Co-crystalization and in vitro biological characterization of 5-Aryl-4-(5-substituted-2-4-dihydroxyphenyl)-1,2,3-thiadiazole Hsp90 inhibitors

A potential therapeutic strategy for targeting cancer that has gained much interest is the inhibition of the ATP binding and ATPase activity of the molecular chaperone Hsp90. We have determined the structure of the human Hsp90α N-terminal domain in complex with a series of 5-aryl-4-(5-substituted-2-4-dihydroxyphenyl)-1,2,3-thiadiazoles. The structures provide the molecular details for the activity of these inhibitors. One of these inhibitors, ICPD 34, causes a structural change that affects a mobile loop, which adopts a conformation similar to that seen in complexes with ADP, rather than the conformation generally seen with the pyrazole/isoxazole-resorcinol class of inhibitors. Competitive binding to the Hsp90 N-terminal domain was observed in a biochemical assay, and these compounds showed antiproliferative activity and induced apoptosis in the HCT116 human colon cancer cell line. These inhibitors also caused induction of the heat shock response with the upregulation of Hsp72 and Hsp27 protein expression and the depletion of Hsp90 clients, CRAF, ERBB2 and CDK4, thus confirming that antiproliferative activity was through the inhibition of Hsp90. The presence of increased levels of the cleavage product of PARP indicated apoptosis in response to Hsp90 inhibitors. This work provides a framework for the further optimization of thiadiazole inhibitors of Hsp90. Importantly, we demonstrate that the thiadiazole inhibitors display a more limited core set of interactions relative to the clinical trial candidate NVP-AUY922, and consequently may be less susceptible to resistance derived through mutations in Hsp9

Optical Bandgap Formation in AlInGaN Alloys

We report on the spectral dynamics of the reflectivity, site-selectively excited photoluminescence,photoluminescence excitation, and time-resolved luminescence in quaternary AlInGaN epitaxial layers grown on GaN templates. The incorporation of a few percents of In into AlGaN causes significant smoothening of the band-bottom potential profile in AlInGaN layers owing to improved crystal quality. An abrupt optical bandgap indicates that a nearly lattice-matched AlInGaN/GaN heterostructure with large energy band offsets can be grown for high-efficiency light-emitting devices

Optical bandgap formation in AlInGaN alloys

We report on the spectral dynamics of the reflectivity, site-selectively excited photoluminescence,photoluminescence excitation, and time-resolved luminescence in quaternary AlInGaN epitaxial layers grown on GaN templates. The incorporation of a few percents of In into AlGaN causes significant smoothening of the band-bottom potential profile in AlInGaN layers owing to improved crystal quality. An abrupt optical bandgap indicates that a nearly lattice-matched AlInGaN/GaN heterostructure with large energy band offsets can be grown for high-efficiency light-emitting devices

Trauma exposure and factors associated with ICD-11 PTSD and complex PTSD in adolescence: a cross-cultural study in Japan and Lithuania

Aims: Cross-cultural studies of posttraumatic stress disorder (PTSD) and complex PTSD (CPTSD) based on ICD-11 diagnostic criteria are scarce, especially in adolescence. The study aimed to evaluate the trauma exposure, prevalence and factors associated with PTSD and CPTSD in general populations of adolescents in Lithuania and Japan. Methods: The study sample comprised 1746 adolescents from Lithuania (n = 832) and Japan (n = 914), 49.8% female. The mean age of study participants was 15.52 (S.D. = 1.64), ranging from 12 to 18 years. ICD-11 posttraumatic disorders were assessed using the International Trauma Questionnaire – Child and Adolescent version (ITQ-CA). Results: More than half of the adolescents in a total sample (61.5%) reported exposure to at least one traumatic event in their lifetime, 80.0% in Lithuania and 44.6% in Japan, with a higher prevalence of interpersonal trauma in Lithuania and more natural disaster exposure in Japan. The prevalence of PTSD was 5.2% (95% CI 3.8–6.9%) and 2.3% (95% CI 1.4–3.5%), CPTSD 12.3% (95% CI 10.1–14.7%) and 4.1% (95% CI 2.9–5.5%) in Lithuanian and Japanese samples, respectively. Cumulative trauma exposure, female gender, loneliness and financial difficulties in family predicted both PTSD and CPTSD in the total sample. Loneliness discriminated CPTSD v. PTSD in both Lithuanian and Japanese samples. Conclusions: This cross-cultural study is among the first which reported different patterns of trauma exposure in Asian Japanese and Lithuanian adolescents in Europe. Despite differences in trauma exposure and PTSD/CPTSD prevalence, we found similar predictors in both studies, particularly the importance of cumulative trauma exposure for PTSD/CPTSD, and social interpersonal factors for the risk of CPTSD. The study supports the universality of traumatic stress reactions to adverse life experiences in adolescence across cultures and regions and highlights different levels of traumatisation of adolescents in various countries

PI3Kδ as a Novel Therapeutic Target in Pathological Angiogenesis

Diabetic retinopathy is the most common microvascular complication of diabetes, characterized by the formation of fibrovascular membranes that consist of a variety of cells including vascular endothelial cells (ECs). New therapeutic approaches for this diabetic complication are urgently needed. Here, we report that in cultured human retinal microvascular (HRECs) high glucose induced expression of p110, which was also expressed in ECs of fibrovascular membranes from diabetic patients. This catalytic subunit of a receptor regulated PI3K isoform is known to be highly-enriched in leukocytes. Using genetic and pharmacological approaches, we show that p110 activity in cultured ECs controls Akt activation, cell proliferation, migration, and tube formation induced by vascular endothelial growth factor, basic fibroblast growth factor, and epidermal growth factor. Using a mouse model of oxygen-induced retinopathy, p110 inactivation was found to attenuate pathological retinal angiogenesis. p110 inhibitors have been approved for use in human B-cell malignancies. Our data suggest that antagonizing p110 constitutes a previously-unappreciated therapeutic opportunity for diabetic retinopathy

