closely involved in neuroendocrine functions. We now report that transcription of cyclooxygenase-2 (COX-2), the rate limiting enzyme in prostaglandin biosynthesis, was inhibited by TTF-1. Double immunohistochemistry demonstrated that TTF-1 was expressed in the astrocytes and endothelial cells of blood vessel in the hypothalamus. Promoter assays and electrophoretic mobility shift assays showed that TTF-1 inhibited COX-2 transcription by binding to specific binding domains in the COX-2 promoter. Furthermore, blocking TTF-1 synthesis by intracerebroventricular injection of an antisense oligomer induced an increase of COX-2 synthesis in non-neuronal cells of the rat hypothalamus, and resulted in animals' hyperthermia. These results suggest that TTF-1 is physiologically involved in the control of thermogenesis by regulating COX-2 transcription in the brain

Relationship between cyclooxygenase 8473T>C polymorphism and the risk of lung cancer: a case-control study

BACKGROUND: Cyclooxygenase-2 (COX-2) plays an important role in the development of lung cancer. DNA sequence variations in the COX-2 gene may lead to altered COX-2 production and/or activity, and so they cause inter-individual differences in the susceptibility to lung cancer. To test this hypothesis, we investigated the association between the 8473T>C polymorphism in the 3'-untranslated region of the COX-2 gene and the risk of lung cancer in a Korean population. METHODS: The COX-2 genotypes were determined using PCR-based primer-introduced restriction analysis in 582 lung cancer patients and in 582 healthy controls that were frequency-matched for age and gender. RESULTS: The distribution of the COX-2 8473T>C genotypes was not significantly different between the overall lung cancer cases and the controls. However, when the cases were categorized by the tumor histology, the combined 8473 TC + CC genotype was associated with a significantly decreased risk of adenocarcinoma as compared with the 8473 TT genotype (adjusted OR = 0.64; 95% CI = 0.46–0.90, P = 0.01). On the stratification analysis, the protective effect of the combined 8473 TC + CC genotype against adenocarcinoma was statistically significant in the males, older individuals and ever-smokers (adjusted OR = 0.59; 95% CI = 0.39–0.91, P = 0.02; adjusted OR = 0.55; 95% CI = 0.33–0.93, P = 0.03; and adjusted OR = 0.57; 95% CI = 0.37–0.87, P = 0.01, respectively). CONCLUSION: These findings suggest that the COX-2 8473T>C polymorphism could be used as a marker for the genetic susceptibility to adenocarcinoma of the lung

Rare Exonic Minisatellite Alleles in MUC2 Influence Susceptibility to Gastric Carcinoma

BACKGROUND: Mucins are the major components of mucus and their genes share a common, centrally-located region of sequence that encodes tandem repeats. Mucins are well known genes with respect to their specific expression levels; however, their genomic levels are unclear because of complex genomic properties. In this study, we identified eight novel minisatellites from the entire MUC2 region and investigated how allelic variation in these minisatellites may affect susceptibility to gastrointestinal cancer. METHODOLOGY/PRINCIPLE FINDINGS: We analyzed genomic DNA from the blood of normal healthy individuals and multi-generational family groups. Six of the eight minisatellites exhibited polymorphism and were transmitted meiotically in seven families, following Mendelian inheritance. Furthermore, a case-control study was performed that compared genomic DNA from 457 cancer-free controls with DNA from individuals with gastric (455), colon (192) and rectal (271) cancers. A statistically significant association was identified between rare exonic MUC2-MS6 alleles and the occurrence of gastric cancer: odds ratio (OR), 2.56; 95% confidence interval (CI), 1.31-5.04; and p = 0.0047. We focused on an association between rare alleles and gastric cancer. Rare alleles were divided into short (40, 43 and 44) and long (47, 50 and 54), according to their TR (tandem repeats) lengths. Interestingly, short rare alleles were associated with gastric cancer (OR = 5.6, 95% CI: 1.93-16.42; p = 0.00036). Moreover, hypervariable MUC2 minisatellites were analyzed in matched blood and cancer tissue from 28 patients with gastric cancer and in 4 cases of MUC2-MS2, minisatellites were found to have undergone rearrangement. CONCLUSIONS/SIGNIFICANCE: Our observations suggest that the short rare MUC2-MS6 alleles could function as identifiers for risk of gastric cancer. Additionally, we suggest that minisatellite instability might be associated with MUC2 function in cancer cells

Dysregulation of autophagy and stress granule-related proteins in stress-driven Tau pathology

