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Behavior of pesticides in water-sediment systems

Many kinds of pesticides and their metabolites have been detected in various water bodies and bottom sediments even under normal agricultural practices (USEPA 1997; Gilliom 2001; Martin et al. 2003). Pesticides can potentially enter surface water by several routes and be partitioned to bottom sediments even if they are appropriately used for crop protection in accordance with good agricultural practices. Spray drift, surface runoff, and field drainage are relevant routes of exposure, and contamination via groundwater discharge may occur. The direct application of pesticides to water occures either for rice protection in a paddy field or for control of undesirable emergent vegetation of weeds and algae.

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Isoxazole – Wikipedia,
Isoxazole | C3H3NO – PubChem

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Novel small molecule targeting the hemagglutinin stalk of influenza viruses

Combating influenza is one of the perennial global public health issues to be managed. Antiviral drugs are useful for the treatment of influenza in the absence of an appropriate vaccine. However, the appearance of resistant strains necessitates a constant search for new drugs. In this study, we investigated novel anti-influenza drug candidates using in vitro and in vivo assays. We identified anti-influenza hit compounds using a high-throughput screening method with a green fluorescent protein-tagged recombinant influenza virus. Through subsequent analyses of their cytotoxicity and pharmacokinetic properties, one candidate (IY7640) was selected for further evaluation. In a replication kinetics analysis, IY7640 showed greater inhibitory effects during the early phase of viral infection than the viral neuraminidase inhibitor oseltamivir. In addition, we observed that hemagglutinin (HA)-mediated membrane fusion was inhibited by IY7640 treatment, indicating that the HA stalk region, which is highly conserved across various (sub)types of influenza viruses, May be the molecular target of IY7640. In an escape mutant analysis in cells, amino acid mutations were identified at the HA stalk region of the 2009 pandemic H1N1 (pH1N1) virus. Even though the in vivo efficacy of IY7640 did not reach complete protection in a lethal challenge study in mice, these results suggest that IY7640 has potential to be developed as a new type of anti-influenza drug. IMPORTANCE Anti-influenza drugs with broad-spectrum efficacy against antigenically diverse influenza viruses can be highly useful when no vaccines are available. To develop new anti-influenza drugs, we screened a number of small molecules and identified a strong candidate, IY7640. When added at the time of or after influenza virus infection, IY7640 was observed to successfully inhibit or reduce viral replication in cells. We subsequently discovered that IY7640 targets the stalk region of the influenza HA protein, which exhibits a relatively high degree of amino acid sequence conservation across various (sub)types of influenza viruses. Furthermore, IY7640 was observed to block HA-mediated membrane fusion of H1N1, H3N2, and influenza B viruses in cells. Although it appears less effective against strains other than H1N1 subtype viruses in a challenge study in mice, we suggest that the small molecule IY7640 has potential to be optimized as a new anti-influenza drug.

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Isoxazole – Wikipedia,
Isoxazole | C3H3NO – PubChem

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Cocrystals of zonisamide: Physicochemical characterization and sustained release solid forms

We report four cocrystals of the antiepileptic drug, zonisamide (ZNS), which encounters half-life fluctuation when administered adjunctly with other antiepileptic drugs. Single crystals for two of the novel cocrystals of ZNS were successfully prepared from solvent evaporation experiments and their crystal structures were determined. Pharmaceutically acceptable cocrystals were analyzed for their dissolution rate, solubility and stability to draw conclusions on the impact of cocrystallization on the physicochemical properties of ZNS. It was found that the cocrystals showed lower solubility and dissolution rates and offer potential benefits in the development of sustained release formulations of ZNS which could address issues regarding its half-life fluctuation. Recent attempts to explore newer therapeutic applications have suggested ZNS as a potential drug for weight loss management. In this regard, the cocrystal of ZNS with caffeine, which has also been used in weight loss management, promises potential applications in the development of a novel fixed-dose combination drug which could offer synergistic therapeutic benefits in the treatment of obesity.

