Modulation of VEGF-A alternative splicing as a novel treatment in chronic kidney disease.

This is the final version of the article. Available from MDPI via the DOI in this record.Vascular endothelial growth factor A (VEGF-A) is a prominent pro-angiogenic and pro-permeability factor in the kidney. Alternative splicing of the terminal exon of VEGF-A through the use of an alternative 3' splice site gives rise to a functionally different family of isoforms, termed VEGF-Axxxb, known to have anti-angiogenic and anti-permeability properties. Dysregulation of the VEGF-Axxx/VEGF-Axxxb isoform balance has recently been reported in several kidney pathologies, including diabetic nephropathy (DN) and Denys-Drash syndrome. Using mouse models of kidney disease where the VEGF-A isoform balance is disrupted, several reports have shown that VEGF-A165b treatment/over-expression in the kidney is therapeutically beneficial. Furthermore, inhibition of certain splice factor kinases involved in the regulation of VEGF-A terminal exon splicing has provided some mechanistic insight into how VEGF-A splicing could be regulated in the kidney. This review highlights the importance of further investigation into the novel area of VEGF-A splicing in chronic kidney disease pathogenesis and how future studies may allow for the development of splicing-modifying therapeutic drugs.This work was supported by grants to Seb Oltean from British Heart Foundation (PG/15/53/31371), Richard Bright VEGF Research Trust and Diabetes UK (17/000568). These grants include funds for Open Access publishing

Assessment of Kidney Function in Mouse Models of Glomerular Disease

This is the final version. Available from JoVE via the DOI in this record.The use of murine models to mimic human kidney disease is becoming increasingly common. Our research is focused on the assessment of glomerular function in diabetic nephropathy and podocyte-specific VEGF-A knock-out mice; therefore, this protocol describes the full kidney work-up used in our lab to assess these mouse models of glomerular disease, enabling a vast amount of information regarding kidney and glomerular function to be obtained from a single mouse. In comparison to alternative methods presented in the literature to assess glomerular function, the use of the method outlined in this paper enables the glomerular phenotype to be fully evaluated from multiple aspects. By using this method, the researcher can determine the kidney phenotype of the model and assess the mechanism as to why the phenotype develops. This vital information on the mechanism of disease is required when examining potential therapeutic avenues in these models. The methods allow for detailed functional assessment of the glomerular filtration barrier through measurement of the urinary albumin creatinine ratio and individual glomerular water permeability, as well as both structural and ultra-structural examination using the Periodic Acid Schiff stain and electron microscopy. Furthermore, analysis of the genes dysregulated at the mRNA and protein level enables mechanistic analysis of glomerular function. This protocol outlines the generic but adaptable methods that can be applied to all mouse models of glomerular disease

RESEARCHES RELATED TO THE CHEMICAL FIGHT OF THE COLORADO BUG LEPTINOTARSA DECEMLINEATA SAY

Between 1999-2002, Colorado bug fight experiences were annually organized in Cimpenesti. Experimental fields were organized on the land of certain cultivators of the area. The best results in fighting the Colorado bug were obtained with the following products: 290 FS Prestige – 0.8 l/ton; 480 SC Calypso – 80 ml/ha; SC 200 Confidor – 160 ml/ha; EC 10 Rimon – 0.25 l/ha; SC 150 Nomolt – 0.15 l/ha; D 50/500 Nurelle – 0.5 l/ha; SP 20 Mospilan – 0.06 l/ha

Gravitational Waves from Preheating in M-flation

Matrix inflation, or M-flation, is a string theory motivated inflationary model with three scalar field matrices and gauge fields in the adjoint representation of the $\mathbf{U}(N)$ gauge group. One of these $3N^2$ scalars appears as the effective inflaton while the rest of the fields (scalar and gauge fields) can play the role of isocurvature fields during inflation and preheat fields afterwards. There is a region in parameter space and initial field values, "the hilltop region," where predictions of the model are quite compatible with the recent Planck data. We show that in this hilltop region, if the inflaton ends up in the supersymmetric vacuum, the model can have an embedded preheating mechanism. Couplings of the preheat modes are related to the inflaton self-couplings and therefore are known from the CMB data. Through lattice simulations performed using a symplectic integrator, we numerically compute the power spectra of gravitational waves produced during the preheating stage following M-flation. The preliminary numerical simulation of the spectrum from multi-preheat fields peaks in the GHz band with an amplitude $\Omega_{\mathrm{gw}}h^{2} \propto 10^{-16}$, suggesting that the model has concrete predictions for the ultra-high frequency gravity-wave probes. This signature could be used to distinguish the model from rival inflationary modelsComment: v1:27 pages and 7 figures; v2: typos corrected; v3: references added; v4: matched the JCAP versio

Modulation of Receptor Tyrosine Kinase Activity through Alternative Splicing of Ligands and Receptors in the VEGF-A/VEGFR Axis.

