Optimization of TRPV6 Calcium Channel Inhibitors Using a 3D Ligand-Based Virtual Screening Method

Herein, we report the discovery of the first potent and selective inhibitor of TRPV6, a calcium channel overexpressed in breast and prostate cancer, and its use to test the effect of blocking TRPV6-mediated Ca2+-influx on cell growth. The inhibitor was discovered through a computational method, xLOS, a 3D-shape and pharmacophore similarity algorithm, a type of ligand-based virtual screening (LBVS) method described briefly here. Starting with a single weakly active seed molecule, two successive rounds of LBVS followed by optimization by chemical synthesis led to a selective molecule with 0.3 μM inhibition of TRPV6. The ability of xLOS to identify different scaffolds early in LBVS was essential to success. The xLOS method may be generally useful to develop tool compounds for poorly characterized targets.

Genome-wide Association Studies Identify Genetic Loci Associated with Albuminuria in Diabetes

Elevated concentrations of albumin in the urine, albuminuria, are a hallmark of diabetic kidney disease and associate with increased risk for end-stage renal disease and cardiovascular events. To gain insight into the pathophysiological mechanisms underlying albuminuria, we conducted meta-analyses of genome-wide association studies and independent replication in up to 5,825 individuals of European ancestry with diabetes mellitus and up to 46,061 without diabetes, followed by functional studies. Known associations of variants in CUBN, encoding cubilin, with the urinary albumin-to-creatinine ratio (UACR) were confirmed in the overall sample (p=2.4*10(-10)). Gene-by-diabetes interactions were detected and confirmed for variants in HS6ST1 and near RAB38/CTSC. SNPs at these loci demonstrated a genetic effect on UACR in individuals with but not without diabetes. The change in average UACR per minor allele was 21% for HS6ST1 and 13% for RAB38/CTSC (p=6.3*10(-7) and 5.8*10(-7), respectively). Experiments using streptozotocin-treated diabetic Rab38 knockout and control rats showed higher urinary albumin concentrations and reduced amounts of megalin and cubilin at the proximal tubule cell surface in Rab38 knockout vs. control rats. Relative expression of RAB38 was higher in tubuli of patients with diabetic kidney disease compared to controls. The loci identified here confirm known and highlight novel pathways influencing albuminuria.

Telomerase Is Essential for Zebrafish Heart Regeneration.

After myocardial infarction in humans, lost cardiomyocytes are replaced by an irreversible fibrotic scar. In contrast, zebrafish hearts efficiently regenerate after injury. Complete regeneration of the zebrafish heart is driven by the strong proliferation response of its cardiomyocytes to injury. Here we show that, after cardiac injury in zebrafish, telomerase becomes hyperactivated, and telomeres elongate transiently, preceding a peak of cardiomyocyte proliferation and full organ recovery. Using a telomerase-mutant zebrafish model, we found that telomerase loss drastically decreases cardiomyocyte proliferation and fibrotic tissue regression after cryoinjury and that cardiac function does not recover. The impaired cardiomyocyte proliferation response is accompanied by the absence of cardiomyocytes with long telomeres and an increased proportion of cardiomyocytes showing DNA damage and senescence characteristics. These findings demonstrate the importance of telomerase function in heart regeneration and highlight the potential of telomerase therapy as a means of stimulating cell proliferation upon myocardial infarction.

Post-translational modifications of voltage-gated sodium channels in chronic pain syndromes.

