Deciphering the Curly Arrow Representation and Electron Flow for the 1,3-Dipolar Rearrangement between Acetonitrile Oxide and (1S,2R,4S)‑2-Cyano-7-oxabicyclo[2.2.1]hept-5-en-2-yl Acetate Derivatives

This study is focused on describing the molecular mechanism beyond the molecular picture provided by the evolution of molecular orbitals, valence bond structures along the reaction progress, or conceptual density functional theory. Using bonding evolution theory (BET) analysis, we have deciphered the mechanism of the 1,3-dipolar rearrangement between acetonitrile oxide and (1S,2R,4S)-2-cyano-7-oxabicyclo[2.2.1]hept-5-en-2-yl acetate derivatives. The BET study revealed that the formation of the C−C bond takes place via a usual sharing model before the O−C one that is also formed in the halogenated species through a not very usual sharing model. The mechanism includes depopulation of the electron density at the N−C triple bond and creation of the V(N) and V(C) monosynaptic basins, depopulation of the former C−C double bond with the creation of V(C,C) basins, and final formation of the V(O,C) basin associated with the O−C bond. The topological changes along the reaction pathway take place in a highly synchronous way. BET provides a convenient quantitative method for deriving curly arrows and electron flow representation to unravel molecular mechanisms

The radical character of the acenes: A density matrix renormalization group study

We present a detailed investigation of the acene series using high-level wavefunction theory. Our ab-initio Density Matrix Renormalization Group algorithm has enabled us to carry out Complete Active Space calculations on the acenes from napthalene to dodecacene correlating the full pi-valence space. While we find that the ground-state is a singlet for all chain-lengths, examination of several measures of radical character, including the natural orbitals, effective number of unpaired electrons, and various correlation functions, suggests that the longer acene ground-states are polyradical in nature.Comment: 10 pages, 8 figures, supplementary material, to be published in J. Chem. Phys. 127, 200

RIP1-HAT1-SirT complex identification and targeting in treatment and prevention of cancer

Purpose: Alteration in cell death is a hallmark of cancer. A functional role regulating survival, apoptosis, and necroptosis has been attributed to RIP1/3 complexes.Experimental Design: We have investigated the role of RIP1 and the effects of MC2494 in cell death induction, using different methods as flow cytometry, transcriptome analysis, immunoprecipitation, enzymatic assays, transfections, mutagenesis, and in vivo studies with different mice models.Results: Here, we show that RIP1 is highly expressed in cancer, and we define a novel RIP1/3-SIRT1/2-HAT1/4 complex. Mass spectrometry identified five acetylations in the kinase and death domain of RIP1. The novel characterized pan-SIRT inhibitor, MC2494, increases RIP1 acetylation at two additional sites in the death domain. Mutagenesis of the acetylated lysine decreases RIP1-dependent cell death, suggesting a role for acetylation of the RIP1 complex in cell death modulation. Accordingly, MC2494 displays tumor-selective potential in vitro, in leukemic blasts ex vivo, and in vivo in both xenograft and allograft cancer models. Mechanistically, MC2494 induces bona fide tumor-restricted acetylated RIP1/caspase-8-mediated apoptosis. Excitingly, MC2494 displays tumor-preventive activity by blocking 7,12-dimethylbenz(α)anthracene-induced mammary gland hyperproliferation in vivoConclusions: These preventive features might prove useful in patients who may benefit from a recurrence-preventive approach with low toxicity during follow-up phases and in cases of established cancer predisposition. Thus, targeting the newly identified RIP1 complex may represent an attractive novel paradigm in cancer treatment and prevention

Studies on High Density Planting and Nutrient Requirement of Banana in Different States of India

