The Bad, the Good, and the Ugly about Oxidative Stress

Alzheimer's disease (AD), Parkinson's disease (PD), and cancer (e.g., leukemia) are the most devastating disorders affecting millions of people worldwide. Except for some kind of cancers, no effective and/or definitive therapeutic treatment aimed to reduce or to retard the clinic and pathologic symptoms induced by AD and PD is presently available. Therefore, it is urgently needed to understand the molecular basis of these disorders. Since oxidative stress (OS) is an important etiologic factor of the pathologic process of AD, PD, and cancer, understanding how intracellular signaling pathways respond to OS will have a significant implication in the therapy of these diseases. Here, we propose a model of minimal completeness of cell death signaling induced by OS as a mechanistic explanation of neuronal and cancer cell demise. This mechanism might provide the basis for therapeutic design strategies. Finally, we will attempt to associate PD, cancer, and OS. This paper critically analyzes the evidence that support the “oxidative stress model” in neurodegeneration and cancer

Effect of row orientation on soil water content and vine water status on a Cabernet franc vineyard in Madrid, spain

The aim of this study was to evaluate the effects of row orien¬tation on vine and soil water status in an irrigated vineyard. The trial was developed during 2006, 2007 and 2008, in the South East region of Madrid (Spain) on 5-year old Cabernet franc grapevines (Vitis vinifera L.) grafted onto 140Ru. Plant spacing was 2.5 m x 1.5 m and vines were trained to a VSP. Four orientations were stu¬died: North-South (N-S), East-West (E-W), Northeast-Southwest (N+45) and North-South +20o (N+20). Irrigation (0.4•ET0) started when shoot growth stopped. Soil water availability was measured using a TDR technique with forty buried probes. Row orientation did not have any effect on water consumption in the vineyard. At maturity, leaf water potential was measured at predawn, early mor¬ning, midday and 14:00 solar time, on both canopy sides - sun and shade – ; the early morning measurement was the one that better differentiated treatments. Leaf water potential was a good indica¬tor of plant water status. Differences between (N-S and E-W) and (N+20 and N+45) treatments were obtained both on sun and shade canopy sides, N+20 and N+45 having lower leaf water potentials then drier leaves. The water stress integral shows that N-S and E-W reach the end of maturation with a greater level of hydration than N+45 and N+20. As a whole, N+45 and N+20 orientations, without affecting too much the soil available water content, induce regularly more water stress to the vine at some periods, probably due to an higher sunlight interception in early morning which makes water limitation for the vine more early and thus more severe during the day

Repositioning small molecule drugs as allosteric inhibitors of the BFT-3 toxin from enterotoxigenic Bacteroides fragilis

Bacteroides fragilis is an abundant commensal component of the healthy human colon. However, under dysbiotic conditions, enterotoxigenic B. fragilis (ETBF) may arise and elicit diarrhea, anaerobic bacteremia, inflammatory bowel disease, and colorectal cancer. Most worrisome, ETBF is resistant to many disparate antibiotics. ETBF's only recognized specific virulence factor is a zinc-dependent metallopeptidase (MP) called B. fragilis toxin (BFT) or fragilysin, which damages the intestinal mucosa and triggers disease-related signaling mechanisms. Thus, therapeutic targeting of BFT is expected to limit ETBF pathogenicity and improve the prognosis for patients. We focused on one of the naturally occurring BFT isoforms, BFT-3, and managed to repurpose several approved drugs as BFT-3 inhibitors through a combination of biophysical, biochemical, structural, and cellular techniques. In contrast to canonical MP inhibitors, which target the active site of mature enzymes, these effectors bind to a distal allosteric site in the proBFT-3 zymogen structure, which stabilizes a partially unstructured, zinc-free enzyme conformation by shifting a zinc-dependent disorder-to-order equilibrium. This yields proBTF-3 incompetent for autoactivation, thus ablating hydrolytic activity of the mature toxin. Additionally, a similar destabilizing effect is observed for the activated protease according to biophysical and biochemical data. Our strategy paves a novel way for the development of highly specific inhibitors of ETBF-mediated enteropathogenic conditions

Validación de un instrumento para medir el respeto de la autonomía del paciente en situación terminal durante la toma de decisiones médicas sobre el final de la vida

