Benzbromarone, quercetin, and folic acid inhibit amylin aggregation

Human Amylin, or islet amyloid polypeptide (hIAPP), is a small hormone secreted by pancreatic ß-cells that forms aggregates under insulin deficiency metabolic conditions, and it constitutes a pathological hallmark of type II diabetes mellitus. In type II diabetes patients, amylin is abnormally increased, self-assembled into amyloid aggregates, and ultimately contributes to the apoptotic death of ß-cells by mechanisms that are not completely understood. We have screened a library of approved drugs in order to identify inhibitors of amylin aggregation that could be used as tools to investigate the role of amylin aggregation in type II diabetes or as therapeutics in order to reduce ß-cell damage. Interestingly, three of the compounds analyzed—benzbromarone, quercetin, and folic acid—are able to slow down amylin fiber formation according to Thioflavin T binding, turbidimetry, and Transmission Electron Microscopy assays. In addition to the in vitro assays, we have tested the effect of these compounds in an amyloid toxicity cell culture model and we have found that one of them, quercetin, has the ability to partly protect cultured pancreatic insulinoma cells from the cytotoxic effect of amylin. Our data suggests that quercetin can contribute to reduce oxidative damage in pancreatic insulinoma ß cells by modulating the aggregation propensity of amylin

Microscopic study of the morphology and metabolic activity of Fusarium oxysporum f. sp. gladioli treated with Jatropha curcas oil and derivatives

AbstractThe fungus Fusarium oxysporum f. sp. gladioli is one of the main pathogenic microorganisms of the ornamental genus Gladiolus. The attack of this microorganism includes corms and different plant phenological stages. In this study, different microscopic techniques and fluorochromes were used to evaluate the effect of J. curcas oil and acylglycerides, namely trilinolein, triolein, monomyristin and dimyristin, on the morphology, membrane integrity (%), viability (%) and germination (%) of F. oxsporum f sp. gladioli. Phase-contrast optical photomicrographs and scanning microscopy showed that J. curcas oil and the triglycerides triolein and trilinolein caused the formation of numerous vacuoles, alterations in the morphology of the outer covering of the mycelium and conidia, and inhibition of membrane activity in the fungus during 24h of incubation. The fluorochromes used detected no permanent damage to the viability of the conidia. The high germination percentage of the conidia of Fusarium oxysporum f. sp. gladioli indicates that the damage caused by the application of the treatments was fungistatic rather than fungicidal and did not cause cell death

Configuration Complexities of Hydrogenic Atoms

The Fisher-Shannon and Cramer-Rao information measures, and the LMC-like or shape complexity (i.e., the disequilibrium times the Shannon entropic power) of hydrogenic stationary states are investigated in both position and momentum spaces. First, it is shown that not only the Fisher information and the variance (then, the Cramer-Rao measure) but also the disequilibrium associated to the quantum-mechanical probability density can be explicitly expressed in terms of the three quantum numbers (n, l, m) of the corresponding state. Second, the three composite measures mentioned above are analytically, numerically and physically discussed for both ground and excited states. It is observed, in particular, that these configuration complexities do not depend on the nuclear charge Z. Moreover, the Fisher-Shannon measure is shown to quadratically depend on the principal quantum number n. Finally, sharp upper bounds to the Fisher-Shannon measure and the shape complexity of a general hydrogenic orbital are given in terms of the quantum numbers.Comment: 22 pages, 7 figures, accepted i

TIGAR inclusion pathology is specific for Lewy body diseases

BACKGROUND: We previously reported up-regulation of tigarb (the zebrafish orthologue? of human TIGAR, TP53 - Induced Glycolysis and Apoptosis Regulator) in a zebrafish pink1-/- model of Parkinson's disease (PD). Genetic inactivation of tigarb led to the rescue of dopaminergic neurons and mitochondrial function in pink-/- zebrafish. The aim of this study was to determine the relevance of TIGAR for human PD, investigate its disease specificity and identify relevant upstream and downstream mechanisms. MATERIALS AND METHODS: TIGAR Immunohistochemistry using a range of antibodies was undertaken for detailed assessment of TIGAR in formalin-fixed, paraffin-embedded tissue from post mortem brains of PD patients and other neurodegenerative disorders (n = 10 controls, 10 PD cases, 10 dementia with Lewy bodies, 5 motor neurone disease (MND), 3 multiple system atrophy (MSA) and complemented by immunohistochemistry for p53, hexokinase I (HK-I) and hexokinase II (HK-II; n = 4 control, 4 PD, and 4 dementia with Lewy bodies). RESULTS: TIGAR was detected in Lewy bodies and Lewy neurites in the substantia nigra of sporadic PD and Dementia with Lewy bodies (DLB) patients. Staining of adjacent sections confirmed the presence of TIGAR alongside alpha-synuclein in these LB and Neurites. In contrast, TIGAR-positive aggregates were not seen in cortical Lewy bodies. TIGAR protein was also absent in both TDP-43-positive inclusions in MND and glial cytoplasmic inclusions in MSA. Subsequent investigation of the TIGAR-upstream regulator p53 and the downstream targets HK-I and HK-II in PD brains suggested a possible mild increase in HK-I. CONCLUSIONS: TIGAR protein, is present in SN Lewy bodies of both sporadic PD and DLB. The absence of TIGAR protein in the pathological inclusions of MND or MSA suggests disease specificity and further raises the possibility that TIGAR may be involved in PD pathogenesis

