Conformational control of anticancer activity: the application of arene-linked dinuclear ruthenium(II) organometallics

Dinuclear metal complexes have emerged as a promising class of biologically active compounds which possess unique anticancer activity. Here, we describe a novel series of arene-linked dinuclear organometallic Ru(II) complexes, where the relative conformation of the ruthenium centres is controlled by the stereochemical configuration of 1,2-diphenylethylenediamine linker moieties, as confirmed by X-ray crystallography. The reactivity and cytotoxicity of these compounds is compared to flexible dinuclear and mononuclear analogues, demonstrating in all cases the complexes can undergo aquation, coordinate to typical biological donor ligands and importantly, in the case of dinuclear analogues, crosslink oligonucleotide and peptide sequences. Differences in the conformation of the isomeric dinuclear compounds lead to significantly different levels of cytotoxicity against A2780, A2780cisR and HEK-293 cell lines; isomers with a closed conformation are significantly more cytotoxic than isomers with a more open conformation and they are also significantly less susceptible to acquired resistance mechanisms operating in the A2780cisR cell line. These rigid dinuclear compounds possess markedly increased cytotoxicity relative to the non-cytotoxic mononuclear analogues that does not appear to be related to differences in complex lipophilicity or cellular uptake, which, in general, remain similar in magnitude across the series. Thus, the molecular conformation of such dinuclear species may be crucial in determining the nature of the adducts formed on coordination to biological targets in a cellular environment, and opens up a novel route toward the development of more active metal-based anticancer agents

Notes on the diet of seven terrestrial frogs in three agroecosystems and forest remnants in Northwestern São Paulo State, Brazil.

Anurans are predators of a great diversity of invertebrates, but studies on agroecosystems are very scarce. Herein we described the diet composition of seven species of terrestrial anurans captured in three different agroecosystems (corn, soybean and rubber tree) and in forest remnants of the Northwestern region of São Paulo state, Brazil. Ten prey categories were identified in the stomachs of 80 specimens belonging to the families Bufonidae, Leptodactylidae and Microhylidae. Hymenoptera (Formicidae) was consumed by all species. Coleoptera was the most frequent item, consumed by six of the even species followed by Araneae and Isoptera. Isoptera was the most abundant item followed by Formicidae, Coleoptera and Araneae. Adults and juveniles of Physalaemus nattereri, the most abundant species in our study, consumed Formicidae and Isoptera more than other food items and there is not a significant difference in the abundance of consumed prey items between the age categories. In summary, the majority of the studied species can be considered generalists predators and, probably, consumed the prey items available in the environment. The most abundant species found in our study can be considered here as having a specialized diet, by consuming social insects in great frequency.Published online on 12 August 2015

Differences in telomere length between sporadic and familial cutaneous melanoma

BACKGROUND: Several pieces of evidence indicate that a complex relationship exists between constitutional telomere length (TL) and the risk of cutaneous melanoma. Although the general perception is that longer telomeres increase melanoma risk, some studies do not support this association. We hypothesise that discordant data are due to the characteristics of the studied populations. OBJECTIVES: To evaluate the association of telomere length with familial and sporadic melanoma. METHODS: TL was measured by multiplex quantitative PCR in leukocytes from 310 melanoma patients according to familial/sporadic and single/multiple cancers and 216 age-matched controls. RESULTS: Patients with sporadic melanoma were found to have shorter telomeres as compared to those with familial melanoma. In addition, shorter telomeres, while tending to reduce the risk of familial melanoma regardless of single or multiple tumors, nearly trebled the risk of single sporadic melanoma. CONCLUSIONS: This is the first time that TL has been correlated to opposite effects on melanoma risk according to the presence or absence of familial predisposition. Individual susceptibility to melanoma should be taken into account when assessing the role of TL as a risk factor. This article is protected by copyright. All rights reserved

Towards a New Cathedral: Mechanolatry and Metaphysics in the milieu of Colin St John Wilson