In the peripheral sensory nervous system the neuronal expression of voltage-gated sodium channels (Navs) is very important for the transmission of nociceptive information since they give rise to the upstroke of the action potential (AP). Navs are composed of nine different isoforms with distinct biophysical properties. Studying the mutations associated with the increase or absence of pain sensitivity in humans, as well as other expression studies, have highlighted Nav1.7, Nav1.8, and Nav1.9 as being the most important contributors to the control of nociceptive neuronal electrogenesis. Modulating their expression and/or function can impact the shape of the AP and consequently modify nociceptive transmission, a process that is observed in persistent pain conditions. Post-translational modification (PTM) of Navs is a well-known process that modifies their expression and function. In chronic pain syndromes, the release of inflammatory molecules into the direct environment of dorsal root ganglia (DRG) sensory neurons leads to an abnormal activation of enzymes that induce Navs PTM. The addition of small molecules, i.e., peptides, phosphoryl groups, ubiquitin moieties and/or carbohydrates, can modify the function of Navs in two different ways: via direct physical interference with Nav gating, or via the control of Nav trafficking. Both mechanisms have a profound impact on neuronal excitability. In this review we will discuss the role of Protein Kinase A, B, and C, Mitogen Activated Protein Kinases and Ca++/Calmodulin-dependent Kinase II in peripheral chronic pain syndromes. We will also discuss more recent findings that the ubiquitination of Nav1.7 by Nedd4-2 and the effect of methylglyoxal on Nav1.8 are also implicated in the development of experimental neuropathic pain. We will address the potential roles of other PTMs in chronic pain and highlight the need for further investigation of PTMs of Navs in order to develop new pharmacological tools to alleviate pain.

Isotone Recursive Methods for Overlapping Generation Models with Stochastic Nonclassical Production

Based on an order-theoretic approach, we derive sufficient conditions for the existence, characterization, and computation of Markovian equilibrium decision processes and stationary Markov equilibrium on minimal state spaces for a large class of stochastic overlapping generations models. In contrast to all previous work, we consider reduced-form stochastic production technologies that allow for a broad set of equilibrium distortions such as public policy distortions, social security, monetary equilibrium, and production nonconvexities. Our order-based methods are constructive, and we provide monotone iterative algorithms for computing extremal stationary Markov equilibrium decision processes and equilibrium invariant distributions, while avoiding many of the problems associated with the existence of indeterminacies that have been well-documented in previous work. We provide important results for existence of Markov equilibria for the case where capital income is not increasing in the aggregate stock. Finally, we conclude with examples common in macroeconomics such as models with fiat money and social security. We also show how some of our results extend to settings with unbounded state spaces.

Theory of uncertainty in illness in patients with cancer of unknown primary origin: Structure providers as antecedents of uncertainty in a population of cancer patients with an unknown primary diagnosis

Uncertainty has been found to be a major component of the cancer experience and can dramatically affect psychosocial adaptation and outcomes of a patient's disease state (McCormick, 2002). Patients with a diagnosis of Carcinoma of Unknown Primary (CUP) may experience higher levels of uncertainty due to the unpredictability of current and future symptoms, limited treatment options and an undetermined life expectancy. To date, only one study has touched upon uncertainty and its' effects on those with CUP but no information exists concerning the effects of uncertainty regarding diagnosis and treatment on the distress level and psychosocial adjustment of this population (Parker & Lenzi, 2003). ^ Mishel's Uncertainty in Illness Theory (1984) proposes that uncertainty is preceded by three variables, one of which being Structure Providers. Structure Providers include credible authority, the degree of trust and confidence the patient has with their doctor, education and social support. It was the goal of this study to examine the relationship between uncertainty and Structure Providers to support the following hypotheses: (1) There will be a negative association between credible authority and uncertainty, (2) There will be a negative association between education level and uncertainty, and (3) There will be a negative association between social support and uncertainty. ^ This cross-sectional analysis utilized data from 219 patients following their initial consultation with their oncologist. Data included the Mishel Uncertainty in Illness Scale (MUIS) which was used to determine patients' uncertainty levels, the Medical Outcomes Study-Social Support Scale (MOSS-SSS) to assess patients, levels of social support, the Patient Satisfaction Questionnaire (PSQ-18) and the Cancer Diagnostic Interview Scale (CDIS) to measure credible authority and general demographic information to assess age, education, marital status and ethnicity. ^ In this study we found that uncertainty levels were generally higher in this sample as compared to other types of cancer populations. And while our results seemed to support most of our hypothesis, we were only able to show significant associations between two. The analyses indicated that credible authority measured by both the CDIS and the PSQ was a significant predictor of uncertainty as was social support measured by the MOSS-SS. Education has shown to have an inconsistent pattern of effect in relation to uncertainty and in the current study there was not enough data to significantly support our hypothesis. ^ The results of this study generally support Mishel's Theory of Uncertainty in Illness and highlight the importance of taking into consideration patients, psychosocial factors as well as employing proper communication practices between physicians and their patients.^