Multiclasificadores basados en aprendizaje automático como herramienta para la evaluación del perfil neurotóxico de líquidos iónicos

Los líquidos iónicos poseen un perfil fisicoquímico único, el cual los provee de un amplio rango de aplicaciones. Su variabilidad estructural casi ilimitada permite su diseño para tareas específicas. Sin embargo, su sustentabilidad, específicamente su seguridad desde el punto de vista toxicológico, ha sido frecuentemente cuestionada. Este último aspecto limita significativamente el cumplimiento de las regulaciones establecidas por la Unión Europea para el registro, evaluación, autorización y restricción de compuestosquímicos (REACH), así como su aplicación final. Debido a que la mayoría de los líquidos iónicos no han sido sintetizados, se hace evidente la importancia del desarrollo de herramientas quimioinformáticas que, de forma eficiente, permitan evaluar el potencial toxicológico de estos compuestos. En este sentido, el uso combinado de múltiples clasificadores ha demostrado superar las limitaciones de desempeño asociadas al uso de clasificadores individuales. En el presente trabajo fueron evaluadas varias estrategias alternativas de multiclasificadores basados en técnicas de aprendizaje automático supervisado, como herramientas para la evaluación del perfil neurotóxico de líquidos iónicos basado en la inhibición de la enzima acetilcolinesterasa, como indicador de neurotoxicidad. Se obtuvieron dos multiclasificadores con una alta capacidad predictiva sobre un conjunto de validación externa (no utilizado en el proceso de aprendizaje de los modelos). De acuerdo a los resultados obtenidos el 96% de un conjunto de nuevos líquidos iónicos podrá ser correctamente clasificado con la utilizaciónde estos multiclasificadores, los cuales constituyen herramientas de toma de decisión útiles en el campo del diseño y desarrollo de nuevos líquidos iónicos sustentables

Investigating the topology of interacting networks - Theory and application to coupled climate subnetworks

Network theory provides various tools for investigating the structural or functional topology of many complex systems found in nature, technology and society. Nevertheless, it has recently been realised that a considerable number of systems of interest should be treated, more appropriately, as interacting networks or networks of networks. Here we introduce a novel graph-theoretical framework for studying the interaction structure between subnetworks embedded within a complex network of networks. This framework allows us to quantify the structural role of single vertices or whole subnetworks with respect to the interaction of a pair of subnetworks on local, mesoscopic and global topological scales. Climate networks have recently been shown to be a powerful tool for the analysis of climatological data. Applying the general framework for studying interacting networks, we introduce coupled climate subnetworks to represent and investigate the topology of statistical relationships between the fields of distinct climatological variables. Using coupled climate subnetworks to investigate the terrestrial atmosphere's three-dimensional geopotential height field uncovers known as well as interesting novel features of the atmosphere's vertical stratification and general circulation. Specifically, the new measure "cross-betweenness" identifies regions which are particularly important for mediating vertical wind field interactions. The promising results obtained by following the coupled climate subnetwork approach present a first step towards an improved understanding of the Earth system and its complex interacting components from a network perspective

Distributed flow optimization and cascading effects in weighted complex networks

We investigate the effect of a specific edge weighting scheme $\sim (k_i k_j)^{\beta}$ on distributed flow efficiency and robustness to cascading failures in scale-free networks. In particular, we analyze a simple, yet fundamental distributed flow model: current flow in random resistor networks. By the tuning of control parameter $\beta$ and by considering two general cases of relative node processing capabilities as well as the effect of bandwidth, we show the dependence of transport efficiency upon the correlations between the topology and weights. By studying the severity of cascades for different control parameter $\beta$, we find that network resilience to cascading overloads and network throughput is optimal for the same value of $\beta$ over the range of node capacities and available bandwidth

Hedonism and the experience machine

Money isn’t everything, so what is? Many government leaders, social policy theorists, and members of the general public have a ready answer: happiness. This paper examines an opposing view due to Robert Nozick, which centres on his experience-machine thought experiment. Despite the example's influence among philosophers, the argument behind it is riddled with difficulties. Dropping the example allows us to re-version Nozick's argument in a way that makes it far more forceful - and less dependent on people's often divergent intutions about the experience machine

Designing a new science-policy communication mechanism for the UN Convention to Combat Desertification

The United Nations Convention to Combat Desertification (UNCCD) has lacked an efficient mechanism to access scientific knowledge since entering into force in 1996. In 2011 it decided to convene an Ad Hoc Working Group on Scientific Advice (AGSA) and gave it a unique challenge: to design a new mechanism for science-policy communication based on the best available scientific evidence. This paper outlines the innovative 'modular mechanism' which the AGSA proposed to the UNCCD in September 2013, and how it was designed. Framed by the boundary organization model, and an understanding of the emergence of a new multi-scalar and polycentric style of governing, the modular mechanism consists of three modules: a Science-Policy Interface (SPI); an international self-governing and self-organizing Independent Non-Governmental Group of Scientists; and Regional Science and Technology Hubs in each UNCCD region. Now that the UNCCD has established the SPI, it is up to the worldwide scientific community to take the lead in establishing the other two modules. Science-policy communication in other UN environmental conventions could benefit from three generic principles corresponding to the innovations in the three modules-joint management of science-policy interfaces by policy makers and scientists; the production of synthetic assessments of scientific knowledge by autonomous and accountable groups of scientists; and multi-scalar and multi-directional synthesis and reporting of knowledge