Antecedents: El respecte per l'autonomia de la persona consisteix a considerar-les preferències i valors de la persona malalta durant la presa de decisions sobre el tipus d'atenció que rep i és un element bioeticojurídic. No obstant això, no hi ha instruments validats sobre aquest fenomen que ajudin a aclarir la percepció del metge sobre aquest principi. Objectiu: Elaborar, validar mitjançant un judici d'experts i pilotejar per obtenir la consistència interna d'un instrument que avalua el nivell d'acord dels metges sobre els diferents elements que constitueixen el respecte per l'autonomia de la persona malalta en l'etapa terminal. Mètodes: Estudi transversal. Mètode de validació per judici de deu experts de Mèxic. L'instrument es va pilotejar en metges d'un hospital públic d'alta especialitat per determinar-ne la consistència interna. Resultats: Es va generar un instrument de 15 ítems amb un índex de validesa de contingut de 0.82 per a 10 experts. Va ser pilotejat en una mostra de 96 metges. S'obtingué un alfa de Cronbach de 0.694. Conclusions: Es va desenvolupar, validar i avaluar la consistència interna d'un qüestionari per mesurar el nivell d'acord de metges que atenen persones malaltes en etapa terminal amb relació als aspectes constitutius sobre el respecte de la seva autonomia. Se'n recomana l'aplicació en metges per corroborar-ne la utilitat i afavorir un diagnòstic situacional sobre la situació estudiada.Background: Respect for the autonomy of the person consists in considering the preferences and values of the sick person when making decisions about the type of care they receive and is a bioethical-legal element. However, there are no validated instruments on this phenomenon that help to clarify the physician's perception of this principle. Objective: To elaborate, validate through expert judgment and determine the internal consistency of an instrument that evaluates the level of agreement that the doctors have on the different elements that constitute respect for the autonomy of the terminally ill person. Methods: Cross-sectional study. The expert judgment validation method was used with a panel of ten experts from Mexico. The instrument was piloted in doctors of a highly specialized public hospital to determinate its internal consistency. Results: An instrument of 15 items was generated with a content validity index of 0.82 for 10 experts. It was piloted in a sample of 96 doctors (31.3% female and 68.7% male) and with an average age of 30 years. The Cronbach's alpha was 0.694. Conclusions: A questionnaire was developed to measure the level of agreement that the doctor who cares for terminally ill people has in relation to the constitutive aspects of respect for their autonomy. Based on the results of the validation and internal consistency, its application in medical populations is recommended to corroborate its usefulness and favor a simple situational diagnosis of the situation studied.Antecedentes: El respeto por la autonomía de la persona consiste en considerarlas preferencias y valores de la persona enferma durante la toma de decisions sobre el tipo de atención que recibe y es un elemento bioético-jurídico. Sin embargo, no existen instrumentos validados sobre este fenómeno que ayuden aclarificar la percepción del médico sobre este principio. Objetivo: Elaborar, validar mediante juicio de expertos y pilotear para obtener la consistencia interna de un instrumento que evalúa el nivel de acuerdo de los médicos sobre los diferentes elementos que constituyen el respeto por la  autonomía de la persona enferma en etapa terminal. Métodos: Estudio transversal. Método de validación por juicio de diez expertos de México. El instrumento se piloteó en médicos de un hospital público de alta especialidad para determinar la consistencia interna del mismo. Resultados: Se generó un instrumento de 15 ítems con un índice de validez de contenido de 0.82 para 10 expertos. Fue piloteado en una muestra de 96 médicos. Se obtuvo un alfa de Cronbach de 0.694. Conclusiones: Se desarrolló, validó y evaluó la consistencia interna de un cuestionario para medir el nivel de acuerdo de médicos que atienden a persones enfermas en etapa terminal con relación a los aspectos constitutivos sobre el respeto de su autonomía. Se recomienda su aplicación en médicos para corroborar su utilidad y favorecer un diagnóstico situacional sobre la situación estudiada

Hard x-ray characterization of a HEFT single-reflection prototype

We have measured the hard X-ray reflectivity and imaging performance from depth graded W/Si multilayer coated mirror segments mounted in a single reflection cylindrical prototype for the hard X-ray telescopes to be flown on the High Energy Focusing Telescope (HEFT) balloon mission. Data have been obtained in the energy range from 18 - 170 keV at the European Synchrotron Radiation Facility and at the Danish Space Research Institute at 8 keV. The modeling of the reflectivity data demonstrate that the multilayer structure can be well described by the intended power law distribution of the bilayer thicknesses optimized for the telescope performance and we find that all the data is consistent with an interfacial width of 4.5 Å. We have also demonstrated that the required 5% uniformity of the coatings is obtained over the mirror surface and we have shown that it is feasible to use similar W/Si coatings for much higher energies than the nominal energy range of HEFT leading the way for designing Gamma-ray telescopes for future astronomical applications. Finally we have demonstrate 35 arcsecond Half Power Diameter imaging performance of the one bounce prototype throughout the energy range of the HEFT telescopes

Differences in Adipose Tissue and Lean Mass Distribution in Patients with Collagen VI Related Myopathies Are Associated with Disease Severity and Physical Ability

