Excitatory neurotransmission mediated by the N‐methyl‐D‐aspartate subtype of ionotropic glutamate receptors is fundamental to the development and function of the mammalian central nervous system. ...NMDA receptors require both glycine and glutamate for activation with NR1 and NR2 forming glycine and glutamate sites, respectively. Mechanisms to describe agonist and antagonist binding, and activation and desensitization of NMDA receptors have been hampered by the lack of high‐resolution structures. Here, we describe the cocrystal structures of the NR1 S1S2 ligand‐binding core with the agonists glycine and D‐serine (DS), the partial agonist D‐cycloserine (DCS) and the antagonist 5,7‐dichlorokynurenic acid (DCKA). The cleft of the S1S2 ‘clamshell’ is open in the presence of the antagonist DCKA and closed in the glycine, DS and DCS complexes. In addition, the NR1 S1S2 structure reveals the fold and interactions of loop 1, a cysteine‐rich region implicated in intersubunit allostery.
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•To investigate if NIR spectroscopy can assess water and chloride ion content in cement paste.•Absorption peak intensities of the OH group increased as moisture content ...rose.•Absorption peak intensities of Friedel’s salt increased with higher chloride content.•Quantitative analysis with NIR spectroscopy possible for ordinary Portland cement.
Chloride induced deterioration of concrete structures is well underway when the damage is visually detected during inspection. If such damage was identified using a non-destructive method, inspection costs would reduce significantly. We tested the use of near-infrared (NIR) spectroscopy for non-destructive multicomponent analysis of cement pastes. Cement paste samples with varying chloride-ion concentrations and humidity were prepared for different cement types. Reflectance spectra were obtained, then total moisture content (v/v) and chloride ion concentrations were measured using destructive testing as a reference. A correlation was observed between the measured water amount/chloride ion concentration and respective NIR absorption values.
Few nomograms can predict overall survival (OS) after curative resection of advanced gastric cancer (AGC), and these nomograms were developed using data from only a few large centers over a long time ...period. The aim of this study was to develop and externally validate an elaborative nomogram that predicts 5-year OS after curative resection for serosa-negative, locally AGC using a large amount of data from multiple centers in Japan over a short time period (2001–2003).
Of 39 859 patients who underwent surgery for gastric cancer between 2001 and 2003 at multiple centers in Japan, we retrospectively analyzed 5196 patients with serosa-negative AGC who underwent Resection A according to the 13th Japanese Classification of Gastric Carcinoma. The data of 3085 patients who underwent surgery from 2001 to 2002 were used as a training set for the construction of a nomogram and Web software. The data of 2111 patients who underwent surgery in 2003 were used as an external validation set.
Age at operation, gender, tumor size and location, macroscopic type, histological type, depth of invasion, number of positive and examined lymph nodes, and lymphovascular invasion, but not the extent of lymphadenectomy, were associated with OS. Discrimination of the developed nomogram was superior to that of the TNM classification (concordance indices of 0.68 versus 0.61; P < 0.001). Moreover, calibration was accurate.
We have developed and externally validated an elaborative nomogram that predicts the 5-year OS of postoperative serosa-negative AGC. This nomogram would be helpful in the assessment of individual risks and in the consideration of additional therapy in clinical practice, and we have created freely available Web software to more easily and quickly predict OS and to draw a survival curve for these purposes.
MYC activation at modest levels has been frequently found in hepatocellular carcinoma. However, its significance in hepatocarcinogenesis has remained obscure. Here we examined the role of Myc ...activation in mouse liver tumours induced by hepatocytic expression of myristoylated AKT (AKT) and/or mutant HRAS
(HRAS) via transposon-mediated gene integration. AKT or HRAS alone required 5 months to induce liver tumours, whereas their combination generated hepatocellular carcinoma within 8 weeks. Co-introduction of AKT and HRAS induced lipid-laden preneoplastic cells that grew into nodules composed of tumour cells with or without intracytoplasmic lipid, with the latter being more proliferative and associated with spontaneous Myc expression. AKT/HRAS-induced tumorigenesis was almost completely abolished when MadMyc, a competitive Myc inhibitor, was expressed simultaneously. The Tet-On induction of MadMyc in preneoplastic cells significantly inhibited the progression of AKT/HRAS-induced tumours; its induction in transformed cells suppressed their proliferative activity with alterations in lipid metabolism and protein translation. Transposon-mediated Myc overexpression facilitated tumorigenesis by AKT or HRAS, and when it was co-introduced with AKT and HRAS, diffusely infiltrating tumours without lipid accumulation developed as early as 2 weeks. Examination of the dose-responses of Myc in the enhancement of AKT/HRAS-induced tumorigenesis revealed that a reduction to one-third retained enhancing effect but three-times greater introduction damped the process with increased apoptosis. Myc overexpression suppressed the mRNA expression of proteins involved in the synthesis of fatty acids, and when combined with HRAS introduction, it also suppressed the mRNA expression of proteins involved in their degradation. Finally, the MYC-positive human hepatocellular carcinoma was characterized by the cytoplasm devoid of lipid accumulation, prominent nucleoli and a higher proliferative activity. Our results demonstrate that in hepatocarcinogenesis induced by both activated AKT and HRAS, activation of endogenous Myc is an enhancing factor and adequate levels of Myc deregulation further facilitate the process with alterations in cellular metabolism.
