Ligand and base additive effects on the reversibility of nucleophilic addition in palladium-catalyzed allylic aminations monitored by nucleophile crossover

A nucleophile crossover experiment was used to monitor the reversibility of nucleophilic addition of benzylamine to π-allylpalladium complexes. Dppe, dppp, dppb, and PHOX showed more crossover than PPh₃ and dppm in both DMF and dichloromethane. Crossover was inhibited by the addition of DBU or Cs₂CO₃, but much less elimination to diene side products was observed with Cs₂CO₃. Analysis of percent crossover vs. percent reaction completion using the PHOX ligand revealed that with added DBU or Cs₂CO₃ crossover only began occurring after 100% completion had been reached.     

Dibenzofuran Derivatives Inspired from Cercosporamide as Dual Inhibitors of Pim and CLK1 Kinases

Pim kinases (proviral integration site for Moloney murine leukemia virus kinases) are overexpressed in various types of hematological malignancies and solid carcinomas, and promote cell proliferation and survival. Thus, Pim kinases are validated as targets for antitumor therapy. In this context, our combined efforts in natural product-inspired library generation and screening furnished very promising dibenzo[b,d]furan derivatives derived from cercosporamide. Among them, lead compound 44 was highlighted as a potent Pim-1/2 kinases inhibitor with an additional nanomolar IC₅₀ value against CLK1 (cdc2-like kinases 1) and displayed a low micromolar anticancer potency towards the MV4-11 (AML) cell line, expressing high endogenous levels of Pim-1/2 kinases. The design, synthesis, structure–activity relationship, and docking studies are reported herein and supported by enzyme, cellular assays, and Galleria mellonella larvae testing for acute toxicity.     

Programmed Multiple C-H Bond Functionalization of the Privileged 4-hydroxyquinoline Template

The introduction of substituents on bare heterocyclic scaffolds can selectively be achieved by directed C−H functionalization. However, such methods have only occasionally been used, in an iterative manner, to decorate various positions of a medicinal scaffold to build chemical libraries. We herein report the multiple, site selective, metal-catalyzed C−H functionalization of a “programmed” 4-hydroxyquinoline. This medicinally privileged template indeed possesses multiple reactive sites for diversity-oriented functionalization, of which four were targeted. The C-2 and C-8 decorations were directed by an N-oxide, before taking benefit of an O-carbamoyl protection at C-4 to perform a Fries rearrangement and install a carboxamide at C-3. This also released the carbonyl group of 4-quinolones, the ultimate directing group to functionalize position 5. Our study highlights the power of multiple C−H functionalization to generate diversity in a biologically relevant library, after showing its strong antimalarial potential.     

New Bioactive Peptides Identified from a Tilapia Byproduct Hydrolysate Exerting Effects on DPP-IV Activity and Intestinal Hormones Regulation after Canine Gastrointestinal Simulated Digestion

Like their owners, dogs and cats are more and more affected by overweight and obesity-related problems and interest in functional pet foods is growing sharply. Through numerous studies, fish protein hydrolysates have proved their worth to prevent and manage obesity-related comorbidities like diabetes. In this work, a human in vitro static simulated gastrointestinal digestion model was adapted to the dog which allowed us to demonstrate the promising effects of a tilapia byproduct hydrolysate on the regulation of food intake and glucose metabolism. Promising effects on intestinal hormones secretion and dipeptidyl peptidase IV (DPP-IV) inhibitory activity were evidenced. We identify new bioactive peptides able to stimulate cholecystokinin (CCK) and glucagon-like peptide 1 (GLP-1) secretions, and to inhibit the DPP-IV activity after a transport study through a Caco-2 cell monolayer.     

Impact of the industry on franchise chain efficiency: a meta-DEA and context-dependent DEA approach

A meta-DEA (Data Envelopment Analysis) approach is used to analyse the impact of the industry in which the franchisor operates its business on its chain efficiency by comparing chain efficiency between and across industries (retail versus services). To provide realistic short-term and long-term objectives to inefficient chains, a level-by-level benchmarking path is developed with the context-dependent DEA approach. Furthermore, the joint implementation of both approaches enables an identification of chains for which the industry influences their efficiency, an evaluation of the efficiency share that results from industry-specific factors rather than factors common to the franchise sector as a whole, and the characterization of an implementable and achievable benchmarking defining level-by-level improvements of chain efficiency and taking into account chain characteristics. Such an analysis can help franchisors to define their future strategic and managerial orientations.     

