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Highly regio- and diastereoselective 3+2]-cycloadditions involving indolediones and alpha,beta-disubstituted nitroethylenes
No full textA highly diastereoselective 3 + 2]-cycloaddition strategy involving multiple oxindoles and several alpha,beta-disubstituted nitroethylenes is developed to access tetra-substituted alpha-spiropyrrolidine frameworks. A variety of alpha-amino acids were employed for the first time in order to generate azomethine ylides under thermal conditions, affording regioisomers 13 and 14 merely by changing the alpha-substituents (R = H and substituted carbons) of the alpha-amino acids. The reaction tolerates various sterically demanding, electron-rich and electron-deficient aryl and nitrogen substituents on glycines, oxindoles and nitroethylenes. The operational simplicity, such as the use of a metal-free and non-inert environment, the utilization of non-halogenated solvents and the ease of isolation, adhering to the principles of green chemistry, makes this process attractive for scale-up opportunities. The reaction delivers good yields (80-94%) and diastereoselectivities (up to 98 : 2) in favor of (cis,cis)-spirooxindoles, with opposite regioselectivity compared to beta-nitrostyrenes under identical conditions. Two spiropyrrolidine cycloadducts with unprotected amides exhibited significant activity against Gram-positive MRSA
Silicate, Oxide and Sulphide Trends in Neo-Archean Rocks from the Nilgiri Block, Southern India: the Role of Fluids During High-grade Metamorphism
No full textThe Nilgiri Block, southern India represents an exhumed section of lower, late Archean (2500 Ma) crust. The northern highlands of the Nilgiri Block are characterized by metagabbros with pyroxenite inlayers. A two-pyroxene granulite zone acts as a transition between the metagabbros and charnockites, which are exposed in the central and southern part of the Nilgiri highlands. Thermobarometry results indicate a SW-NE regional trend both in temperature (similar to 650-800 degrees C) and in pressure (700-1100 MPa) over the Nilgiri highlands. In the charnockites, composite rutile-ilmenite grains are the dominant oxide assemblage. In the two-pyroxene granulites, hemo-ilmenite-magnetite is dominant with coexisting rutile-ilmenite composite grains in a few samples in the vicinity of the boundary with the charnockites. In the metagabbros, hemo-ilmenite-magnetite is the dominant oxide assemblage. The principal sulphide mineral in the charnockite is pyrrhotite with minor pyrite-chalcopyrite exsolution lamellae or blebs. In the two-pyroxene granulites and the metagabbros, the principal sulphide assemblage consists of discrete pyrite grains with magnetite rims and pyrite-pyrrhotite-chalcocopyrite associations. From these observations, a specific oxidation trend is seen. The northern granulite-facies metagabbros and two-pyroxene granulites of the Nilgiri highlands are highly oxidized compared with the charnockites from the central and southern regions. This higher oxidation state is proposed to be the result of highly oxidizing agents (probably as SO3) in low H2O activity grain boundary NaCl saline fluids with a dissolved CaSO4 component present during granulite-facies metamorphism of the metagabbros and two-pyroxene granulites. Eventually these agents became more reducing, owing to the inherent buffering of the original tonalite-granodiorite granitoids at the graphite-CO2 buffer, such that S took the form of H2S during the granulite-facies metamorphism of the charnockites. At the same time, these saline fluids were also responsible the solid-state conversion of biotite and amphibole to orthopyroxene and clinopyroxene in the metagabbro, two-pyroxene granulite, and charnockite
Temozolomide induces activation of Wnt/beta-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy
