Explore the vast range of titles available.

The G-protein-coupled estrogen receptor (GPER) has been described to exert several cardioprotective effects. However, the exact mechanism involved in cardiac protection remains unclear. The aim of this study is to investigate the role of GPER activation on excitation–contraction coupling (ECC) and the possibility that such effect participates in cardioprotection. The cardiac myocytes of male Wistar rats were isolated with a digestive buffer and loaded with Fura-2-AM for the measurement of intracellular calcium transient (CaT). Sarcomere shortening (SS) and L-type calcium current (ICaL) were also registered. The confocal technique was used to measure nitric oxide (NO) production in cells loaded with DAF-FM-diacetate. Cardiac myocytes exposed to 17-β-estradiol (E2, 10 nM) or G-1 (1 μM) for fifteen minutes decreased CaT, SS, and ICaL. These effects were prevented using G-36 (antagonist of GPER, 1 μM), L-Name (NO synthase -NOS- inhibitor, 100 nM), or wortmannin (phosphoinositide-3-kinase -PI3K- inhibitor, 100 nM). Moreover, G1 increased NO production, and this effect was abolished in the presence of wortmannin. We concluded that the selective activation of GPER with E2 or G1 in the isolated cardiac myocytes of male rats induced a negative inotropic effect due to the reduction in ICaL and the decrease in CaT. Finally, the pathway that we proposed to be implicated in these effects is PI3K-NOS-NO.

The soluble adenylyl cyclase (sAC) was identified in the heart as another source of cyclic AMP (cAMP). However, its cardiac physiological function is unknown. On the other hand, the cardiac Na+/HCO3− cotransporter (NBC) promotes the cellular co-influx of HCO3− and Na+. Since sAC activity is regulated by HCO3−, our purpose was to investigate the potential functional relationship between NBC and sAC in the cardiomyocyte. Rat ventricular myocytes were loaded with Fura-2, Fluo-3, or BCECF to measure Ca2+ transient (Ca2+i) by epifluorescence, Ca2+ sparks frequency (CaSF) by confocal microscopy, or intracellular pH (pHi) by epifluorescence, respectively. Sarcomere or cell shortening was measured with a video camera as an index of contractility. The NBC blocker S0859 (10 μM), the selective inhibitor of sAC KH7 (1 μM), and the PKA inhibitor H89 (0.1 μM) induced a negative inotropic effect which was associated with a decrease in Ca2+i. Since PKA increases Ca2+ release through sarcoplasmic reticulum RyR channels, CaSF was measured as an index of RyR open probability. The generation of CaSF was prevented by KH7. Finally, we investigated the potential role of sAC activation on NBC activity. NBC-mediated recovery from acidosis was faster in the presence of KH7 or H89, suggesting that the pathway sAC-PKA is negatively regulating NBC function, consistent with a negative feedback modulation of the HCO3− influx that activates sAC. In summary, the results demonstrated that the complex NBC-sAC-PKA plays a relevant role in Ca2+ handling and basal cardiac contractility.

We present the findings of a study based on a new inelastic electron-scattering experiment on the 12C nucleus focusing on the kinematic region of Q2=0.8GeV2/c2. The measured cross section is sensitive to the transverse response function and provides a stringent test of theoretical models, as well as of the theoretical assumptions made in Monte-Carlo event-generator codes developed for the interpretation of neutrino-nucleus experiments, such as DUNE and HyperK. We find that modern generators such as GENIE and GiBUU reproduce our new experimental data within 10%.

