Nitrogen is a requirement for the photochemical induced 3-azabicyclo[3.3.1]nonane skeletal rearrangement!

Specific 3-azabicyclo[3.3.1]nonane derivatives undergo skeletal cleavage when subjected to light or Lewis acidic conditions affording novel heteratricycles, which is in stark contrast to 3-oxabicyclo[3.3.1]nonanes. (c) 2005 Elsevier Ltd. All rights reserved.

Gastrointestinal absorption of Heparin by lipidization or coadministration with penetration enhancers

A review with 93 references. Heparins are high molecular weight, hydrophilic polyanions, which are unstable under acidic conditions; and therefore they exhibit poor oral bioavailability. Consequently they must be administered via the parenteral route which is expensive, inconvenient, and limits use by outpatients. The development of an oral form of heparin is warranted. This review examined the literature, mostly published between January 2000 and January 2005, pertaining to the gastrointestinal absorption of heparin by lipidization or coadministration with penetration enhancers. A lipidization strategy that was examined involved conjugation of low molecular weight heparin with deoxycholic acid. The majority of studies examined the ability of different formulations, typically utilizing penetration enhancers, to improve heparin bioavailability. The penetration enhancers used included fatty acids, Labrasol™, Gelucire 44/14™, polycationic lipophilic-core dendrons, saponins, mono-N-carboxymethyl chitosan, Carbopol® 934P, a combination of thiolated polycarbophil and glutathione, polymeric nanoparticles, polymeric microparticles, sodium N-[8-(2-hydroxybenzoyl) amino]caprylate (SNAC), and sodium N-[10-(2-hydroxybenzoyl)amino]decanoate (SNAD). The variety of models used and doses of heparin/penetration enhancers applied, however, made it difficult to compare the results between studies. Nevertheless, all of the reviewed drug delivery systems showed therapeutic value and confirmation of the promising results obtained from animal studies, by progression to clinical trials, is necessary. Overall, progress has been made in the quest for an oral heparin formulation.

Synthesis of novel cylic monomers for hydrogel polymers

The aim of the project was to synthesise hydrophilic derivatives of 1,2-dihydroxy-3,5-cyclohexadiene (DHCD) and to copolymerise these derivatives with 2-hydroxyethyl methacrylate (HEMA), to give a completely new range of hydrogel materials. It was thought that hydro gels incorporating hydrophilic derivatives of DHCD could have good mechanical properties and good water binding ability. A model compound for cis-DHCD was sought, as cis-DHCD was expensive and stable under only a narrow range of conditions. Catechol was found to be an excellent model for cis-DHCD, as 1H NMR spectroscopy indicated that both compounds contained eclipsed hydroxy groups and flat rings. A number of catechol derivatives were prepared in good yield, under non-acidic conditions at room temperature. The limited availabilty of cis-DHCD led to an investigation into synthesising hydrophilic derivatives of both cis and trans-DHCD indirectly. Hydrophobic derivatives were easily prepared by indirect routes, but it was found that hydrophilic derivatives were considerably more difficult to synthesise. A number of novel routes to both cis and trans-DHCD were also explored. Copolymerisation of diacetate, dimethylcarbonate and dipivalate derivatives of cis-DHCD with HEMA, to form a hitherto unknown group of hydrogels, is reported. Hydrogels containing these monomers showed significant improvements in both tensile strength and Youngs modulus, at both equivalent composition and water content, over the corresponding HEMA / styrene and HEMA / methyl methacrylate analogues. It was observed that derivatives of trans-DHCD polymerise with difficulty. 1H NMR studies indicated that both faces of the ring were shielded by the pendant groups thereby preventing efficient polymerisation of the trans monomers.

