Late time afterglow observations reveal a collimated relativistic jet in the ejecta of the binary neutron star merger GW170817

The binary neutron star (BNS) merger GW170817 was the first astrophysical source detected in gravitational waves and multi-wavelength electromagnetic radiation. The almost simultaneous observation of a pulse of gamma-rays proved that BNS mergers are associated with at least some short gamma-ray bursts (GRBs). However, the gamma-ray pulse was faint, casting doubts on the association of BNS mergers with the luminous, highly relativistic outflows of canonical short GRBs. Here we show that structured jets with a relativistic, energetic core surrounded by slower and less energetic wings produce afterglow emission that brightens characteristically with time, as recently seen in the afterglow of GW170817. Initially, we only see the relatively slow material moving towards us. As time passes, larger and larger sections of the outflow become visible, increasing the luminosity of the afterglow. The late appearance and increasing brightness of the multi-wavelength afterglow of GW170817 allow us to constrain the geometry of its ejecta and thus reveal the presence of an off-axis jet pointing about 30 degrees away from Earth. Our results confirm a single origin for BNS mergers and short GRBs: GW170817 produced a structured outflow with a highly relativistic core and a canonical short GRB. We did not see the bright burst because it was beamed away from Earth. However, approximately one in 20 mergers detected in gravitational waves will be accompanied by a bright, canonical short GRB.Comment: Models updated with new data and added references. Accepted for publication in PRL, 8 pages, 7 figures and 1 table. A grid of models, jet properties, and python interpolating routine is available at http://www.science.oregonstate.edu/~lazzatid/cocoon.htm

Omega-3 fatty acids decrease CRYAB, production of oncogenic prostaglandin E-2 and suppress tumor growth in medulloblastoma

Aims: Medulloblastoma (MB) is one of the most common malignant central nervous system tumors of childhood. Despite intensive treatments that often leads to severe neurological sequelae, the risk for resistant relapses remains significant. In this study we have evaluated the effects of the omega 3-long chain polyunsaturated fatty acids (omega 3-LCPUFA) docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) on MB cell lines and in a MB xenograft model.Main methods: Effects of omega 3-LCPUFA treatment of MB cells were assessed using the following: WST-1 assay, cell death probes, clonogenic assay, ELISA and western blot. MB cells were implanted into nude mice and the mice were randomized to DHA, or a combination of DHA and EPA treatment, or to control group. Treatment effects in tumor tissues were evaluated with: LC-MS/MS, RNA-sequencing and immunohistochemistry, and tumors, erythrocytes and brain tissues were analyzed with gas chromatography.Key findings: omega 3-LCPUFA decreased prostaglandin E2 (PGE(2)) secretion from MB cells, and impaired MB cell viability and colony forming ability and increased apoptosis in a dose-dependent manner. DHA reduced tumor growth in vivo, and both PGE(2) and prostacyclin were significantly decreased in tumor tissue from treated mice compared to control animals. All omega 3-LCPUFA and dihomo-gamma-linolenic acid increased in tumors from treated mice. RNA-sequencing revealed 10 downregulated genes in common among omega 3-LCPUFA treated tumors. CRYAB was the most significantly altered gene and the downregulation was confirmed by immunohistochemistry.Significance: Our findings suggest that addition of DHA and EPA to the standard MB treatment regimen might be a novel approach to target inflammation in the tumor microenvironment

Fatty acid metabolism and the basis of brown adipose tissue function

Obesity has reached epidemic proportions, leading to severe associated pathologies such as insulin resistance, cardiovascular disease, cancer and type 2 diabetes. Adipose tissue has become crucial due to its involvement in the pathogenesis of obesity-induced insulin resistance, and traditionally white adipose tissue has captured the most attention. However in the last decade the presence and activity of heat-generating brown adipose tissue (BAT) in adult humans has been rediscovered. BAT decreases with age and in obese and diabetic patients. It has thus attracted strong scientific interest, and any strategy to increase its mass or activity might lead to new therapeutic approaches to obesity and associated metabolic diseases. In this review we highlight the mechanisms of fatty acid uptake, trafficking and oxidation in brown fat thermogenesis. We focus on BAT's morphological and functional characteristics and fatty acid synthesis, storage, oxidation and use as a source of energy

Using Magnetic Extractants for Removal of Pollutants from Water Via Magnetic Filtration