No full textGlioblastoma (GBM) is the most aggressive type of glioma. Temozolomide (TMZ) is currently the drug of choice used for post-operative chemotherapy of GBM. However, the presence of intrinsic and acquired resistance hinders the success of chemotherapy. To understand the TMZ resistant mechanisms in glioma, we investigated the alterations in cellular signaling pathways by performing transcriptome analysis of TMZ treated glioma cells. Gene Set Enrichment Analysis (GSEA) indicated a significant enrichment of Wnt/beta-catenin signaling besides many other pathways in TMZ treated cells. Further, we demonstrate that TMZ treatment increased the activity from TOPflash reporter, (a Wnt responsive reporter), enhanced the levels of pGSK-3 beta (S9) and reduced the levels of p-beta-catenin (S33/37/T41) with a concomitant increase in transcript and protein levels of Wnt targets in a concentration and time-dependent manner. While TMZ treated cells did not show alteration in any of the Wnt ligands, PI3K inhibitor (LY294002) treatment repressed Akt activation and abolished the TMZ-mediated induction of Wnt/beta-catenin pathway. In addition, we show that Wnt/beta-catenin signaling activation by TMZ is independent of ATM/Chk2 pathway. Further, we also demonstrate the activation of mTOR pathway after TMZ treatment. Thus, our results demonstrate that activation of Wnt/beta-catenin pathway involves an ATM/Chk2- independent PI3K/Akt/GSK-3 cascade in TMZ treated cells and further provides mechanistic basis for the chemoresistance of glioma to TMZ
Rapid C-13 NMR hyperpolarization delivered from para-hydrogen enables the low concentration detection and quantification of sugars
No full textMonosaccharides, such as glucose and fructose, are important to life. In this work we highlight how the rapid delivery of improved C-13 detectability for sugars by nuclear magnetic resonance (NMR) can be achieved using the para-hydrogen based NMR hyperpolarization method SABRE-Relay (Signal Amplification by Reversible Exchange-Relay). The significant C-13 signal enhancements of 250 at a high field of 9.4 T, and 3100 at a low field of 1 T, enable the detection of trace amounts of these materials as well as the quantification of their tautomeric makeup. Using studies on C-13 and H-2 isotopically labelled agents we demonstrate how hyperpolarization lifetime (T-1) values can be extended, and how singlet states with long lifetimes can be created. The precise quantification of d-glucose-C-13(6)-d(7) at the millimolar concentration level is shown to be possible within minutes in conjunction with a linear hyperpolarized response as a function of concentration. In addition to the measurements using labelled materials, low concentration detection is also illustrated for millimolar samples with natural abundance C-13 where isomeric form quantification can be achieved with a single transient
Lock and key-based nanozyme model to understand the substituent effect on the hydrolysis of organophosphate-based nerve agents by Zr-incorporated cerium oxide
No full textNanozymes are efficient class of synthetic enzymes capable of performing multi-step redox sensitive enzyme mimetic reactions on their surface with high turnover frequency and recyclability. It has been shown that the introduction of vacancies on the CeO2 surface transforms it into phosphotriesterase-like mimetic nanozyme, which can be used for the hydrolysis of neurotoxic organophosphate-based nerve agents. Further, the introduction of Zr in CeO2 nanozyme provides structural stability along with generating vacancies in the surface which can perform simultaneously two-step hydrolysis of the nerve agents. Herein, we describe the reasons for the difference in the degradation pathways used for various substituted organophosphate substrates and the selectivity involved by Zr-incorporated CeO2 nanozyme resembling a lock-and-key fit enzyme model
Structural analysis of glutathionyl hemoglobin using native mass spectrometry
No full textGlutathionylation is an example of reversible post-translation modification of proteins where free and accessible cysteine residues of proteins undergo thiol-disulfide exchange with oxidized glutathione (GSSG). In general, glutathionylation occurs under the condition of elevated oxidative stress in vivo. In human hemoglobin, Cys93 residue of beta globin chain was found to undergo this oxidative modification. Glutathionyl hemoglobin (GSHb) was reported to act as a biomarker of oxidative stress under several clinical conditions such as chronic renal failure, iron deficiency anemia, hyperlipidemia, diabetes mellitus, Friedreich's ataxia, atherosclerosis. Previously we showed that the functional abnormality associated with six-fold tighter oxygen binding of GSHb supposedly attributed to the conformational transition of the deoxy state of GSHb towards oxy hemoglobin like conformation. In the present study, we investigated the structural integrity and overall architecture of the quaternary structure of GSHb using native mass spectrometry and ion mobility mass spectrometry platforms. The dissociation equilibrium constants of both tetramer/dimer (K-d1) and dimer/monomer equilibrium (K-d2) was observed to increase by 1.91 folds and 3.64 folds respectively. However, the collision cross-section area of the tetrameric hemoglobin molecule remained unchanged upon glutathionylation. The molecular dynamics simulation data of normal human hemoglobin and GSHb was employed to support our experimental findings