Architectural debates of the 1950s – particularly between ‘empirical’ and ‘formal’ strands of Modernism – are highlighted by a study of the architectural projects, biography and milieu of Colin St John Wilson

Drosophila melanogaster cloak their eggs with pheromones, which prevents cannibalism

This is the final version. Available from Public Library of Science via the DOI in this recordData Availability: All relevant data are within the paper and its Supporting Information files: S1 Data and S2 Data.Oviparous animals across many taxa have evolved diverse strategies that deter egg predation, providing valuable tests of how natural selection mitigates direct fitness loss. Communal egg laying in nonsocial species minimizes egg predation. However, in cannibalistic species, this very behavior facilitates egg predation by conspecifics (cannibalism). Similarly, toxins and aposematic signaling that deter egg predators are often inefficient against resistant conspecifics. Egg cannibalism can be adaptive, wherein cannibals may benefit through reduced competition and added nutrition, but since it reduces Darwinian fitness, the evolution of anticannibalistic strategies is rife. However, such strategies are likely to be nontoxic because deploying toxins against related individuals would reduce inclusive fitness. Here, we report how D. melanogaster use specific hydrocarbons to chemically mask their eggs from cannibal larvae. Using an integrative approach combining behavioral, sensory, and mass spectrometry methods, we demonstrate that maternally provisioned pheromone 7,11-heptacosadiene (7,11-HD) in the eggshell’s wax layer deters egg cannibalism. Furthermore, we show that 7,11-HD is nontoxic, can mask underlying substrates (for example, yeast) when coated upon them, and its detection requires pickpocket 23 (ppk23) gene function. Finally, using light and electron microscopy, we demonstrate how maternal pheromones leak-proof the egg, consequently concealing it from conspecific larvae. Our data suggest that semiochemicals possibly subserve in deceptive functions across taxa, especially when predators rely on chemical cues to forage, and stimulate further research on deceptive strategies mediated through nonvisual sensory modules. This study thus highlights how integrative approaches can illuminate our understanding on the adaptive significance of deceptive defenses and the mechanisms through which they operate.Swiss National Science FoundationEuropean Research CouncilDeutsche ForschungsgemeinschaftBaden Württemberg Stiftung and Zukunftskolleg of the University of Konstan

Accessible technologies for kinetic and kinematic analysis of people with disabilities: a literature review/ Tecnologias acessíveis para análise cinética e cinemática da pessoa com deficiência: uma revisão da literatura

Locomotion is the process by which a being moves from one place to another, including stopping, changing speed, changes in direction and adaptation to changes in terrain. Human walking follows a pattern, and it is one of the forms of locomotion that most calls the attention of researchers. Its variation among a group may indicate pathological conditions that influence the treatment and rehabilitation of patients with low mobility. The objective of this article is to carry out a review for the development of a low-cost instrumented treadmill that can assist in the rehabilitation, treatment and follow-up of patients with stroke, and for that, a search of articles related to the topic was carried out in databases such as ScienceDirect, PubMed and others. The results obtained were satisfactory and enabled the creation of a good database. It was possible to conclude that there is a diversity of existing resources and that it is up to the professionals to direct their choice to the one that suits them best

Monitoring of Land Subsidence in Ravenna Municipality Using Integrated SAR - GPS Techniques: Description and First Results

