The phosphoinositide 3-kinase-dependent activation of Btk is required for optimal eicosanoid production and generation of reactive oxygen species in antigen-stimulated mast cells

Activated mast cells are a major source of the eicosanoids PGD(2) and leukotriene C(4) (LTC(4)), which contribute to allergic responses. These eicosanoids are produced following the ERK1/2-dependent activation of cytosolic phospholipase A(2), thus liberating arachidonic acid, which is subsequently metabolized by the actions of 5-lipoxygenase and cyclooxygenase to form LTC(4) and PGD(2), respectively. These pathways also generate reactive oxygen species (ROS), which have been proposed to contribute to FcepsilonRI-mediated signaling in mast cells. In this study, we demonstrate that, in addition to ERK1/2-dependent pathways, ERK1/2-independent pathways also regulate FcepsilonRI-mediated eicosanoid and ROS production in mast cells. A role for the Tec kinase Btk in the ERK1/2-independent regulatory pathway was revealed by the significantly attenuated FcepsilonRI-dependent PGD(2), LTC(4), and ROS production in bone marrow-derived mast cells of Btk(-/-) mice. The FcepsilonRI-dependent activation of Btk and eicosanoid and ROS generation in bone marrow-derived mast cells and human mast cells were similarly blocked by the PI3K inhibitors, Wortmannin and LY294002, indicating that Btk-regulated eicosanoid and ROS production occurs downstream of PI3K. In contrast to ERK1/2, the PI3K/Btk pathway does not regulate cytosolic phospholipase A(2) phosphorylation but rather appears to regulate the generation of ROS, LTC(4), and PGD(2) by contributing to the necessary Ca(2+) signal for the production of these molecules. These data demonstrate that strategies to decrease mast cell production of ROS and eicosanoids would have to target both ERK1/2- and PI3K/Btk-dependent pathways

Inhibition of HIV derived lentiviral production by TAR RNA binding domain of TAT protein

BACKGROUND: A critical step in the production of new HIV virions involves the TAT protein binding to the TAR element. The TAT protein contains in close proximity its TAR RNA binding domain and protein transduction domain (PTD). The PTD domain of TAT has been identified as being instrumental in the protein's ability to cross mammalian cell and nuclear membranes. All together, this information led us to form the hypothesis that a protein containing the TAR RNA binding domain could compete with the native full length TAT protein and effectively block the TAR RNA binding site in transduced HIV infected cells. RESULTS: We synthesized a short peptide named Tat-P, which contained the TAR RNA binding and PTD domains to examine whether the peptide has the potential of inhibiting TAT dependent HIV replication. We investigated the inhibiting effects of Tat-P in vitro using a HIV derived lentiviral vector model. We found that the TAT PTD domain not only efficiently transduced test cells, but also effectively inhibited the production of lentiviral particles in a TAT dependent manner. These results were also supported by data derived from the TAT activated LTR-luciferase expression model and RNA binding assays. CONCLUSION: Tat-P may become part of a category of anti-HIV drugs that competes with full length TAT proteins to inhibit HIV replication. In addition, this study indicates that the HIV derived lentiviral vector system is a safe and reliable screening method for anti-HIV drugs, especially for those targeting the interaction of TAT and TAR RNAs

Solar Water Splitting Cells

No abstract

Systems Biology Graphical Notation: Process Diagram Level 1

Standard graphical representations have played a crucial role in science and engineering throughout the last century. Without electrical symbolism, it is very likely that our industrial society would not have evolved at the same pace. Similarly, specialised notations such as the Feynmann notation or the process flow diagrams did a lot for the adoption of concepts in their own fields. With the advent of Systems Biology, and more recently of Synthetic Biology, the need for precise and unambiguous descriptions of biochemical interactions has become more pressing. While some ideas have been advanced over the last decade, with a few detailed proposals, no actual community standard has emerged. The Systems Biology Graphical Notation (SBGN) is a graphical representation crafted over several years by a community of biochemists, modellers and computer scientists. Three orthogonal and complementary languages have been created, the Process Diagrams, the Entity Relationship Diagrams and the Activity Flow Diagrams. Using these three idioms a scientist can represent any network of biochemical interactions, which can then be interpreted in an unambiguous way. The set of symbols used is limited, and the grammar quite simple, to allow its usage in textbooks and its teaching directly in high schools. The first level of the SBGN Process Diagram has been publicly released. Software support for SBGN Process Diagram was developed concurrently with its specification in order to speed-up public adoption. Shared by the communities of biochemists, genomicians, theoreticians and computational biologists, SBGN languages will foster efficient storage, exchange and reuse of information on signalling pathways, metabolic networks and gene regulatory maps

