Valine

The unimolecular chemistry of [Cu(II)AA(AA – H)]+ complexes, composed of an intact and a deprotonated amino acid (AA) ligand, have been probed in the gas phase by tandem and multistage mass spectrometry in an electrospray ionization quadrupole ion trap mass spectrometer. The amino acids examined include Gly, Ala, Val, Leu, Ile, t-Leu and Phe. Upon collisionally-activated dissociation (CAD), the [Cu(II)AA(AA – H)]+ complexes undergo decarboxylation with simultaneous reduction of Cu(II) to Cu(I); during this process, a radical site is created at the α-carbon of the decarboxylated ligand (H2N1 – •CαH – CβH2 – R; R = side chain substituent). The radical site is able to move along the backbone of the decarboxylated amino acid to form two new radicals (HN1• – CαH2 – CβH2–R and H2N1 – CαH2 – •CβH – R). From the complexes of Gly and t-Leu, only Cα and N1 radicals can be formed. The whole radical ligand can be lost to form [Cu(I)AA]+ from these three isomeric radicals. Alternatively, further...

BRAF(V600E)-mediated MAPK pathway activation is associated in melanoma cells with IFNAR1 downregulation. IFNAR1 regulates melanoma cell sensitivity to IFNα, a cytokine used for the adjuvant treatment of melanoma. These findings and the limited therapeutic efficacy of BRAF-I prompted us to examine whether the efficacy of IFNα therapy of BRAF(V600E) melanoma can be increased by its combination with BRAF-I. BRAF/NRAS genotype, ERK activation, IFNAR1, and HLA class I expression were tested in 60 primary melanoma tumors from treatment-naive patients. The effect of BRAF-I on IFNAR1 expression was assessed in three melanoma cell lines and in four biopsies of BRAF(V600E) metastases. The antiproliferative, pro-apoptotic and immunomodulatory activity of BRAF-I and IFNα combination was tested in vitro and in vivo utilizing three melanoma cell lines, HLA class I-MA peptide complex-specific T-cells and immunodeficient mice (5 per group for survival and 10 per group for tumor growth inhibition). ...

The emergence of different drug resistant strains of HIV-1 reverse transcriptase (HIV RT) remains of prime interest in relation to viral pathogenesis as well as drug development. Amongst those mutations, M184V was found to cause a complete loss of ligand fitness. In this study, we report the first account of the molecular impact of M184V mutation on HIV RT resistance to 3TC (lamivudine) using an integrated computational approach. This involved molecular dynamics simulation, binding free energy analysis, principle component analysis (PCA) and residue interaction networks (RINs). Results clearly confirmed that M184V mutation leads to steric conflict between 3TC and the beta branched side chain of valine, decreases the ligand (3TC) binding affinity by ∼7 kcal mol(-1) when compared to the wild type, changes the overall conformational landscape of the protein and distorts the native enzyme residue-residue interaction network. The comprehensive molecular insight gained from this study sho...

1. The effects of the N-methyl-D-aspartate (NMDA) antagonist, D-2-amino-5-phosphonovalerate (APV) were examined on synaptic responses evoked by high-frequency stimulation of the Schaffer collateral-commissural pathway, in the presence of Mg2+ (1 or 2 mM) and functional synaptic inhibition. 2. The synaptic response evoked by 100 Hz stimulation comprised fast excitatory postsynaptic potentials (EPSPs) evoked by each shock and a slow depolarization. APV reduced the size of the depolarization without depressing the fast EPSPs. 3. The mean (+/- 1 S.E.) amplitude of the APV-sensitive component (3.0 +/- 0.3 mV), evoked by 100 Hz stimulation at membrane potentials near rest, was invariably smaller than the first fast EPSP (9.8 +/- 0.7 mV). Both of these synaptic components had similar thresholds and increased in amplitude as the stimulus intensity was raised. There was a positive correlation between the amplitude of the two components (r = 0.57, P less than 0.01). 4. The amplitude of the AP...

Tools-4-Metatool (T4M) is a suite of web-tools, implemented in PERL, which analyses, parses, and manipulates files related to Metatool. Its main goal is to assist the work with Metatool. T4M has two major sets of tools: Analysis and Compare. Analysis visualizes the results of Metatool (convex basis, elementary flux modes, and enzyme subsets) and facilitates the study of metabolic networks.

The competitive absorption of blood plasma components including fibrinogen (FG), bovine serum albumin (BSA), and platelet-rich plasma (PRP) on l-valine-based poly(ester urea) (PEU) surfaces were investigated. Using four different PEU polymers, possessing compositionally dependent trends in thermal, mechanical, and critical surface tension measurements, water uptake studies were carried out to determine in vitro behavior of the materials. Quartz crystal microbalance (QCM) measurements were used to quantify the adsorption characteristics of PRP onto PEU thin films by coating the surfaces initially with FG or BSA. Pretreatment of the PEU surfaces with FG inhibited the adsorption of PRP and BSA decreased the absorption 4-fold. In vitro studies demonstrated that cells cultured on l-valine-based PEU thin films allowed attachment and spreading of rat aortic cells. These measurements will be critical toward efforts to use this new class of materials in blood-contacting biomaterials applicat...