The force-frequency relationship (FFR) is an important intrinsic regulatory mechanism of cardiac contractility. However, a decrease (negative FFR) or no effect (flat FFR) on contractile force in response to an elevation of heart rate is present in the normal rat or in human heart failure. Reactive oxygen species (ROS) can act as intracellular signaling molecules activating diverse kinases as calcium-calmodulin-dependent protein kinase II (CaMKII) and p-38 MAP kinase (p-38K). Our aim was to elucidate the intracellular molecules implicated in the FFR of isolated rat ventricular myocytes. The myocytes were field-stimulated via two-platinum electrodes. Sarcomere length was recorded with a video camera. Ca 2+ transients and intracellular pH i were recorded by epifluorescence. Increasing frequency from 0.5 to 3 Hz decreased cell shortening without changes in pH i . This negative FFR was changed to positive FFR when the myocytes were pre-incubated with the ROS scavenger MPG, the NADPH oxidase blocker apocynin, or by inhibiting mitochondrial ROS production with 5-HD. Similar results were obtained when the cells were pre-incubated with the CaMKII blocker, KN-93, or the p-38K inhibitor, SB-202190. Consistently, the levels of phosphorylation of p-38K and the oxidation of CaMKII were significantly higher at 2 Hz than at 0.5 Hz. Despite the presence of positive inotropic effect during stimulation frequency enhancement, Ca 2+ transient amplitudes were reduced in MPG- and SB-202190-treated myocytes. In conclusion, our results indicate that the activation of the intracellular pathway involving ROS-CaMKII-p-38K contributes to the negative FFR of rat cardiomyocytes, likely by desensitizing the response of contractile myofilaments to Ca 2+ .

In developing countries, squatter developments that house more than one-third of the urban population are without infrastructure and built from materials at hand. Analyzing Urban Poverty: GIS in the Developing World demonstrates how geographic information systems (GIS) can be used to improve quality of life in poor urban areas. With 30 years of experience using GIS technology to manage urban problems in Venezuelan barrios, Rosario Giusti de Perez and Ramon Perez describe how they developed sustainable solutions that go beyond conventional planning programs. Chapters cover site analyses of the natural and built environments, visualization of poverty maps, development of appropriate improvement proposals, management of projects, and organization of communities, and encouragement of their participation.

With few exceptions, the marked advances in knowledge about the genetic basis of schizophrenia have not converged on findings that can be confidently used for precise experimental modeling. By applying knowledge of the cellular taxonomy of the brain from single-cell RNA sequencing, we evaluated whether the genomic loci implicated in schizophrenia map onto specific brain cell types. We found that the common-variant genomic results consistently mapped to pyramidal cells, medium spiny neurons (MSNs) and certain interneurons, but far less consistently to embryonic, progenitor or glial cells. These enrichments were due to sets of genes that were specifically expressed in each of these cell types. We also found that many of the diverse gene sets previously associated with schizophrenia (genes involved in synaptic function, those encoding mRNAs that interact with FMRP, antipsychotic targets, etc.) generally implicated the same brain cell types. Our results suggest a parsimonious explanation: the common-variant genetic results for schizophrenia point at a limited set of neurons, and the gene sets point to the same cells. The genetic risk associated with MSNs did not overlap with that of glutamatergic pyramidal cells and interneurons, suggesting that different cell types have biologically distinct roles in schizophrenia. Integration of single-cell RNA sequencing with genome-wide association data implicates specific brain cell types in schizophrenia. Gene sets previously associated with schizophrenia implicate the same cell types, which include pyramidal cells and medium spiny neurons.