Experimental evidence for Wigner's tunneling time

Tunneling of a particle through a potential barrier remains one of the most remarkable quantum phenomena. Owing to advances in laser technology, electric fields comparable to those electrons experience in atoms are readily generated and open opportunities to dynamically investigate the process of electron tunneling through the potential barrier formed by the superposition of both laser and atomic fields. Attosecond-time and angstrom-space resolution of the strong laser-field technique allow to address fundamental questions related to tunneling, which are still open and debated: Which time is spent under the barrier and what momentum is picked up by the particle in the meantime? In this combined experimental and theoretical study we demonstrate that for strong-field ionization the leading quantum mechanical Wigner treatment for the time resolved description of tunneling is valid. We achieve a high sensitivity on the tunneling barrier and unambiguously isolate its effects by performing a differential study of two systems with almost identical tunneling geometry. Moreover, working with a low frequency laser, we essentially limit the non-adiabaticity of the process as a major source of uncertainty. The agreement between experiment and theory implies two substantial corrections with respect to the widely employed quasiclassical treatment: In addition to a non-vanishing longitudinal momentum along the laser field-direction we provide clear evidence for a non-zero tunneling time delay. This addresses also the fundamental question how the transition occurs from the tunnel barrier to free space classical evolution of the ejected electron.Comment: 31 pages, 15 figures including appendi

USE OF FUZZY LOGIC TO INVESTIGATE WEATHER PARAMETER IMPACT ON ELECTRICAL LOAD BASED ON SHORT TERM FORECASTING

Load forecasting guides the power company to make some decisions on generation, transmission and distribution of electrical power. This work presents a solution methodology, using fuzzy logic approach for short term load forecasting (STLF) for Adamawa State University, Mubi.  The proposed methodology utilized fuzzy reasoning decision rules that use the nonlinear relationships between inputs and outputs. The fuzzy logic model was developed in the Simulink environment of a MATLAB software. The model developed was able to forecast a day ahead load (kW) with a mean absolute error (MAPE) of 6.17% and it was observed that weather parameter (temperature) has significant impact on electrical load.  http://dx.doi.org/10.4314/njt.v35i3.1

Statin use and adverse effects among adults \u3e 75 years of age: Insights from the Patient and Provider Assessment of Lipid Management (PALM) registry

Background: Current statin use and symptoms among older adults in routine community practice have not been well characterized since the release of the 2013 American College of Cardiology/American Heart Association guideline. Methods and results: We compared statin use and dosing between adults \u3e75 and ≤75 years old who were eligible for primary or secondary prevention statin use without considering guideline-recommended age criteria. The patients were treated at 138 US practices in the Patient and Provider Assessment of Lipid Management (PALM) registry in 2015. Patient surveys also evaluated reported symptoms while taking statins. Multivariable logistic regression models examined the association between older age and statin use and dosing. Among 6717 people enrolled, 1704 (25%) were \u3e75 years old. For primary prevention, use of any statin or high-dose statin did not vary by age group: any statin, 62.6% in those \u3e75 years old versus 63.1% in those ≤75 years old (P=0.83); high-dose statin, 10.2% versus 12.3% in the same groups (P=0.14). For secondary prevention, older patients were slightly less likely to receive any statin (80.1% versus 84.2% [P=0.003]; adjusted odds ratio, 0.81; 95% confidence interval, 0.66-1.01 [P=0.06]), but were much less likely to receive a high-intensity statin (23.5% versus 36.2% [PP=0.0001]). Among current statin users, older patients were slightly less likely to report any symptoms (41.3% versus 46.6%; P=0.003) or myalgias (27.3% versus 33.3%; Conclusions: Overall use of statins was similar for primary prevention in those aged \u3e75 years versus younger patients, yet older patients were less likely to receive high-intensity statins for secondary prevention. Statins appear to be similarly tolerated in older and younger adult

A UV to Mid-IR Study of AGN Selection

We classify the spectral energy distributions (SEDs) of 431,038 sources in the 9 sq. deg Bootes field of the NOAO Deep Wide-Field Survey (NDWFS). There are up to 17 bands of data available per source, including ultraviolet (GALEX), optical (NDWFS), near-IR (NEWFIRM), and mid-infrared (IRAC/MIPS) data, as well as spectroscopic redshifts for ~20,000 objects, primarily from the AGN and Galaxy Evolution Survey (AGES). We fit galaxy, AGN, stellar, and brown dwarf templates to the observed SEDs, which yield spectral classes for the Galactic sources and photometric redshifts and galaxy/AGN luminosities for the extragalactic sources. The photometric redshift precision of the galaxy and AGN samples are sigma/(1+z)=0.040 and sigma/(1+z)=0.169, respectively, with the worst 5% outliers excluded. Based on the reduced chi-squared of the SED fit for each SED model, we are able to distinguish between Galactic and extragalactic sources for sources brighter than I=23.5. We compare the SED fits for a galaxy-only model and a galaxy+AGN model. Using known X-ray and spectroscopic AGN samples, we confirm that SED fitting can be successfully used as a method to identify large populations of AGN, including spatially resolved AGN with significant contributions from the host galaxy and objects with the emission line ratios of "composite" spectra. We also use our results to compare to the X-ray, mid-IR, optical color and emission line ratio selection techniques. For an F-ratio threshold of F>10 we find 16,266 AGN candidates brighter than I=23.5 and a surface density of ~1900 AGN per deg^2.Comment: Submitted to ApJ, 35 pages, 17 figures, 2 table