DNA mismatch binding and antiproliferative activity of rhodium metalloinsertors

Deficiencies in mismatch repair (MMR) are associated with carcinogenesis. Rhodium metalloinsertors bind to DNA base mismatches with high specificity and inhibit cellular proliferation preferentially in MMR-deficient cells versus MMR-proficient cells. A family of chrysenequinone diimine complexes of rhodium with varying ancillary ligands that serve as DNA metalloinsertors has been synthesized, and both DNA mismatch binding affinities and antiproliferative activities against the human colorectal carcinoma cell lines HCT116N and HCT116O, an isogenic model system for MMR deficiency, have been determined. DNA photocleavage experiments reveal that all complexes bind to the mismatch sites with high specificities; DNA binding affinities to oligonucleotides containing single base CA and CC mismatches, obtained through photocleavage titration or competition, vary from 10^4 to 10^8 M^−1 for the series of complexes. Significantly, binding affinities are found to be inversely related to ancillary ligand size and directly related to differential inhibition of the HCT116 cell lines. The observed trend in binding affinity is consistent with the metalloinsertion mode where the complex binds from the minor groove with ejection of mismatched base pairs. The correlation between binding affinity and targeting of the MMR-deficient cell line suggests that rhodium metalloinsertors exert their selective biological effects on MMR-deficient cells through mismatch binding in vivo

Exploring the cellular accumulation of metal complexes

Transition metal complexes offer great potential as diagnostic and therapeutic agents, and a growing number of biological applications have been explored. To be effective, these complexes must reach their intended target inside the cell. Here we review the cellular accumulation of metal complexes, including their uptake, localization, and efflux. Metal complexes are taken up inside cells through various mechanisms, including passive diffusion and entry through organic and metal transporters. Emphasis is placed on the methods used to examine cellular accumulation, to identify the mechanism(s) of uptake, and to monitor possible efflux. Conjugation strategies that have been employed to improve the cellular uptake characteristics of metal complexes are also described

Selective Cytotoxicity of Rhodium Metalloinsertors in Mismatch Repair-Deficient Cells

Mismatches in DNA occur naturally during replication and as a result of endogenous DNA damaging agents, but the mismatch repair (MMR) pathway acts to correct mismatches before subsequent rounds of replication. Rhodium metalloinsertors bind to DNA mismatches with high affinity and specificity and represent a promising strategy to target mismatches in cells. Here we examine the biological fate of rhodium metalloinsertors bearing dipyridylamine ancillary ligands in cells deficient in MMR versus those that are MMR-proficient. These complexes are shown to exhibit accelerated cellular uptake which permits the observation of various cellular responses, including disruption of the cell cycle, monitored by flow cytometry assays, and induction of necrosis, monitored by dye exclusion and caspase inhibition assays, that occur preferentially in the MMR-deficient cell line. These cellular responses provide insight into the mechanisms underlying the selective activity of this novel class of targeted anticancer agents

Improvement in HSS grade for early stands of hot strip mills - Metallurgical features and mechanical properties assessment

peer reviewedAurora and Kosmos grades are HSS alloys belonging to the complex Fe-Cr-C-X system, where X is a strong carbide former element of the V, Mo or W type. Both alloys were metallurgically characterised prior to their comparison. Metallurgical analyses involved phases identification and carbides quantification by using Scanning Electron Microscopy and Energy Dispersive X rays. Differential Thermal Analysis was performed to allow a better understanding of the solidification sequence of studied alloys while mechanical tests performed were compressive at room temperature and bulk hardness at usual service temperatures. An attempt was made in order to connect experimental results to the good behaviour in operation of Aurora grade. In fact Aurora grade appeared to exhibit strong metallurgical differences when compared to Kosmos grade, especially as concern in nature and amount of carbides

Ideias e criatividade em estampa e formato para calçado

Este artigo mostra de que forma a interdisciplinaridade potencializa a criatividade aplicada em estampas/ texturas e formatos de calçados. Assim, apresentam-se os três métodos de desenvolvimento de ideias utilizados, denominados de Design Caleidoscópico, Wong Wucius e Generaidea. O objetivo é apresentar modelos didáticos para ensinar, promover e desbloquear a criatividade no design e produzir ideias rápidas e em um curto espaço de tempo. Este estudo foi aplicado com acadêmicos e profissionais da área projetual. Os resultados contribuem para a formação de profissionais criativos e inovadores, importantes para o crescimento e diferenciação do mercado

Hippocampus abnormalities in at risk mental states for psychosis? A cross-sectional high resolution region of interest magnetic resonance imaging study

Background: Hippocampal volume (HV) reduction is well documented in schizophrenia. However, it is still unclear whether this change is a pre-existing vulnerability factor, a sign of disease progression, a consequence of environmental factors, such as drug use, antipsychotic medication, or malnutrition. The timing of HV changes is not well established, but a lack of macrostructural hippocampal brain abnormalities before disease onset would rather support a neuroprogressive illness model. Aim: To investigate the timing of HV changes in emerging psychosis. Methods: A cross-sectional MRI study of manually traced HVs in 37 individuals with an At Risk Mental State (ARMS) for psychosis, 23 individuals with First-Episode Psychosis (FEP), and 22 Healthy Controls (HC) was performed. We compared left and right HVs corrected for whole brain volume across groups using analysis of covariance (ANCOVA) with gender as a covariate. Sixteen of 37 ARMS individuals developed a psychotic disorder during follow up (ARMS-T). The mean duration of follow up in ARMS was 25.1 months. Results: The overall ANCOVA model comparing left HVs across FEP, ARMS and HC indicated a significant general group effect (p < .05) with largest volumes in ARMS and smallest in FEP. ARMS-T subjects had significantly larger left HVs compared to FE but no HV differences compared to HC (p < 0.05). Over all groups, we found an asymmetry between the left and right mean HVs and a strong effect of sex. Discussion: The present study suggests that macrostructural hippocampal abnormalities probably occur in the context of the first psychotic breakdown

Structural, optical and electrical properties of a Schottky diode fabricated on Ce doped ZnO nanorods grown using a two step chemical bath deposition

Please read abstract in the article.The South African Research Foundation (NRF) grant no: 91550 and 111744.http://www.elsevier.com/locate/mssp2019-11-15hj2018Physic

Structural, optical and electrical properties of the fabricated Schottky diodes based on ZnO, Ce and Sm doped ZnO films prepared via wet chemical technique

In this study, we fabricated Schottky diode devices on ZnO, Sm and Ce doped and co-doped ZnO thin films grown by the sol–gel spin coating. The structural and optical properties of the sol–gel films are studied, and the electrical characteristics of the Schottky diodes are investigated. The crystalline structure and surface morphology were studied using x-ray diffraction and scanning electron microscopy, respectively. Photoluminescence spectroscopy of all films measured at room temperature showed that the UV emission peak was composed of two peaks located at 388 and 405 nm and no visible light emission was detected. UV–vis study revealed that the optical band gap of ZnO decreased after doping. Room temperature I–V characterization revealed a rectification behaviour of all samples. The Schottky diodes fabricated on (Sm and Ce) co-doped ZnO manifest device properties with good rectification (six orders of magnitude), low ideality factor (1.62) and barrier height of 0.82 eV.The South African National Research Foundation (NRF) grant no: 91550 and 111744.http://www.elsevier.com/locate/matresbuhj2019Physic

MenaQ7 (R) and maintenance of the elastic properties of the arteries: evaluation of a health claim pursuant to Article 13(5) of Regulation (EC) No 1924/2006

Peer reviewedPublisher PD