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Isoxazole – Wikipedia,
Isoxazole | C3H3NO – PubChem

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Stress-dependent miR-980 regulation of Rbfox1/A2bp1 promotes ribonucleoprotein granule formation and cell survival

Upon stress, profound post-transcriptional adjustments of gene expression occur in spatially restricted, subcellular, membraneless compartments, or ribonucleoprotein (RNP) granules, which are formed by liquid phase separation of RNA-binding proteins with low complexity sequence domains (LCDs). Here, we show that Rbfox1 is an LCD-containing protein that aggregates into liquid droplets and amyloid-like fibers and promiscuously joins different nuclear and cytoplasmic RNP granules. Using Drosophila oogenesis as an in vivo system for stress response, we demonstrate a mechanism by which Rbfox1 promotes cell survival. The stress-dependent miRNA miR-980 acts to buffer Rbfox1 levels, since it targets only those Rbfox1 transcripts that contain extended 3?UTRs. Reduced miR-980 expression during stress leads to increased Rbfox1 levels, widespread formation of various RNP granules, and increased cell viability. We show that human RBFOX proteins also contain multiple LCDs and form membraneless compartments, suggesting that the RNP granule-linked control of cellular adaptive responses may contribute to a wide range of RBFOX-associated pathologies in humans.

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Isoxazole – Wikipedia,
Isoxazole | C3H3NO – PubChem

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T-type calcium channel blockers: a patent review (2012?2018)

Introduction: T-type calcium channels are attractive targets for potential treatment of epilepsy inflammatory or neuropathic pain, insomnia, Parkinson?s disease, and cancer. Three isoforms having different biophysical functions are expressed in peripheral and central nerve. Since the withdrawal of mibefradil, the first compound marketed for selective T-type calcium channel blockade, extensive efforts have been made to identify more selective T-type calcium channel blockers. Areas covered: This review covers the 43 patents describing ?organic small molecules as T-type calcium channel blockers?-published since 2012. The most recent similar patent review was published in 2011. Information from a recent review article and relevant research papers has been included, as well as biological data and clinical trial results where available. Expert opinion: Triazinone derivatives, carbazole compounds, and aryl triazole/imidazole amide derivatives display potent blockade activity alpha1H, alpha1G, and pan T-type calcium channel subtypes, respectively, though the specificity of the letter is still unsatisfactory. Nonetheless, improvements seen in the efficacy of compounds targeting alpha1H T-type calcium channels indicate significant progress. Ongoing clinical trials are for the candidates Z944 (Phase II) and ACT-709478 (Phase II) appear promising. These studies may lead to a new generation of inhibitors with higher selectivity, improved physicochemical properties, and reduced side effects.

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Isoxazole – Wikipedia,
Isoxazole | C3H3NO – PubChem

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Dihydroorotate dehydrogenase in oxidative phosphorylation and cancer

Dihydroorotate dehydrogenase (DHODH) is an enzyme of the de novo pyrimidine synthesis pathway that provides nucleotides for RNA/DNA synthesis essential for proliferation. In mammalian cells, DHODH is localized in mitochondria, linked to the respiratory chain via the coenzyme Q pool. Here we discuss the role of DHODH in the oxidative phosphorylation system and in the initiation and progression of cancer. We summarize recent findings on DHODH biology, the progress made in the development of new, specific inhibitors of DHODH intended for cancer therapy, and the mechanistic insights into the consequences of DHODH inhibition.

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Isoxazole – Wikipedia,
Isoxazole | C3H3NO – PubChem

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Gold-catalyzed oxidation of alkynes

Although both alkynes and alkenes form stable complexes with gold,[1] alkynes are selectively activated by gold(I) in the presence of alkenes or other functional groups.[2] This high alkynophilicity of gold(I) actually reflects the higher reactivity of-alkyne gold(I) complexes over-alkene gold(I) complexes toward attack by a wide range of nucleophiles,[ 3] which is the basis for the surge in activity for synthetic applications based on the selective activation of alkynes in complex molecular settings.[2,4-6] The gold-catalyzed oxidation of alkynes takes place with oxidants with a highly polar X+-O-bond, such as sulfoxides and amine N-oxides,[7,8] which attack thealkyne gold(I) complex in a process similar to the addition of alcohols and water to alkynes, one of the prototypical transformations catalyzed by gold.[9-11] This addition reaction gives preferentially or exclusively products of Markovnikov addition[12,13] and can be performed with low catalyst loadings.[14] Two reviews have been published very recently covering developments in the gold(I)-catalyzed oxidation of alkynes.[7,8].