Imbalance of neuronal proteostasis associated with misfolding and aggregation of Tau protein is a common neurodegenerative feature in Alzheimer's disease (AD) and other Tauopathies. Consistent with suggestions that lifetime stress may be an important AD precipitating factor, we previously reported that environmental stress and high glucocorticoid (GC) levels induce accumulation of aggregated Tau; however, the molecular mechanisms for such process remain unclear. Herein, we monitor a novel interplay between RNA-binding proteins (RBPs) and autophagic machinery in the underlying mechanisms through which chronic stress and high GC levels impact on Tau proteostasis precipitating Tau aggregation. Using molecular, pharmacological and behavioral analysis, we demonstrate that chronic stress and high GC trigger mTOR-dependent inhibition of autophagy, leading to accumulation of Tau aggregates and cell death in P301L-Tau expressing mice and cells. In parallel, we found that environmental stress and GC disturb cellular homeostasis and trigger the insoluble accumulation of different RBPs, such as PABP, G3BP1, TIA-1, and FUS, shown to form stress granules (SGs) and Tau aggregation. Interestingly, an mTOR-driven pharmacological stimulation of autophagy attenuates the GC-driven accumulation of Tau and SG-related proteins as well as the related cell death, suggesting a critical interface between autophagy and the response of the SG-related protein in the neurodegenerative potential of chronic stress and GC. These studies provide novel insights into the RNA-protein intracellular signaling regulating the precipitating role of environmental stress and GC on Tau-driven brain pathology.We would like to thank Professor Juergen Gotz, (University of Queensland, Australia) for the kind offer of eGFP-P301LTau SH-SY5Y cells and Dr. Bruno Almeida for his technical assistance. J.M.S. was granted with a PhD fellowship (SRFH/BD/88932/2012) by Portuguese Foundation for Science & Technology (FCT); I.S. is holder of FCT Investigator grants (IF/01799/2013), C.D. is a recipient of PhD fellowship of PHDoc program and co-tutelle PhD student of UMinho-UPMC universities. This work was funded by FCT research grants "PTDC/SAU-NMC/113934/2009" (I.S.), the Portuguese North Regional Operational Program (ON. 2) under the National Strategic Reference Framework (QREN), through the European Regional Development Fund (FEDER) as well as the Project Estrategico co-funded by FCT (PEst-C/SAU/LA0026/2013) and the European Regional Development Fund COMPETE (FCOMP-01-0124-FEDER-037298) as well as the project NORTE-01-0145-FEDER000013, supported by the Northern Portugal Regional Operational Program (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER). In addition, this work was partly funded by Canon Foundation in Europe. This work has been also funded by FEDER funds, through the Competitiveness Factors Operational Programme (COMPETE), and by National funds, through the Foundation for Science and Technology (FCT), under the scope of the project POCI-01-0145FEDER-007038. This study was also supported to BW by grants from NIH (AG050471, NS089544, and ES020395), the BrightFocus Foundation, the Alzheimer Association and the Cure Alzeimer Foundation. Human brain tissue was generously provided by the National Institute of Aging Boston University AD Center (P30AG13846).info:eu-repo/semantics/publishedVersio

Geographic Variation in Advertisement Calls in a Tree Frog Species: Gene Flow and Selection Hypotheses

In a species with a large distribution relative to its dispersal capacity, geographic variation in traits may be explained by gene flow, selection, or the combined effects of both. Studies of genetic diversity using neutral molecular markers show that patterns of isolation by distance (IBD) or barrier effect may be evident for geographic variation at the molecular level in amphibian species. However, selective factors such as habitat, predator, or interspecific interactions may be critical for geographic variation in sexual traits. We studied geographic variation in advertisement calls in the tree frog Hyla japonica to understand patterns of variation in these traits across Korea and provide clues about the underlying forces for variation.We recorded calls of H. japonica in three breeding seasons from 17 localities including localities in remote Jeju Island. Call characters analyzed were note repetition rate (NRR), note duration (ND), and dominant frequency (DF), along with snout-to-vent length.The findings of a barrier effect on DF and a longitudinal variation in NRR seemed to suggest that an open sea between the mainland and Jeju Island and mountain ranges dominated by the north-south Taebaek Mountains were related to geographic variation in call characters. Furthermore, there was a pattern of IBD in mitochondrial DNA sequences. However, no comparable pattern of IBD was found between geographic distance and call characters. We also failed to detect any effects of habitat or interspecific interaction on call characters.Geographic variations in call characters as well as mitochondrial DNA sequences were largely stratified by geographic factors such as distance and barriers in Korean populations of H. japonica. Although we did not detect effects of habitat or interspecific interaction, some other selective factors such as sexual selection might still be operating on call characters in conjunction with restricted gene flow

Effects of dipole orientation and birefringence on the optical emission from thin films

Polymers are frequently used as the emissive material in optical devices such as the light emitting diode. The long chain molecular structure of typical polymer materials together with the spin coating technique by which thin layers are fabricated results in significant optical birefringence. We outline a classical model for spontaneous emission from within such birefringent materials in planar multi-layer structures. We compare the results obtained using this model with experimental data on the radiation pattern produced by a thin film of the conjugated polymer poly[2-methoxy, 5-(2'-ethyl-hexyloxy) 1,4 phenylenevinylene] (MEH-PPV). As a control we also measured the radiation pattern from the dye Lumogen, dispersed as a guest in an optically isotropic thin film of polycarbonate. We find that birefringence and the orientation of the dipole moment of the polymer have to be taken into account to understand the departure from the expected Lambertian radiation pattern that we observe from MEH-PPV. (C) 2000 Elsevier Science B.V. All rights reserved.</p