The Emilia Romagna Region (N-E Italy) and in particular the Adriatic Sea coastline of Ravenna, is affected by a noticeable subsidence that started in the 1950s, when the exploitation of on and off-shore methane reservoirs began, along with the pumping of groundwater for industrial uses. In such area the current subsidence rate, even if lower than in the past, reaches the -2 cm/y. Over the years, local Authorities have monitored this phenomenon with different techniques: spirit levelling, GPS surveys and, more recently, Differential Interferometric Synthetic Aperture Radar (DInSAR) techniques, confirming the critical situation of land subsidence risk. In this work, we present the comparison between the results obtained with DInSAR and GPS techniques applied to the study of the land subsidence in the Ravenna territory. With regard to the DInSAR, the Small Baseline Subset (SBAS) and the Coherent Pixel Technique (CPT) techniques have been used. Different SAR datasets have been exploited: ERS-1/2, ENVISAT, TerraSAR-X and Sentinel-1. Some GPS campaigns have been also carried out in a subsidence prone area. 3D vertices have been selected very close to existing persistent scatterers in order to link the GPS measurement results to the SAR ones. GPS data were processed into the International reference system and the comparisons between the coordinates, for the first 6 months of the monitoring, provided results with the same trend of the DInSAR data, even if inside the precision of the method

Versatile Tool for the Analysis of Metal-Protein Interactions Reveals the Promiscuity of Metallodrug-Protein Interactions

Metallodrug protein interactions contribute to their therapeutic effect (even when DNA is the dominant target), side-effects and are implicit in drug resistance. Here, we provide mass spectrometric-based evidence to show that metallodrug interactions with proteins are considerably more complex than current literature would suggest. Using native-like incubation and electrospray conditions together with an automated tool we designed for exhaustive mass spectra matching, the promiscuity of binding of cisplatin to ubiquitin is revealed, with 14 different binding sites observed. There is a binding preference to negatively charged sites on the protein, consistent with the cationic nature of the cisplatin adduct following aquation. These results have implications in metallodrug development and beyond to the toxicological effects of metal ions more generally

Altered tumor formation and evolutionary selection of genetic variants in the human MDM4 oncogene

A large body of evidence strongly suggests that the p53 tumor suppressor pathway is central in reducing cancer frequency in vertebrates. The protein product of the haploinsufficient mouse double minute 2 (MDM2) oncogene binds to and inhibits the p53 protein. Recent studies of human genetic variants in p53 and MDM2 have shown that single nucleotide polymorphisms (SNPs) can affect p53 signaling, confer cancer risk, and suggest that the pathway is under evolutionary selective pressure (1–4). In this report, we analyze the haplotype structure of MDM4, a structural homolog of MDM2, in several different human populations. Unusual patterns of linkage disequilibrium (LD) in the haplotype distribution of MDM4 indicate the presence of candidate SNPs that may also modify the efficacy of the p53 pathway. Association studies in 5 different patient populations reveal that these SNPs in MDM4 confer an increased risk for, or early onset of, human breast and ovarian cancers in Ashkenazi Jewish and European cohorts, respectively. This report not only implicates MDM4 as a key regulator of tumorigenesis in the human breast and ovary, but also exploits for the first time evolutionary driven linkage disequilibrium as a means to select SNPs of p53 pathway genes that might be clinically relevant

Altered tumor formation and evolutionary selection of genetic variants in the human MDM4 oncogene

A large body of evidence strongly suggests that the p53 tumor suppressor pathway is central in reducing cancer frequency in vertebrates. The protein product of the haploinsufficient mouse double minute 2 (MDM2) oncogene binds to and inhibits the p53 protein. Recent studies of human genetic variants in p53 and MDM2 have shown that single nucleotide polymorphisms (SNPs) can affect p53 signaling, confer cancer risk, and suggest that the pathway is under evolutionary selective pressure (1–4). In this report, we analyze the haplotype structure of MDM4, a structural homolog of MDM2, in several different human populations. Unusual patterns of linkage disequilibrium (LD) in the haplotype distribution of MDM4 indicate the presence of candidate SNPs that may also modify the efficacy of the p53 pathway. Association studies in 5 different patient populations reveal that these SNPs in MDM4 confer an increased risk for, or early onset of, human breast and ovarian cancers in Ashkenazi Jewish and European cohorts, respectively. This report not only implicates MDM4 as a key regulator of tumorigenesis in the human breast and ovary, but also exploits for the first time evolutionary driven linkage disequilibrium as a means to select SNPs of p53 pathway genes that might be clinically relevant