Efforts to construct therapeutically useful models of biological systems require large and diverse sets of data on functional connections between their components. Here we show that cellular responses to combinations of chemicals reveal how their biological targets are connected. Simulations of pathways with pairs of inhibitors at varying doses predict distinct response surface shapes that are reproduced in a yeast experiment, with further support from a larger screen using human tumour cells. The response morphology yields detailed connectivity constraints between nearby targets, and synergy profiles across many combinations show relatedness between targets in the whole network. Constraints from chemical combinations complement genetic studies, because they probe different cellular components and can be applied to disease models that are not amenable to mutagenesis. Chemical probes also offer increased flexibility, as they can be continuously dosed, temporally controlled, and readily combined. After extending this initial study to cover a wider range of combination effects and pathway topologies, chemical combinations may be used to refine network models or to identify novel targets. This response surface methodology may even apply to non‐biological systems where responses to targeted perturbations can be measured. Synopsis Living organisms are built of interacting components, whose function and dysfunction can be described through dynamic network models (Davidson et al , 2002 ). Systems Biology involves the iterative construction of such models (Ideker et al , 2001 ), and may eventually improve the understanding of diseases using in silico simulations. Such simulations may eventually permit drugs to be prioritized for clinical trials, reducing potential risks and increasing the likelihood of successful outcomes. Given the complexity of biological systems, constructing realistic models will require large and diverse sets of connectivity data. Chemical combinations provide a new window into biological connectivity. Information gleaned from targeted combinations, such as paired mutations (Tong et al , 2004 ), has proven to be especially useful for revealing functional interactions between components. We have been screening chemical combinations for therapeutic synergies (Borisy et al , 2003 ; Zimmermann et al , 2007 ), collecting full‐dose matrices where combinations are tested in all possible pairings of serially diluted single agent doses (Figure 1 ). Such screens yield a variety of response surfaces with distinct shapes for combinations that work through different known mechanisms, suggesting that combination effects may contain information on the nature of functional connections between drug targets. Simulations of biological pathways predict synergistic responses to inhibitors that depend on target connectivity. We explored theoretical predictions by simulating a metabolic pathway with pairs of inhibitors aimed at different targets with varying doses. We found that the shape of each combination response depended on how the inhibitor pair's targets were connected in the pathway (Figure 2 ). The predicted response shapes were robust to plausible variations in the simulated pathway that did not affect the network topology (e.g., kinetic assumptions, parameter values, and nonlinear response functions), but were very sensitive to topological alterations in the modelled network (e.g., feedback regulation or changing the type of junction at a branch point). These findings suggest that connectivity of the inhibitor targets has a major influence on combination response morphology. The predicted shapes were experimentally confirmed in yeast combination experiments. The proliferation experiment used drugs focused on the sterol biosynthesis pathway, which is mostly linear between the targets covered in this study, and is known to be regulated by negative feedback (Gardner et al , 2001 ). The combinations between sterol inhibitors confirmed expectations from our simulations, showing dose‐additive responses for pairs targeting the same enzyme and strong synergies across enzymes of the shape predicted in our simulations for linear pathways under negative feedback. Combinations across pathways showed much more variable responses with a trend towards less synergy on average. Further experimental support was obtained from human cells. A combination screen of 90 annotated drugs in a human tumour cell line (HCT116) proliferation assay produced strong synergies for combinations within pathways and more variable effects between targeted functions. Synergy profiles (sets of all synergy scores involving each drug) also showed a greater degree of similarity for pairs of drugs with related targets. Finally, the most extreme outliers were dominated by inhibitors of kinases that are especially critical for HCT116 proliferation (Awwad et al , 2003 ), with effects that are consistent across mechanistic replicates, showing that chemical combinations can highlight biologically relevant cellular processes. This study demonstrates the potential of chemical combinations for exploring functional connectivity in biological systems. This information complements genetic studies by providing more details through variable dosing, by directly targeting single domains of multi‐domain proteins, and by probing cell types that are not amenable to mutagenesis. Responses from large chemical combination screens can be used to identify molecular targets through chemical–genetic profiling (Macdonald et al , 2006 ), or to directly constrain network models by means of a prediction‐validation procedure (Ideker et al , 2001 ). This initial exploration can be extended to cover a wider range of response shapes and network topologies, as well as to combinations of three or more chemical agents. Moreover, this approach may even be applicable to non‐biological systems where responses to targeted perturbations can be measured. Chemical synergies can be novel probes of biological systems. Simulated response shapes depend on target connectivity in a pathway. Experiments with yeast and cancer cells confirm simulated effects. Profiles across many combinations yield target location information.

This paper concentrates on economic, institutional, financial and legal matters that have a direct impact on sustainable planning and development. It reflects the research that is being developed in colonias on the Texas side of the US - Mexico border region. Colonias in Texas are defined as areas with substandard housing, inadequate plumbing and sewage disposal systems, and low-income residents. Three case-studies are presented: the first refers to micro businesses and their potential to promote local economic development; the second is related to the \\“legalization” of \\“informal” developments; and the third refers to the sustainability of micro-credit for house improvement. Colonias, mainly isolated from urban areas, are starting to enjoy a relatively stable population, and regardless of the many difficulties they face, colonias are showing signs of being livable communities. This paper discusses these low-income communities from the point of view of promoting local economic and community sustainable development.

We study the evolution of the (e,e'p) cross section on nuclei with increasing asymmetry between the number of neutrons and protons. The calculations are done within the framework of the nonrelativistic and relativistic distorted-wave impulse approximation. In the nonrelativistic model phenomenological Woods-Saxon and Hartree-Fock wave functions are used for the proton bound-state wave functions, in the relativistic model the wave functions are solutions of Dirac-Hartree equations. The models are first tested against experimental data on 40 Ca and 48Ca nuclei, and then they are applied to a set of spherical calcium isotopes.