The objective of this research was the development of new magnetic methods for the removal of contaminants from water via magnetic filtration. These processes provide several advantages such as extremely rapid separations and remote operation that promotes safety and prevents health problems to workers. Since most of the pollutants in water are weakly magnetic or diamagnetic, they are not amenable to magnetic filtration. For this reason, magnetically-active extractants were synthesized that allow the separation of such species via magnetic filtration. In the first aspect of this research, novel composite materials were synthesized based on iron, hematite, or magnetite for removal of hydrocarbons. The surface of the iron and iron oxides were derivitized with alkylalkoxysilane reagents and siloxane polymers in order to provide hydrophobic active sites for hydrocarbons. All extractants demonstrated excellent performance and reduced the concentration of decane in spiked water to the parts per billon level. Indeed, some extractants showed a powerful ability to extract and remove decane concentration to less than 1 ppb. The second aspect involved the synthesis of coated magnetite nanoparticles prepared by treating magnetite nanoparticles with amino- or mercaptomethoxy-silane. The aminosilsesquioxane extractant was functionalized by a pyridine group. The performance of the synthesized extractants was investigated for the removal of radioactive substances (uranium) and heavy metals (mercury and copper) from water. It was found that the resulting materials were highly effective for purifying water contains these toxic metal ions. In the case of magnetite nanoparticles coated with diaminosilane, the uranium uptake can be as high as 125 % by weight. Finally, Novel composite and nanocomposite materials were determined to be excellent single component magnetic filtration aids. The synthesized extractants can also be used for other contaminants and might have other potential applications (e.g. catalysts, drug delivery agents)Chemistry Departmen

Design, synthesis and pharmacological studies of structural analogues modeled on bioactive natural products

2009 - 2010Microsomal prostaglandin E2 synthase-1 (mPGES-1) is the enzyme responsible for the conversion of the cyclooxygenase (COX)-derived prostaglandins (PG)H2 into PGE2. This enzyme is deeply involved in different pathologies; in fact it is over-expressed in several inflammatory disorders[1] as well as in some human tumours.[2;3] Hence, the inhibition of mPGES-1 has been proposed as a promising approach for the development of safer drugs in inflammatory disorders, devoid of classical NSAID side effects.[4] Indeed, this enzyme is responsible for the biosynthesis of inducible PGE2 as a response to inflammatory stimuli[5] whereas it doesn’t affect constitutive PGE2 involved in crucial physiological functions. Today two are the main approaches employed in the inhibition of mPGES-1 activity.[6] The first consists in the negative modulation of its expression, while the second one concerns the direct and selective inhibition of the enzyme. In order to identify novel molecules able to block mPGES-1, in the first part of this project we focused our attention on the design and synthesis of molecules able to inhibit the expression of our target enzyme. Specifically, as first task we decided to undertake the structural optimization of a γ-hydroxybutenolide related to petrosaspongiolide M (PM) 5, compound 6, that showed to be a potent negative modulator of mPGES-1 expression (IC50 = 1.80 μM).[7;8] In the course of our investigation we identified two new hits that revealed an increased activity compared to the parent molecule 6, compounds 30 (IC50 = 0.79 μM) and 31e (IC50 = 0.85 μM).[9] Encouraged by these results, in order to amplify the chemical diversity of the γ-hydroxybutenolide scaffold and identify new lead structures able to inhibit mPGES-1 expression, we decided to develop a new collection of PM-derivatives featuring amido-aromatic portions linked to the γ-hydroxybutenolide scaffold. These compounds are currently under biological investigations whose outcomes could suggest new guidelines useful in the discovery of more effective agents. As second task, we concentrated our efforts on the development of molecules able to directly interfere with mPGES-1. Owing to the lack of its crystallographic structure in protein data bank (PDB), we decided to choose, as model for our investigations, microsomal glutathione transferase 1 (MGST-1), an enzyme belonging to membrane associated proteins in eicosanoid and gluthatione metabolism (MAPEG) family and showing a high homology sequence with our selected target.[10] On the basis of virtual screening outcomes, we designed and synthesized a collection of potential mPGES-1 inhibitors based on 1,4-disubstituted triazole moiety, a scaffold extensively employed in drug discovery that can be obtained through click chemistry approach, a powerful tool for the rapid exploration of the chemical universe based on practical and reliable chemical reactions. The biological evaluation of these compounds allowed us to individuate three new potential anti-inflammatory agents: (I) compound 54 displaying selectivity for mPGES-1 with an IC50 value of 3.2 μM, (II) compound 70 that dually inhibits 5-lipoxygenase (5-LO) and mPGES-1 and (III) compound 57 acting as 5-lipoxygenase-activating protein (FLAP) inhibitor (IC50 = 0.4 μM).[11] On the basis of these results, as last task of this project, we directed our attention on the new hit 54, emerged as a selective inhibitor of mPGES-1. In more details, on the basis of the suggestions coming from both the biological screening and the 3D model of interaction with MGST-1, aiming at improving its biological activity, we decided to rely on some well-reasoned structural changes of the basic molecule in order to enhance the binding affinity for the target enzyme. In this perspective, a new collection of triazole derivatives has been efficiently synthesized and their biological profile is currently under investigation. [edited by author]IX n.s