Logistic regression with incompletely observed binary

Logistic regression is one of the most important tools in the analysis of epidemiological and clinical data. Such data often contain missing values for one or more variables. Common practice is to eliminate all individuals for whom any information is missing. This deletion approach does not make efficient use of available information and often introduces bias.^ Two methods were developed to estimate logistic regression coefficients for mixed dichotomous and continuous covariates including partially observed binary covariates. The data were assumed missing at random (MAR). One method (PD) used predictive distribution as weight to calculate the average of the logistic regressions performing on all possible values of missing observations, and the second method (RS) used a variant of resampling technique. Additional seven methods were compared with these two approaches in a simulation study. They are: (1) Analysis based on only the complete cases, (2) Substituting the mean of the observed values for the missing value, (3) An imputation technique based on the proportions of observed data, (4) Regressing the partially observed covariates on the remaining continuous covariates, (5) Regressing the partially observed covariates on the remaining continuous covariates conditional on response variable, (6) Regressing the partially observed covariates on the remaining continuous covariates and response variable, and (7) EM algorithm. Both proposed methods showed smaller standard errors (s.e.) for the coefficient involving the partially observed covariate and for the other coefficients as well. However, both methods, especially PD, are computationally demanding; thus for analysis of large data sets with partially observed covariates, further refinement of these approaches is needed. ^

Investigación actual acerca de Alberto Magno : inventario referido a la hermenéutica

El interés científico por Alberto Magno ha crecido enormemente a nivel mundial desde el final de los años ‘90. Esto se deja ver en la cantidad de estudios acerca de su obra y su repercusión, en la traducción de sus escritos del latín a las lenguas modernas, así como en el progreso del proyecto de largo plazo de la edición históricocrítica de sus obras completas Alberti Magni Opera Omnia. El último informe de investigación sumario de 1999 documenta el comienzo de este desarrollo. Se echa de menos una mirada panorámica sobre la continuación de su transcurso y sobre la presente situación de la investigación. Con la actual contribución se intentará remediar, en principio, este déficit en un punto importante. En una breve mirada retrospectiva sobre las primeras interpretaciones acerca del pensador Alberto Magno, entre otras, las de Martin Grabmann, Bernhard Geyer y Étienne Gilson, nosotros presentamos un primer y selectivo inventario concerniente a la hermenéutica de su comprensión en la investigación actual. Esta mirada panorámica muestra, con algunos ejemplos destacados, las líneas de desarrollo y los desplazamientos en la interpretación de la obra y el pensar del Doctor Universalis, al tiempo que resalta y aprecia los avances de la investigación en este campo, los cuales han sido favorecidos a través de su creciente interdependencia mundial.

El término religio, su aparición y su uso en Eneida de Virgilio

El término "religio" en la antigüedad difiere en muchos aspectos del término "religión" en la actualidad, en consecuencia, en nuestro trabajo se intenta conceptualizar el vocablo a partir de su aparición y uso en Eneida. Asimismo, se establece un paralelismo entre el concepto de pietas, término que describe la relación entre la esfera humana y la divina, religio caracterizada como la consecuencia de dicha relación y el rito como la forma pragmática de ésta última. El objetivo del trabajo es determinar las acepciones que utiliza Virgilio y destacar su funcionalidad en la obra teniendo en cuenta las relaciones sistemáticas antes nombradas. Se estudiarán los siguientes pasajes: libro II, VV. 151, 188, 365, 715; libro III, VV. 363, 409; libro VII, VV. 172, 608; libro VIII, VV. 349, 598; libro XII, VV.182