Excitatory neurotransmission mediated by NMDA (N-methyl-D-aspartate) receptors is fundamental to the physiology of the mammalian central nervous system. These receptors are heteromeric ion channels ...that for activation require binding of glycine and glutamate to the NR1 and NR2 subunits, respectively. NMDA receptor function is characterized by slow channel opening and deactivation, and the resulting influx of cations initiates signal transduction cascades that are crucial to higher functions including learning and memory. Here we report crystal structures of the ligand-binding core of NR2A with glutamate and that of the NR1-NR2A heterodimer with glutamate and glycine. The NR2A-glutamate complex defines the determinants of glutamate and NMDA recognition, and the NR1-NR2A heterodimer suggests a mechanism for ligand-induced ion channel opening. Analysis of the heterodimer interface, together with biochemical and electrophysiological experiments, confirms that the NR1-NR2A heterodimer is the functional unit in tetrameric NMDA receptors and that tyrosine 535 of NR1, located in the subunit interface, modulates the rate of ion channel deactivation.
Cholangiocarcinoma (CC) is a highly malignant carcinoma. We attempted to clarify the prognostic significance of c-Met overexpression and its association with clinicopathological factors in patients ...with CC.
One hundred and eleven patients with intrahepatic CC (IHCC) and 136 patients with extrahepatic CC (EHCC) who had undergone curative surgery were divided immunohistologically into c-Met(high) and c-Met(low) groups. Clinicopathological factors and outcomes were compared between the groups. c-Met and epidermal growth factor receptor (EGFR) expression was also examined in 10 CC cell lines.
The positivity of c-Met was 45.0% in IHCC and 68.4% in EHCC; c-Met(high) expression was demonstrated in 11.7% of IHCC and 16.2% of EHCC. c-Met(high) expression was significantly correlated with the 5-year survival rate for CC overall (P=0.0046) and for IHCC (P=0.0013), histopathological classification in EHCC, and for EGFR overexpression in both IHCC and EHCC. Coexpression and coactivation of c-Met and EGFR were also observed in CC cell lines. Multivariate analysis revealed that c-Met(high) expression was an independent predictor of poor overall and disease-free survival in patients with IHCC.
c-Met overexpression is associated with EGFR expression and is a poor prognostic factor in CC.
S-1, an oral fluoropyrimidine, plus cisplatin (SP) is a standard regimen for advanced gastric cancer (AGC) in East Asia. To date, no studies have evaluated the efficacy and safety of trastuzumab ...combined with SP in patients with human epidermal growth factor receptor type 2 (HER2)-positive AGC.
Patients with HER2-positive AGC received S-1 (80-120 mg per day) orally on days 1-14, cisplatin (60 mg m(-2)) intravenously on day 1, and trastuzumab (course 1, 8 mg kg(-1); course 2 onward, 6 mg kg(-1)) intravenously on day 1 of a 21-day cycle. The primary end point was response rate (RR); secondary end points included overall survival (OS), progression-free survival (PFS), time to treatment failure (TTF), and adverse events.
A total of 56 patients were enrolled. In the full analysis set of 53 patients, the confirmed RR was 68% (95% confidence interval (CI)=54-80%), and the disease control rate was 94% (95% CI=84-99%). Median OS, PFS, and TTF were estimated as 16.0, 7.8, and 5.7 months, respectively. Major grade 3 or 4 adverse events included neutropaenia (36%), anorexia (23%), and anaemia (15%).
Trastuzumab in combination with SP showed promising antitumour activity and manageable toxic effects in patients with HER2-positive AGC.
BACKGROUND AND AIMS: Global warming is gaining significance as a threat to natural and managed ecosystems since temperature is one of the major environmental factors affecting plant productivity. ...Hence, the effects of moderate temperature increase on the growth and development of the tomato plant (Lycopersicon esculentum) were investigated. METHODS: Plants were grown at 32/26 °C as a moderately elevated temperature stress (METS) treatment or at 28/22 °C (day/night temperatures) as a control with natural light conditions. Vegetative growth and reproductive development as well as sugar content and metabolism, proline content and translocation in the androecium were investigated. KEY RESULTS: METS did not cause a significant change in biomass, the number of flowers, or the number of pollen grains produced, but there was a significant decrease in the number of fruit set, pollen viability and the number of pollen grains released. Glucose and fructose contents in the androecium (i.e. all stamens from one flower) were generally higher in the control than METS, but sucrose was higher in METS. Coincidently, the mRNA transcript abundance of acid invertase in the androecium was decreased by METS. Proline contents in the androecium were almost the same in the control and METS, while the mRNA transcript level of proline transporter 1, which expresses specifically at the surface of microspores, was significantly decreased by METS. CONCLUSIONS: The research indicated that failure of tomato fruit set under a moderately increased temperature above optimal is due to the disruption of sugar metabolism and proline translocation during the narrow window of male reproductive development.
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•Quantitative analysis by direct extraction of NIR absorption peak intensity.•Selectivity problem due to overlaps of hydroxide peaks in characteristic absorption.•NIR spectrum of ...synthesized Kuzel’s salt, similar to Friedel’s salt and monosulphate.•Quantitative analysis based on Bayesian statistics for automatic peak identification.•Correlation between extracted NIR peaks of Friedel’s salt and XRD/XRF measurements.
This is a fundamental study of a non-destructive and contactless equipment to evaluate the chloride ion on concrete, with near infrared spectroscopy. Non-destructive measurements on Friedel’s salt, generated by ingress of chloride ion into concrete, have been studied; characteristic absorption unique to each substance was utilized to qualitative and quantitative analyses. However, there has been a difficulty in separating absorption peak of Friedel’ salt from that of other hydrates. This study investigates the method to extract the absorption peak of Friedel’s salt by Bayes’ theorem for quantitative evaluation, and its validity was confirmed using some conventional methods.
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