An intramolecular nitro-Mannich route to functionalised tetrahydroquinolines

A simple protocol for the diastereoselective synthesis of 3-nitrotetrahydroquinolines has been developed using an intramolecular nitro-Mannich reaction. In situ formation of an imine generated from treatment of 2-(2-nitroethyl)phenylamine with an aldehyde, in EtOH at room temperature, and subsequent addition of NH4OH, led to the formation of trans-products in high yield and diastereoselectivity for 15 representative examples

Silent onset of postmenopausal endometriosis in a woman with renal failure in hormone replacement therapy: a case report

<p>Abstract</p> <p>Introduction</p> <p>Postmenopausal endometriosis is a rare form of a common disease, since the absence of estrogenic hormone production should halt disease progression.</p> <p>Case presentation</p> <p>We present the case of a 54-year-old Italian Caucasian woman in surgical menopause with a history of ovarian endometriosis, who underwent voluntary hormone replacement therapy for seven years. She developed postrenal renal failure due to bilateral compression of the pelvic ureteral tract caused by two large, deeply infiltrating endometriotic nodules with no pelvic pain. She underwent operative laparoscopy with adhesiolysis of enteroenteric adhesions and excision of the endometriotic nodules encompassing the juxtavesical tract of the ureters, without obtaining improvement of renal failure.</p> <p>Conclusion</p> <p>Postmenopausal endometriosis can manifest itself in an unpredictable and potentially very serious manner. It is therefore important to carefully evaluate the risks and benefits of administering hormone replacement therapy to patients with previous endometriosis.</p

Controlled interfacial assembly of 2D curved colloidal crystals and jammed shells

Assembly of colloidal particles on fluid interfaces is a promising technique for synthesizing two-dimensional micro-crystalline materials useful in fields as diverse as biomedicine1, materials science2, mineral flotation3 and food processing4. Current approaches rely on bulk emulsification methods, require further chemical and thermal treatments, and are restrictive with respect to the materials employed5-9. The development of methods that exploit the great potential of interfacial assembly for producing tailored materials have been hampered by the lack of understanding of the assembly process. Here we report a microfluidic method that allows direct visualization and understanding of the dynamics of colloidal crystal growth on curved interfaces. The crystals are periodically ejected to form stable jammed shells, which we refer to as colloidal armour. We propose that the energetic barriers to interfacial crystal growth and organization can be overcome by targeted delivery of colloidal particles through hydrodynamic flows. Our method allows an unprecedented degree of control over armour composition, size and stability.Comment: 18 pages, 5 figure

Disruption of ER-mitochondria tethering and signalling in C9orf72-associated amyotrophic lateral sclerosis and frontotemporal dementia

Hexanucleotide repeat expansions in C9orf72 are the most common cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The mechanisms by which the expansions cause disease are not properly understood but a favoured route involves its translation into dipeptide repeat (DPR) polypeptides, some of which are neurotoxic. However, the precise targets for mutant C9orf72 and DPR toxicity are not fully clear, and damage to several neuronal functions has been described. Many of these functions are regulated by signalling between the endoplasmic reticulum (ER) and mitochondria. ER-mitochondria signalling requires close physical contacts between the two organelles that are mediated by the VAPB-PTPIP51 ‘tethering’ proteins. Here, we show that ER-mitochondria signalling and the VAPB-PTPIP51 tethers are disrupted in neurons derived from induced pluripotent stem (iPS) cells from patients carrying ALS/FTD pathogenic C9orf72 expansions and in affected neurons in mutant C9orf72 transgenic mice. In these mice, disruption of the VAPB-PTPIP51 tethers occurs prior to disease onset suggesting that it contributes to the pathogenic process. We also show that neurotoxic DPRs disrupt the VAPB-PTPIP51 interaction and ER-mitochondria contacts and that this may involve activation of glycogen synthase kinases-3β (GSK3β), a known negative regulator of VAPB-PTPIP51 binding. Finally, we show that these DPRs disrupt delivery of Ca2+ from ER stores to mitochondria, which is a primary function of the VAPB-PTPIP51 tethers. This delivery regulates a number of key neuronal functions that are damaged in ALS/FTD including bioenergetics, autophagy and synaptic function. Our findings reveal a new molecular target for mutant C9orf72-mediated toxicity