Rice husk SiO2 (NPs) supported-BO3H3: a highly active, solvent-free and recyclable catalyst to dihydropyrimidin-2(1H)ones-(thiones) and coumarin-3-carboxylic acid synthesis
No full text3,4-Dihydropyrimidin-2(1H)ones(thiones) (DHPM) and coumarin-3-carboxylic acid are obtained in excellent to good yield by employing green catalyst under solvent-free condition. The condensation of substituted arylaldehyde, 1,3-diketoester and urea/thiourea in the presence of green catalyst after 1 h of stirring at 50 degrees C resulted in DHPM. The reaction of substituted o-hydroxybenzaldehyde with Meldrum's acid in the presence of catalyst under sonication for a few minutes gave coumarin-3-carboxylic acid. Here, we have used Lewis acid catalyst RHA-SiO2(NPs)-BO3H3 derived from the agro-waste of rice husk, a heterogeneous catalyst for important organic scaffold synthesis. The reaction required low catalyst loading (1.2 mg) to achieve a target product under solvent-free condition. A series of other derivatives of heterogeneous catalysts synthesized are RHA-SiO2, RHA-SiO2(NPs), RHA-SiO2-BO3H3. We examined their catalytic activity in the synthesis of DHPM and coumarin-3-carboxylic acid. Only the reaction catalysed by RHA-SiO2(NPs)-BO3H3 gave excellent yield of the product. The final isolated pure product has been fully characterized by various spectroscopic methods and confirmed
Grain Boundary Processes in Strengthening, Weakening, and Superplasticity
No full textGrain boundaries provide strength to materials at low temperatures by impeding slip transfer and they weaken materials at high temperatures by intergranular creep processes such as grain boundary sliding (GBS) and diffusion creep. At very fine nanocrystalline grain sizes of <10 nm, it is possible to observe grain boundary weakening rather than strengthening at room temperature. Superplastic flow is observed in a wide range of materials, but the common phenomenology of a high strain rate sensitivity and extensive GBS may arise from varying importance of GBS accommodated by dislocations, diffusion creep, and interface-controlled diffusion creep. Thus, superplasticity in metals and ceramics involves GBS with dislocation accommodation and interface-controlled diffusion creep, respectively. It is recognized that grains retain their equiaxed shapes during diffusion creep by grain switching and grain growth. Ultrafine-grained and nanocrystalline materials with a high strain rate sensitivity of >0.3 deform with a large GBS contribution to total strain of approximate to 40-80%. There are a limited number of studies showing superplasticity in fine-grained high-entropy alloys, involving GBS accommodated by dislocations
Modulation of Indian monsoon by water vapor and cloud feedback over the past 22,000 years
No full textTo predict how monsoons will evolve in the 21st century, we need to understand how they have changed in the past. In paleoclimate literature, the major focus has been on the role of solar forcing on monsoons but not on the amplification by feedbacks internal to the climate system. Here we have used the results from a transient climate simulation to show that feedbacks amplify the effect of change in insolation on the Indian summer monsoon. We show that during the deglacial (22 ka to 10 ka) monsoons were predominantly influenced by rising water vapor due to increasing sea surface temperature, whereas in the Holocene (10 ka to 0 ka) cloud feedback was more important. These results are consistent with another transient simulation, thus increasing confidence despite potential model biases. We have demonstrated that insolation drives monsoon through different pathways during cold and warm periods, thereby highlighting the changing role of internal factors