Mutations in human collagen VI genes cause a spectrum of musculoskeletal conditions in children and adults collectively termed collagen VI-related myopathies (COL6-RM) characterized by a varying degree of muscle weakness and joint contractures and which include Ullrich Congenital Muscular Dystrophy (UCMD) and Bethlem Myopathy (BM). Given that collagen VI is one of the most abundant extracellular matrix proteins in adipose tissue and its emerging role in energy metabolism we hypothesized that collagen VI deficiency might be associated with alterations in adipose tissue distribution and adipokines serum profile. We analyzed body composition by means of dual-energy X-ray absorptiometry in 30 pediatric and adult COL6-RM myopathy patients representing a range of severities (UCMD, intermediate-COL6-RM, and BM). We found a distinctive pattern of regional adipose tissue accumulation which was more evident in children at the most severe end of the spectrum. In particular, the accumulation of fat in the android region was a distinguishing feature of UCMD patients. In parallel, there was a decrease in lean mass compatible with a state of sarcopenia, particularly in ambulant children with an intermediate phenotype. All children and adult patients that were sarcopenic were also obese. These changes were significantly more pronounced in children with collagen VI deficiency than in children with Duchenne Muscular Dystrophy of the same ambulatory status. High molecular weight adiponectin and leptin were significantly increased in sera from children in the intermediate and BM group. Correlation analysis showed that the parameters of fat mass were negatively associated with motor function according to several validated outcome measures. In contrast, lean mass parameters correlated positively with physical performance and quality of life. Leptin and adiponectin circulating levels correlated positively with fat mass parameters and negatively with lean mass and thus may be relevant to the disease pathogenesis and as circulating markers. Taken together our results indicate that COL6-RM are characterized by specific changes in total fat mass and distribution which associate with disease severity, motor function, and quality of life and which are clinically meaningful and thus should be taken into consideration in the management of these patients

Biodegradation of alkyl branched aromatic alkanoic naphthenic acids by Pseudomonas putida KT2440

The majority of the world's crude oil reserves consist of highly biodegraded heavy and super heavy crude oils and oil sands that have not yet been fully exploited. These vast resources contain complex mixtures of carboxylic acids known as naphthenic acids (NAs). NAs cause major environmental and economic problems, as they are recalcitrant, corrosive and toxic. Although aromatic acids make up a small proportion of most NA mixtures, they have demonstrable toxicities to some organisms (e.g. some bacteria and algae) and ideally need to be removed or reduced by remediation. The present study analysed the ability of Pseudomonas putida KT2440 to degrade highly recalcitrant aromatic acids, as exemplified by the alkyl phenylalkanoic acid (4'-t-butylphenyl)-4-butanoic acid (t-BPBA) and the more degradable (4'-n-butylphenyl)-4-butanoic acid (n-BPBA). n-BPBA was completely metabolized after 14 days, with the production of a persistent metabolite identified as (4'-n-butylphenyl)ethanoic acid (BPEA) which resulted from removal of two carbon atoms from the carboxyl side chain (beta-oxidation) as observed previously with a mixed consortium. However, when n-BPBA concentration was increased two-fold, degradation decreased by 56% with a concomitant six-fold decrease in cell numbers, suggesting that at greater concentrations, n-BPBA may be toxic to P. putida KT2440. In contrast, P. putida KT2440 was unable to degrade the highly recalcitrant t-BPBA even after 49 days. These findings have implications for NA bioremediation in the environment. © 2011

X-ray scatter measurements from thermally slumped thin glass substrates for the HEFT hard x-ray telescopes

We have performed x-ray specular reflectivity and scattering measurements of thermally slumped glass substrates on x-ray diffractometers utilizing a rotating anode x-ray source at the Danish Space Research Institute (DSRI) and synchrotron radiation at the European Synchrotron Radiation Facility (ESRF) optics Bending Magnet beamline. In addition, we tested depth graded W/Si multilayer-coated slumped glass using x-ray specular reflectivity measurements at 8.048 keV and 28 keV and energy-dispersive measurements in the 20-50 keV rang at a double-axis diffractometer at the Orsted Laboratory, University of Copenhagen. The thermally slumped glass substrates will be used to fabricate the hard x-ray grazing incidence optics for the High-Energy Focusing Telescope. We compared the measurements to the SODART- mirrors from the SRG telescope mission program. The surface scatter measurement of the thermally slumped glass substrates yields Half Power Diameters (HPD's) of single- bounce mirrors of full-illuminated lengths of ~ 40 arcseconds for typical substrates and as low as ~ 10 arcseconds for the best substrates, whereas the SODART mirrors yields HPD's of ~ 80 arcseconds with very little variation. Both free-standing glass substrates and prototype mounted and multilayer-coated optics were tested. The result demonstrate that the surface scatter contribution, plus any contribution from the mounting procedure, to the Half Power Diameter from a telescope using the slumped glass optics will be in the subarcminute range.In addition we measured low surface microroughness, yielding high reflectivity, from the glass substrates, as well as from the depth graded W/Si multilayer-coated glass glass (interfacial width 4.2 Å)