The influence of semantic and phonological factors on syntactic decisions: An event-related brain potential study

During language production and comprehension, information about a word's syntactic properties is sometimes needed. While the decision about the grammatical gender of a word requires access to syntactic knowledge, it has also been hypothesized that semantic (i.e., biological gender) or phonological information (i.e., sound regularities) may influence this decision. Event-related potentials (ERPs) were measured while native speakers of German processed written words that were or were not semantically and/or phonologically marked for gender. Behavioral and ERP results showed that participants were faster in making a gender decision when words were semantically and/or phonologically gender marked than when this was not the case, although the phonological effects were less clear. In conclusion, our data provide evidence that even though participants performed a grammatical gender decision, this task can be influenced by semantic and phonological factors

Artificial boundary conditions for the linearized Benjamin-Bona-Mahony equation

International audienceWe consider various approximations of artificial boundary conditions for linearized Benjamin-Bona-Mahoney equation. Continuous (respectively discrete) artificial boundary conditions involve non local operators in time which in turn requires to compute time convolutions and invert the Laplace transform of an analytic function (respectively the Z-transform of an holomorphic function). In this paper, we derive explicit transparent boundary conditions both continuous and discrete for the linearized BBM equation. The equation is discretized with the Crank Nicolson time discretization scheme and we focus on the difference between the upwind and the centered discretization of the convection term. We use these boundary conditions to compute solutions with compact support in the computational domain and also in the case of an incoming plane wave which is an exact solution of the linearized BBM equation. We prove consistency, stability and convergence of the numerical scheme and provide many numerical experiments to show the efficiency of our tranparent boundary conditions

Hsp90 governs dispersion and drug resistance of fungal biofilms

Fungal biofilms are a major cause of human mortality and are recalcitrant to most treatments due to intrinsic drug resistance. These complex communities of multiple cell types form on indwelling medical devices and their eradication often requires surgical removal of infected devices. Here we implicate the molecular chaperone Hsp90 as a key regulator of biofilm dispersion and drug resistance. We previously established that in the leading human fungal pathogen, Candida albicans, Hsp90 enables the emergence and maintenance of drug resistance in planktonic conditions by stabilizing the protein phosphatase calcineurin and MAPK Mkc1. Hsp90 also regulates temperature-dependent C. albicans morphogenesis through repression of cAMP-PKA signalling. Here we demonstrate that genetic depletion of Hsp90 reduced C. albicans biofilm growth and maturation in vitro and impaired dispersal of biofilm cells. Further, compromising Hsp90 function in vitro abrogated resistance of C. albicans biofilms to the most widely deployed class of antifungal drugs, the azoles. Depletion of Hsp90 led to reduction of calcineurin and Mkc1 in planktonic but not biofilm conditions, suggesting that Hsp90 regulates drug resistance through different mechanisms in these distinct cellular states. Reduction of Hsp90 levels led to a marked decrease in matrix glucan levels, providing a compelling mechanism through which Hsp90 might regulate biofilm azole resistance. Impairment of Hsp90 function genetically or pharmacologically transformed fluconazole from ineffectual to highly effective in eradicating biofilms in a rat venous catheter infection model. Finally, inhibition of Hsp90 reduced resistance of biofilms of the most lethal mould, Aspergillus fumigatus, to the newest class of antifungals to reach the clinic, the echinocandins. Thus, we establish a novel mechanism regulating biofilm drug resistance and dispersion and that targeting Hsp90 provides a much-needed strategy for improving clinical outcome in the treatment of biofilm infections