Amino acid, peptide and drug transport across monolayers of human intestinal (CAC0-2) cells in vitro

The properties of Caco-2 monolayers were compared on aluminium oxide and nitrocellulose permeable-supports. On nitrocellulose, Caco-2 cells displayed a higher rate of taurocholic acid transport than those cultured on aluminium oxide inserts. In addition, Caco-2 cells grown on these two inserts were not comparable with respect to cell morphology, cell numbers and transepithelial electrical resistance. The low adsorption potential of the aluminium oxide inserts, particularly for high molecular weight or lipophilic ligands, offers a distinct advantage over nitrocellulose inserts for drug transport studies. The carrier-mediated uptake and transport of the imino acid (L-proline) and the acidic amino acids (L-aspartate and L-glutamate) have been studied. At pH7.4, L-proline uptake is mediated via an A-system carrier. Elevated uptake and transport under acidic conditions occurs by activation of a distinct carrier population. Acidic amino acid transport is mediated via a X-AG system. The flux of baclofen, CGP40116 andCGP40117 across Caco-2 monolayers was described by passive transport. The transport of three peptides, thyrotrophin-releasing hormone, SQ29852 and cyclosporin were investigated. Thyrotrophin-releasing hormone transport acrossCaco-2 monolayers was characterised by a minor saturable (carrier-mediated,approximately 25%) pathway, superimposed onto a major non-saturable (diffusional)pathway. SQ29852 uptake into Caco-2 monolayers is described by a major saturable mechanism (Km = 0.91 mM) superimposed onto a minor passive component.However, the initial-rate of SQ29852 transport is consistent with a passive transepithelial transport mechanism. These data highlight the possibility that itsbasolateral efflux is severely retarded such that the passive paracellular transportdictates the overall transepithelial transport characteristics. In addition, modelsuitable for investigating the transepithelial transport of cyclosporin A has been developed. A modification of the conventional Caco-2 model has been developed which has a calcium-free Ap donor-solution and a Bl receiver-solution containing the minimumcalcium concentration required to maintain monolayer integrity (100 μM). The influence of calcium and magnesium on the absorption of [14C]pamidronate was evaluated by comparing its transport across the conventional and minimum calciumCaco-2 models. Ap calcium and magnesium ions retard the Ap-to-Bl flux of pamidronate across Caco-2 monolayers. The effect of self-emulsifying oleic acid-Tween 80 formulations on Caco-2monolayer integrity has been investigated. Oleic acid-Tween 80 (1 0:1) formulations produced a dose-dependent disruption of Caco-2 monolayer integrity. This disruption was related to the oleic acid content of the formulation.

Three-dimensional nitrogen-doped graphene supported molybdenum disulfide nanoparticles as an advanced catalyst for hydrogen evolution reaction

An efficient three-dimensional (3D) hybrid material of nitrogen-doped graphene sheets (N-RGO) supporting molybdenum disulfide (MoS2) nanoparticles with high-performance electrocatalytic activity for hydrogen evolution reaction (HER) is fabricated by using a facile hydrothermal route. Comprehensive microscopic and spectroscopic characterizations confirm the resulting hybrid material possesses a 3D crumpled few-layered graphene network structure decorated with MoS2 nanoparticles. Electrochemical characterization analysis reveals that the resulting hybrid material exhibits efficient electrocatalytic activity toward HER under acidic conditions with a low onset potential of 112 mV and a small Tafel slope of 44 mV per decade. The enhanced mechanism of electrocatalytic activity has been investigated in detail by controlling the elemental composition, electrical conductance and surface morphology of the 3D hybrid as well as Density Functional Theory (DFT) calculations. This demonstrates that the abundance of exposed active sulfur edge sites in the MoS2 and nitrogen active functional moieties in N-RGO are synergistically responsible for the catalytic activity, whilst the distinguished and coherent interface in MoS 2 /N-RGO facilitates the electron transfer during electrocatalysis. Our study gives insights into the physical/chemical mechanism of enhanced HER performance in MoS2/N-RGO hybrids and illustrates how to design and construct a 3D hybrid to maximize the catalytic efficiency.