Ophthalmic herpes simplex viral keratitis (HSVK) is responsible for a range of ocular manifestations from superficial epithelial disease to stromal keratitis and endotheliitis. The Herpetic Eye Disease Study (HEDS) has guided the management of herpetic eye disease for almost twenty years, but newer medications such as valacyclovir are now available and are considered to have better bioavailability than acyclovir. In this review, we examine the existing evidence on the pathogenesis of different HSVK disease modalities and the role of oral and topically administered antiviral drugs in the treatment of herpes simplex viral keratitis.

Introduction: Mastocytosis is a clonal mast cell proliferative disease, devided into cutaneous and systemic forms. The characteristic symptoms are caused by neoplastic mast cell infiltrations in different organs and/or the release of mediators. Aim: The aim of the authors was to summarize their clinical observations in patients with mastocytosis. Method: 22 adult patients diagnosed consecutively with mastocytosis were enrolled in the study. Skin and bone marrow biopsies were taken to establish the diagnosis and perform c-KIT mutation (D816V) analysis. Results: One of the 22 patients had teleangiectasia macularis eruptiva perstans, while 20/22 patients had urticaria pigmentosa. All patients had cutaneous lesions. In 12 patients iliac crest biopsy was performed and 9 of them had bone marrow involvement, classified as indolent systemic mastocytosis. The c-kit mutation D816V was found in one subject both in skin and bone marrow samples. The patients were treated with antihistamine, PUVA...

There are several new and emerging medication interventions for both the acute and maintenance treatment phases of schizophrenia. Recently approved are 2 new dopamine receptor partial agonists, brexpiprazole and cariprazine, as well as 2 new long-acting injectable antipsychotic formulations, aripiprazole lauroxil and 3-month paliperidone palmitate. Although differences in efficacy compared to other available choices are not expected, the new oral options offer different tolerability profiles that may be attractive for individual patients who have had difficulties with older medications. The new long-acting injectable options provide additional flexibility in terms of increasing the time interval between injections. In Phase III of clinical development is a novel antipsychotic, lumateperone (ITI-007), that appears to have little in the way of significant adverse effects. Deutetrabenazine and valbenazine are agents in Phase III for the treatment of tardive dyskinesia, a condition that...

This is the first description of the application of molten tetrabutylammonium bromide (TBAB) in the presence of triphenyl phosphite (TPP) for the synthesis of novel polyamides (PAs). Monomer diacid, 5-[(9,10-dihydro-9,10-ethanoanthracene-11,12-dicarboximido)-3-methylbutanoylamino]isophthalic acid (4), having anthracenic and amino acid S-valine pendant group, was synthesized in four steps. Several novel, optically active PAs were prepared by the condensation of synthesized diacid monomer 4 with various aromatic diamines using two different techniques: a mixture of N-methyl-2-pyrrolidone (NMP)/TPP/pyridine/calcium chloride (method I) and combination of TPP with TBAB (method II). The main goal of the present paper was to prepare novel PAs in a green media by removal of toxic reagents. Therefore, TBAB/TPP was used as a novel, easy, safe and eco-friendly method for the preparation of aromatic PAs. This method is compared with the polymerization reaction under conventional solvent and in the case of TBAB as a new method, higher yields, inherent viscosities and thermally stable of PAs are gained. The resulting polymers showed good solubility in polar aprotic solvents such as dimethyl sulfoxide, NMP, N,N-dimethylacetamide and N,N-dimethylformamide. These polymers are characterized with respect to chemical structure and purity by means of specific rotation experiments, FT-IR, 1H NMR spectroscopy techniques and elemental analysis. The obtained PAs exhibit good thermal stability up to 335°C for 10% weight loss in nitrogen atmosphere and glass transition temperatures fell in the rang of 177-185°C.

Amyotrophic lateral sclerosis (ALS) is a fatal, progressive neurodegenerative disease characterized by the destruction of motor neurons in the spinal cord and brain. A subset of ALS cases are linked to dominant mutations in copper-zinc superoxide dismutase (SOD1). The pathogenic SOD1 variants A4V and G93A have been the foci of multiple studies aimed at understanding the molecular basis for SOD1-linked ALS. The A4V variant is responsible for the majority of familial ALS cases in North America, causing rapidly progressing paralysis once symptoms begin and the G93A SOD1 variant is overexpressed in often studied murine models of the disease. Here we report the three-dimensional structures of metal-free A4V and of metal-bound and metal-free G93A SOD1. In the metal-free structures, the metal-binding loop elements are observed to be severely disordered, suggesting that these variants may share mechanisms of aggregation proposed previously for other pathogenic SOD1 proteins.