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Isoxazole – Wikipedia,
Isoxazole | C3H3NO – PubChem

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Synthesis, crystal structure, docking and antifungal activity of a new pyrazole acylurea compound

The title compound N-((3,5-dimethylphenyl)carbamoyl)-1-methyl-3-(trifluorome-thyl)-1H-pyrazole-4-carboxamide (C15H15F3N4O2) was synthesized, and its structure was confirmed by 1H NMR, H RMS and X-ray diffraction. It crystallizes in the triclinic system, space group P1 with a = 11.7147(5), b = 11.7935(5), c = 13.6620(5) A, alpha = 69.755(7), beta = 66.182(6), gamma = 72.100(7), Dc = 1.423 g/cm3, Z = 4, V = 1588.88(11) A3, the final R = 0.0347 and wR = 0.1005 for 7171 observed reflections with I > 2sigma(I). The preliminary biological test showed that the title compound has antifungal activities against Fusarium oxysporum, Pseudomonas syringae, Corynespora mazei and Botrytis cinerea at 100 mug/mL as 5.19%, 53.50%, 88.55% and 70.62%, respectively. The docking results indicated the hydrogen bonds formed between the compound and SHD.

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Isoxazole – Wikipedia,
Isoxazole | C3H3NO – PubChem

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Context-Dependent and Disease-Specific Diversity in Protein Interactions within Stress Granules

Stress granules (SGs) are transient ribonucleoprotein (RNP) aggregates that form during cellular stress and are increasingly implicated in human neurodegeneration. To study the proteome and compositional diversity of SGs in different cell types and in the context of neurodegeneration-linked mutations, we used ascorbate peroxidase (APEX) proximity labeling, mass spectrometry, and immunofluorescence to identify ?150 previously unknown human SG components. A highly integrated, pre-existing SG protein interaction network in unstressed cells facilitates rapid coalescence into larger SGs. Approximately 20% of SG diversity is stress or cell-type dependent, with neuronal SGs displaying a particularly complex repertoire of proteins enriched in chaperones and autophagy factors. Strengthening the link between SGs and neurodegeneration, we demonstrate aberrant dynamics, composition, and subcellular distribution of SGs in cells from amyotrophic lateral sclerosis (ALS) patients. Using three Drosophila ALS/FTD models, we identify SG-associated modifiers of neurotoxicity in vivo. Altogether, our results highlight SG proteins as central to understanding and ultimately targeting neurodegeneration. Interactions between stress granule proteins exist ahead of a stress response and candidate SG proteins modify disease phenotypes in vivo.

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Isoxazole – Wikipedia,
Isoxazole | C3H3NO – PubChem

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Synthesis of functionalized tetrasubstituted pyrazolyl heterocycles – A review

Heterocyclic chemistry constitutes an essential branch of organic chemistry and heterocycles are widely known to display an array of biological properties. Pyrazoles represent key structural motifs in heterocyclic chemistry and are present in a large number of biologically active molecules relevant to the pharmaceutical and agrochemical industries. Compounds incorporating the pyrazolyl structural unit are being developed in a wide variety of therapeutic areas including CNS, metabolic diseases, and oncology. The current review summarizes recent advances in the synthesis of tetrasubstituted pyrazoles. The contents are discussed in five sections: (a) 1,3-dipolar cycloadditions, (b) related 1,3-dipolar cycloadditions, (c) condensations, (d) allenylphosphonates, and (e) synthesis of fused pyrazole containing heterocycles.

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Isoxazole – Wikipedia,
Isoxazole | C3H3NO – PubChem