El término religio, su aparición y su uso en Eneida de Virgilio

El término "religio" en la antigüedad difiere en muchos aspectos del término "religión" en la actualidad, en consecuencia, en nuestro trabajo se intenta conceptualizar el vocablo a partir de su aparición y uso en Eneida. Asimismo, se establece un paralelismo entre el concepto de pietas, término que describe la relación entre la esfera humana y la divina, religio caracterizada como la consecuencia de dicha relación y el rito como la forma pragmática de ésta última. El objetivo del trabajo es determinar las acepciones que utiliza Virgilio y destacar su funcionalidad en la obra teniendo en cuenta las relaciones sistemáticas antes nombradas. Se estudiarán los siguientes pasajes: libro II, VV. 151, 188, 365, 715; libro III, VV. 363, 409; libro VII, VV. 172, 608; libro VIII, VV. 349, 598; libro XII, VV.182

El término religio, su aparición y su uso en Eneida de Virgilio

El término "religio" en la antigüedad difiere en muchos aspectos del término "religión" en la actualidad, en consecuencia, en nuestro trabajo se intenta conceptualizar el vocablo a partir de su aparición y uso en Eneida. Asimismo, se establece un paralelismo entre el concepto de pietas, término que describe la relación entre la esfera humana y la divina, religio caracterizada como la consecuencia de dicha relación y el rito como la forma pragmática de ésta última. El objetivo del trabajo es determinar las acepciones que utiliza Virgilio y destacar su funcionalidad en la obra teniendo en cuenta las relaciones sistemáticas antes nombradas. Se estudiarán los siguientes pasajes: libro II, VV. 151, 188, 365, 715; libro III, VV. 363, 409; libro VII, VV. 172, 608; libro VIII, VV. 349, 598; libro XII, VV.182

Geochemistry of Lesser Antilles forearc sediments

Oceanic sediments contain the products of erosion of continental crust, biologic activity and chemical precipitation. These processes create a large diversity of their chemical and isotopic compositions. Here we focus on the influence of the distance from a continental platform on the trace element and isotopic compositions of sediments deposited on the ocean floor and highlight the role of zircons in decoupling high-field strength elements and Hf isotopic compositions from other trace elements and Nd isotopic compositions. We report major and trace element concentrations as well as Sr and Hf isotopic data for 80 sediments from the Lesser Antilles forearc region. The trace-element characteristics and the Sr and Hf isotopic compositions are generally dominated by detrital material from the continental crust but are also variably influenced by chemical or biogenic carbonate and pure biogenic silica. Next to the South American continent, at DSDP Site 144 and on Barbados Island, sediments, coarse quartz arenites, exhibit marked Zr and Hf excesses that we attribute to the presence of zircon. In contrast, the sediments from DSDP Site 543, which were deposited farther away from the continental platform, consist of fine clay and they show strong deficiencies in Zr and Hf. The enrichment or depletion of Zr-Hf is coupled to large changes in Hf isotopic compositions (-30 < epsilon-Hf < +4) that vary independently from the Nd isotopes. We interpret this feature as a clear expression of the "zircon effect" suggested by Patchett and coauthors in 1984. Zircon-rich sediments deposited next to the South American continent have very low epsilon-Hf values inherited from old zircons. In contrast, in detrital clay-rich sediments deposited a few hundred kilometers farther north, the mineral fraction is devoid of zircon and they have drastically higher epsilon-Hf values inherited from finer, clay-rich continental material. In the two DSDP sites, average Hf isotopes are very unradiogenic relative to other oceanic sediments worldwide (epsilon-Hf = -14.4 and -7.4) and they define the low Hf end member of the sedimentary field in Hf-Nd space. Their compositions correspond to end members that, when mixed with mantle, are able to reproduce the pattern of volcanic rocks from the Lesser Antilles. More generally, we find a relationship between Nb/Zr ratios and the vertical deviation of Hf isotope ratios from the Nd-Hf terrestrial array and we suggest that this relationship can be used as a tool to distinguish sediment input from fractionation during melting during the formation of arc lavas.