Double-Scaled Potential Profile in a Group-III Nitride Alloy Revealed by Monte Carlo Simulation of Exciton Hopping

The temperature dependences of the peak position and width of the photoluminescence band in Al0.1In0.01Ga0.89N layers were explained by Monte Carlo simulation of exciton localization and hopping. The introduction of a doubled-scaled potential profile due to inhomogeneous distribution of indium allowed obtaining a good quantitative fit of the experimental data. Hopping of excitons was assumed to occur through localized states distributed on a 16 meV energy scale within the In-rich clusters with the average energy in these clusters dispersed on a larger (42 meV) scale

Enhancement of lipase activity in non-aqueous media upon immobilization on multi-walled carbon nanotubes

<p>Abstract</p> <p>Background</p> <p>Immobilization of biologically active proteins on nanosized surfaces is a key process in bionanofabrication. Carbon nanotubes with their high surface areas, as well as useful electronic, thermal and mechanical properties, constitute important building blocks in the fabrication of novel functional materials.</p> <p>Results</p> <p>Lipases from <it>Candida rugosa </it>(CRL) were found to be adsorbed on the multiwalled carbon nanotubes with very high retention of their biological activity (97%). The immobilized biocatalyst showed 2.2- and 14-fold increases in the initial rates of transesterification activity in nearly anhydrous hexane and water immiscible ionic liquid [Bmim] [PF6] respectively, as compared to the lyophilized powdered enzyme. It is presumed that the interaction with the hydrophobic surface of the nanotubes resulted in conformational changes leading to the 'open lid' structure of CRL. The immobilized enzyme was found to give 64% conversion over 24 h (as opposed to 14% with free enzyme) in the formation of butylbutyrate in nearly anhydrous hexane. Similarly, with ionic liquid [Bmim] [PF6], the immobilized enzyme allowed 71% conversion as compared to 16% with the free enzyme. The immobilized lipase also showed high enantioselectivity as determined by kinetic resolution of (±) 1-phenylethanol in [Bmim] [PF6]. While free CRL gave only 5% conversion after 36 h, the immobilized enzyme resulted in 37% conversion with > 99% enantiomeric excess. TEM studies on the immobilized biocatalyst showed that the enzyme is attached to the multiwalled nanotubes.</p> <p>Conclusion</p> <p>Successful immobilization of enzymes on nanosized carriers could pave the way for reduced reactor volumes required for biotransformations, as well as having a use in the construction of miniaturized biosensensor devices.</p

Double-scaled potential profile in a group-III nitride alloy revealed by Monte Carlo simulation of exciton hopping

The temperature dependences of the peak position and width of the photoluminescence band in Al0.1In0.01Ga0.89N layers were explained by Monte Carlo simulation of exciton localization and hopping. The introduction of a doubled-scaled potential profile due to inhomogeneous distribution of indium allowed obtaining a good quantitative fit of the experimental data. Hopping of excitons was assumed to occur through localized states distributed on a 16 meV energy scale within the In-rich clusters with the average energy in these clusters dispersed on a larger (42 meV) scale

Broadband impedance spectroscopy of some Li+ and Vo** conducting solid electrolytes

The solid electrolyte Li3Ti1.5(PO4)3 compound has been synthesized by solid state reaction and studied by X-ray diffraction. At room temperature the compound belongs to rhombohedral symmetry (space group R3 ̅c) with six formula units in the unit cell. Li3Ti1.5(PO4)3, Li3xLa2/3–xTiO3 (where x = 0.12) Li+-ion conducting, Ce0.8Gd0.2O1.9, (ZrO2)92(Y2O3)8 with fast oxygen vacancy transport ceramic samples were investigated in the frequency range from 1 Hz to 3 GHz in the temperature interval (300-700) K by impedance spectroscopy methods. Two dispersion regions in ionic conductivity spectra for investigated ceramic samples have been found. The dispersions have been attributed to relaxation processes in grain boundaries and in grains of the ceramics

Cambogin Is Preferentially Cytotoxic to Cells Expressing PDGFR

Platelet-derived growth factor receptors (PDGFRs) have been implicated in a wide array of human malignancies, including medulloblastoma (MB), the most common brain tumor of childhood. Although significant progress in MB biology and therapeutics has been achieved during the past decades, MB remains a horrible challenge to the physicians and researchers. Therefore, novel inhibitors targeting PDGFR signaling pathway may offer great promise for the treatment of MB. In the present study, we investigated the cytotoxicity and mechanisms of cambogin in Daoy MB cells. Our results show that cambogin triggers significant S phase cell cycle arrest and apoptosis via down regulation of cyclin A and E, and activation of caspases. More importantly, further mechanistic studies demonstrated that cambogin inhibits PDGFR signaling in Daoy and genetically defined mouse embryo fibroblast (MEF) cell lines. These results suggest that cambogin is preferentially cytotoxic to cells expressing PDGFR. Our findings may provide a novel approach by targeting PDGFR signaling against MB