This is the final version. Available from MDPI via the DOI in this record.Vascular endothelial growth factor A (VEGF-A) signaling is essential for physiological and pathological angiogenesis. Alternative splicing of the VEGF-A pre-mRNA gives rise to a pro-angiogenic family of isoforms with a differing number of amino acids (VEGF-Axxxa), as well as a family of isoforms with anti-angiogenic properties (VEGF-Axxxb). The biological functions of VEGF-A proteins are mediated by a family of cognate protein tyrosine kinase receptors, known as the VEGF receptors (VEGFRs). VEGF-A binds to both VEGFR-1, largely suggested to function as a decoy receptor, and VEGFR-2, the predominant signaling receptor. Both VEGFR-1 and VEGFR-2 can also be alternatively spliced to generate soluble isoforms (sVEGFR-1/sVEGFR-2). The disruption of the splicing of just one of these genes can result in changes to the entire VEGF-A/VEGFR signaling axis, such as the increase in VEGF-A165a relative to VEGF-A165b resulting in increased VEGFR-2 signaling and aberrant angiogenesis in cancer. Research into this signaling axis has recently focused on manipulating the splicing of these genes as a potential therapeutic avenue in disease. Therefore, further research into understanding the mechanisms by which the splicing of VEGF-A/VEGFR-1/VEGFR-2 is regulated will help in the development of drugs aimed at manipulating splicing or inhibiting specific splice isoforms in a therapeutic manner.British Heart FoundationDiabetes U

RESEARCHES RELATED TO THE CHEMICAL FIGHT OF THE COLORADO BUG LEPTINOTARSA DECEMLINEATA SAY

Between 1999-2002, Colorado bug fight experiences were annually organized in Cimpenesti. Experimental fields were organized on the land of certain cultivators of the area. The best results in fighting the Colorado bug were obtained with the following products: 290 FS Prestige – 0.8 l/ton; 480 SC Calypso – 80 ml/ha; SC 200 Confidor – 160 ml/ha; EC 10 Rimon – 0.25 l/ha; SC 150 Nomolt – 0.15 l/ha; D 50/500 Nurelle – 0.5 l/ha; SP 20 Mospilan – 0.06 l/ha

Entropy theorems in classical mechanics, general relativity, and the gravitational two-body problem

In classical Hamiltonian theories, entropy may be understood either as a statistical property of canonical systems, or as a mechanical property, that is, as a monotonic function of the phase space along trajectories. In classical mechanics, there are theorems which have been proposed for proving the non-existence of entropy in the latter sense. We explicate, clarify and extend the proofs of these theorems to some standard matter (scalar and electromagnetic) field theories in curved spacetime, and then we show why these proofs fail in general relativity; due to properties of the gravitational Hamiltonian and phase space measures, the second law of thermodynamics holds. As a concrete application, we focus on the consequences of these results for the gravitational two-body problem, and in particular, we prove the non-compactness of the phase space of perturbed Schwarzschild-Droste spacetimes. We thus identify the lack of recurring orbits in phase space as a distinct sign of dissipation and hence entropy production.Comment: 39 pages, 3 figures; v2: version to appear in Phys. Rev. D, references adde

CHEMICAL CONTROL OF BEAN WEEVIL, ACANTHOSCELIDES OBTECTUS SAY IN STORAGE CONDITION

The paper presents the positive results obtained by some pesticides applied against the bean weevil - Acanthoscelides obtectus Say, after a synthetic rewiew of the potential chemical methods which may be used in the chemical control of the insectes harmful to the stored bean seeds. The chemical control is realised treatments wits syntetic pyrethroid (permetrin, deltametrin) and organophosphoric insecticides (malation, pirimifos metil, fenitrotion and chlrorpirifos-metil)

CHEMICAL CONTROL OF BEAN WEEVIL, ACANTHOSCELIDES OBTECTUS SAY IN STORAGE CONDITION

The paper presents the positive results obtained by some pesticides applied against the bean weevil - Acanthoscelides obtectus Say, after a synthetic rewiew of the potential chemical methods which may be used in the chemical control of the insectes harmful to the stored bean seeds. The chemical control is realised treatments wits syntetic pyrethroid (permetrin, deltametrin) and organophosphoric insecticides (malation, pirimifos metil, fenitrotion and chlrorpirifos-metil)