Forest disturbance map for the Carpathian ecoregion, 1984-2012

Detailed knowledge of forest cover dynamics is crucial for many applications from resource management to ecosystem service assessments. Landsat data provides the necessary spatial, temporal and spectral detail to map and analyze forest cover and forest change processes. With the opening of the Landsat archive, new opportunities arise to monitor forest dynamics on regional to continental scales. In this study we analyzed changes in forest types, forest disturbances, and forest recovery for the Carpathian ecoregion in Eastern Europe. We generated a series of image composites at five year intervals between 1985 and 2010 and utilized a hybrid analysis strategy consisting of radiometric change classification, post-classification comparison and continuous index- and segment-based post-disturbance recovery assessment. For validation of the disturbance map we used a point-based accuracy assessment, and assessed the accuracy of our forest type maps using forest inventory data and statistically sampled ground truth data for 2010. Our Carpathian-wide disturbance map achieved an overall accuracy of 86% and the forest type maps up to 73% accuracy. While our results suggested a small net forest increase in the Carpathians, almost 20% of the forests experienced stand-replacing disturbances over the past 25 years. Forest recovery seemed to only partly counterbalance the widespread natural disturbances and clear-cutting activities. Disturbances were most widespread during the late 1980s and early 1990s, but some areas also exhibited extensive forest disturbances after 2000, especially in the Polish, Czech and Romanian Carpathians. Considerable shifts in forest composition occurred in the Carpathians, with disturbances increasingly affecting coniferous forests, and a relative decrease in coniferous and mixed forests. Both aspects are likely connected to an increased vulnerability of spruce plantations to pests and pathogens in the Carpathians. Overall, our results exemplify the highly dynamic nature of forest cover during times of socio-economic and institutional change, and highlight the value of the Landsat archive for monitoring these dynamics.

Seagrass ecosystem response to long-term high CO2 in a Mediterranean volcanic vent

We examined the long-term effect of naturally acidified water on a Cymodocea nodosa meadow growing at a shallow volcanic CO2 vent in Vulcano Island (Italy). Seagrass and adjacent unvegetated habitats growing at a low pH station (pH = 7.65 ± 0.02) were compared with corresponding habitats at a control station (pH = 8.01 ± 0.01). Density and biomass showed a clear decreasing trend at the low pH station and the below- to above-ground biomass ratio was more than 10 times lower compared to the control. C content and delta 13C of leaves and epiphytes were significantly lower at the low pH station. Photosynthetic activity of C. nodosa was stimulated by low pH as seen by the significant increase in Chla content of leaves, maximum electron transport rate and compensation irradiance. Seagrass community metabolism was intense at the low pH station, with significantly higher net community production, respiration and gross primary production than the control community, whereas metabolism of the unvegetated community did not differ between stations. Productivity was promoted by the low pH, but this was not translated into biomass, probably due to nutrient limitation, grazing or poor environmental conditions. The results indicate that seagrass response in naturally acidified conditions is dependable upon species and geochemical characteristics of the site and highlight the need for a better understanding of complex interactions in these environments.

Capability Matrix : A Framework for Analyzing Capabilities in Value Chains

This paper develops a Capability Matrix for analyzing capabilities of developing country firms that participate in global and national value chains. This is a generic framework to capture firm-level knowledge accumulation in the context of global and local industrial constellations, by integrating key elements of the global value chain (GVC) and technological capabilities (TC) approaches. The framework can visually portray characteristics of firms’ capabilities, and highlight a relatively overlooked factor in the GVC approach: local firms’ endogenous learning efforts in varieties of relationship with lead firms.