A profile decomposition approach to the L^\infty _t(L^{3}_x) Navier–Stokes regularity criterion

In this paper we continue to develop an alternative viewpoint on recent studies of Navier–Stokes regularity in critical spaces, a program which was started in the recent work by Kenig and Koch (Ann Inst H Poincaré Anal Non Linéaire 28(2):159–187, 2011). Specifically, we prove that strong solutions which remain bounded in the space ${L^3(\mathbb R ^3)}$ do not become singular in finite time, a known result established by Escauriaza et al. (Uspekhi Mat Nauk 58(2(350)):3–44, 2003) in the context of suitable weak solutions. Here, we use the method of “critical elements” which was recently developed by Kenig and Merle to treat critical dispersive equations. Our main tool is a “profile decomposition” for the Navier–Stokes equations in critical Besov spaces which we develop here. As a byproduct of this tool, assuming a singularity-producing initial datum for Navier–Stokes exists in a critical Lebesgue or Besov space, we show there is one with minimal norm, generalizing a result of Rusin and Sverak (J Funct Anal 260(3):879–891, 2011).     

Norm Estimates for Weighted Composition Operators on Spaces of Holomorphic Functions

This paper shows that the boundedness of a weighted composition operator on the Hardy–Hilbert space on the disc or half-plane implies its boundedness on a class of related spaces, including weighted Bergman spaces. The methods used involve the study of lower-triangular and causal operators.     

Pricing stock and bond derivatives with a multi-factor Gaussian model

The martingale approach to pricing contingent claims can be applied in a multiple state variable model. The idea is used to derive the prices of derivative securities (futures on stock and bond futures, options on stocks, bonds and futures) given a continuous time Gaussian multi-factor model of the returns of stocks and bonds. The bond market is similar to Langetieg's multi-factor model, which has closed-form solutions. This model is a generalization of Vasicek's model, where the term structure depends on state variables following correlated mean reverting processes. The stock market is affected by systematic and unsystematic risk.     

Refined inequalities on graded Lie groups

We construct a Littlewood–Paley decomposition associated to a Rockland operator on graded Lie groups, which allows us to deduce refined Gagliardo–Nirenberg, Sobolev and Hardy inequalities.     

Are women better mindreaders? Sex differences in neural correlates of mentalizing detected with functional MRI

Background

Oxidative stress plays a key role in the neuropathogenesis of Human Immunodeficiency Virus-1 (HIV-1) infection causing apoptosis of astroglia cells and neurons. Recent data have shown that oxidative stress is also responsible for the acceleration of human fibroblast telomere shortening in vitro. In the present study we analyzed the potential relations occurring between free radicals formation and telomere length during HIV-1 mediated astroglial death.

Results

To this end, U373 human astrocytoma cells have been directly exposed to X4-using HIV-1IIIB strain, for 1, 3 or 5 days and treated (where requested) with N-acetylcysteine (NAC), a cysteine donor involved in the synthesis of glutathione (GSH, a cellular antioxidant) and apoptosis has been evaluated by FACS analysis. Quantitative-FISH (Q-FISH) has been employed for studying the telomere length while intracellular reduced/oxidized glutathione (GSH/GSSG) ratio has been determined by High-Performance Liquid Chromatography (HPLC). Incubation of U373 with HIV-1IIIB led to significant induction of cellular apoptosis that was reduced in the presence of 1 mM NAC. Moreover, NAC improved the GSH/GSSG, a sensitive indicator of oxidative stress, that significantly decreased after HIV-1IIIB exposure in U373. Analysis of telomere length in HIV-1 exposed U373 showed a statistically significant telomere shortening, that was completely reverted in NAC-treated U373.

Conclusion

Our results support the role of HIV-1-mediated oxidative stress in astrocytic death and the importance of antioxidant compounds in preventing these cellular damages. Moreover, these data indicate that the telomere structure, target for oxidative damage, could be the key sensor of cell apoptosis induced by oxidative stress after HIV infection.