An experiment was conducted under the ICAR-All India Coordinated Research Project on Fruits to study the high-density planting (HDP) and nutrient requirement of banana at six research centres across the country, including Bhubaneswar (Orissa), Gandevi (Gujarat), Jalgaon (Maharashtra), Jorhat (Assam), Kannara (Kerala) and Mohanpur (West Bengal) to enable higher productivity of banana and profit to farmers. The objective of this study was to explore the possibility of increasing productivity through the intervention of only per unit plant population (through planting system) and level of nutrition, but without any interference to the regional choices of variety (eg., choice variety Nendran for Kerala or Martaman for West Bengal), production system (mono/poly- clone, single/multi-year plantation, and POP of respective states), for which national productivity ranges are much skewed also. Results indicated that intervention of only plant density could increase the productivity of banana within the existing system of production and choice of a variety of different regions or states. The experiment was laid out in RBD with four planting densities (S1P2, S1P3, S2P2 and S2P3, where S1=2m x 3m, S2=1.8m x 3.6m, P2=2 suckers/hill, P3=3 suckers/hill), three nutrition levels (F1, F2 and F3 , which is 100%, 75% and 50% of RDF) and one with region-specific conventional planting density and nutrition (100% of RDF) practices as control. The results of this experiment showed that HDP (S1P3, 5000 plants /ha) in banana, accommodating three suckers per hill at 2m x 3m spacing increased productivity over the conventional system at the Bhubaneswar, Gandevi, Jorhat, Kannara and Mohanpur centres. The increase in productivity due to HDP (5,000/ha) over control was 28.9% (RDF 25%) to 50.6% (RDF 100%) at Bhubaneswar, 15.2% (RDF 25%) to 21.9% (RDF 100%) at Gandevi, 4.0% (RDF 25%) to 7.4% (RDF 100%) at Jorhat, 33.5% (RDF 25%) to 43.5% (RDF 100%) at Kannara and 46.5% (RDF 25%) to 79.0% (RDF 100%) at Mohanpur centre. The nutrient requirement under HDP was 100% RDF at Kannara, 75% RDF at Bhubaneswar and Mohanpur and 50% RDF at Gandevi and Jorhat centres, which indicates a saving in cost of fertilizer input by 25% -50%. It is, therefore, recommended for HDP (5000 plants/ha) in banana, accommodating three suckers per hill at 2m x 3m (6.6 ft x 3.8 ft) spacing with 50% RDF in the agro-climatic regions of Gandevi and Jorhat, with 75% RDF in the agro-climatic regions of Bhubaneswar and Mohanpur and with 100% RDF in the agro-climatic region of Kannara in order to ensure higher productivity and profit to farmers

A Phase 1 study of the novel gamma-secretase inhibitor PF-03084014 in patients with T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma

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Polymorphisms in MGP gene and their association with lead toxicity

Matrix γ-carboxy glutamic acid protein (MGP) is a 10-kDa secreted protein containing five residues of the vitamin K-dependent calcium binding amino acid γ-carboxyglutamic acid (Gla). This study was carried out to examine the effects of MGP gene promoter polymorphism (T-138C) on blood lead levels (BLL) and hematological parameters in 113 battery manufacturing unit workers occupationally exposed to lead and 102 controls. Genotypes for the MGP T-138C polymorphism were determined by PCR and restriction fragment length digestion. BLL were determined by Anode Stripping Voltammetry using ESA Model 3010B Lead analyzer. Complete blood picture (CBP) was analyzed using ADVIA Cell counter for each sample. The frequencies of MGP–TT, CT and CC genotypes in our population were 38.6%, 44.3%, and 17.2%, respectively. The frequencies for T and C alleles were 0.612 and 0.386, respectively. Although BLL did not differ significantly among genotypes; they were higher in workers with TT/CT genotype compared to CC genotype subjects (76–88 μg/dL vs 22–45 μg/dL, p > 0.05). About 29.2% of volunteers (n = 33) from the occupationally exposed group had hemoglobin levels below 10.0 gms/dl. There was no significant difference in total white cell count and platelet count between occupational and non-exposed groups. The possible role of SNPs in the promoter region of MGP gene with relation to lead toxicity was investigated for the first time in the Indian population; although significance could not be achieved in this study, further assessments over a larger population size may help in better understanding of the consequences of lead exposure

International Veterinary Epilepsy Task Force consensus proposal: Medical treatment of canine epilepsy in Europe

In Europe, the number of antiepileptic drugs (AEDs) licensed for dogs has grown considerably over the last years. Nevertheless, the same questions remain, which include, 1) when to start treatment, 2) which drug is best used initially, 3) which adjunctive AED can be advised if treatment with the initial drug is unsatisfactory, and 4) when treatment changes should be considered. In this consensus proposal, an overview is given on the aim of AED treatment, when to start long-term treatment in canine epilepsy and which veterinary AEDs are currently in use for dogs. The consensus proposal for drug treatment protocols, 1) is based on current published evidence-based literature, 2) considers the current legal framework of the cascade regulation for the prescription of veterinary drugs in Europe, and 3) reflects the authors’ experience. With this paper it is aimed to provide a consensus for the management of canine idiopathic epilepsy. Furthermore, for the management of structural epilepsy AEDs are inevitable in addition to treating the underlying cause, if possible

Does Compound I Vary Significantly between Isoforms of Cytochrome P450?

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