Quinols as novel therapeutic agents. 2.1 4-(1-arylsulfonylindol- 2-yl)-4-hydroxycyclohexa-2,5-dien-1-ones and related agents as potent and selective antitumor agents

A series of substituted 4-(1-arylsulfonylindol-2-yl)-4-hydroxycyclohexa-2, 5-dien-1-ones (indolylquinols) has been synthesized on the basis of the discovery of lead compound 1a and screened for antitumor activity. Synthesis of this novel series was accomplished via the "one-pot" addition of lithiated (arylsulfonyl)indoles to 4,4-dimethoxycyclohexa-2,5-dienone followed by deprotection under acidic conditions. Similar methodology gave rise to the related naphtho-, 1H-indole-, and benzimidazole-substituted quinols. A number of compounds in this new series were found to possess in vitro human tumor cell line activity substantially more potent than the recently reported antitumor 4-substituted 4-hydroxycyclohexa-2,5-dien-1-ones1 with similar patterns of selectivity against colon, renal, and breast cell lines. The most potent compound in the series in vitro, 4-(1-benzenesulfonyl-6-fluoro-1H-indol- 2-yl)-4-hydroxycyclohexa-2,5-dienone (1h), exhibits a mean GI50 value of 16 nM and a mean LC50 value of 2.24 μM in the NCI 60-cell-line screen, with LC50 activity in the HCT 116 human colon cancer cell line below 10 nM. The crystal structure of the unsubstituted indolylquinol 1a exhibits two independent molecules, both participating in intermolecular hydrogen bonds from quinol OH to carbonyl O, but one OH group also interacts intramolecularly with a sulfonyl O atom. This interaction, which strengthens upon ab initio optimization, may influence the chemical environment of the bioactive quinol moiety. In vivo, significant antitumor activity was recorded (day 28) in mice bearing subcutaneously implanted MDA-MB-435 xenografts, following intraperitoneal treatment of mice with compound 1a at 50 mg/kg.

Nighttime dissolution in a temperate coastal ocean ecosystem increases under acidification

Anthropogenic emissions of carbon dioxide (CO2) are causing ocean acidification, lowering seawater aragonite (CaCO3) saturation state (Omega arag), with potentially substantial impacts on marine ecosystems over the 21st Century. Calcifying organisms have exhibited reduced calcification under lower saturation state conditions in aquaria. However, the in situ sensitivity of calcifying ecosystems to future ocean acidification remains unknown. Here we assess the community level sensitivity of calcification to local CO2-induced acidification caused by natural respiration in an unperturbed, biodiverse, temperate intertidal ecosystem. We find that on hourly timescales nighttime community calcification is strongly influenced by Omega arag, with greater net calcium carbonate dissolution under more acidic conditions. Daytime calcification however, is not detectably affected by Omega arag. If the short-term sensitivity of community calcification to Omega arag is representative of the long-term sensitivity to ocean acidification, nighttime dissolution in these intertidal ecosystems could more than double by 2050, with significant ecological and economic consequences.

Data compilation on the biological response to ocean acidification: environmental and experimental context of data sets and related literature

The exponential growth of studies on the biological response to ocean acidification over the last few decades has generated a large amount of data. To facilitate data comparison, a data compilation hosted at the data publisher PANGAEA was initiated in 2008 and is updated on a regular basis (doi:10.1594/PANGAEA.149999). By January 2015, a total of 581 data sets (over 4 000 000 data points) from 539 papers had been archived. Here we present the developments of this data compilation five years since its first description by Nisumaa et al. (2010). Most of study sites from which data archived are still in the Northern Hemisphere and the number of archived data from studies from the Southern Hemisphere and polar oceans are still relatively low. Data from 60 studies that investigated the response of a mix of organisms or natural communities were all added after 2010, indicating a welcomed shift from the study of individual organisms to communities and ecosystems. The initial imbalance of considerably more data archived on calcification and primary production than on other processes has improved. There is also a clear tendency towards more data archived from multifactorial studies after 2010. For easier and more effective access to ocean acidification data, the ocean acidification community is strongly encouraged to contribute to the data archiving effort, and help develop standard vocabularies describing the variables and define best practices for archiving ocean acidification data.

Micropartículas de quitosana estruturadas com aerosil®: estabilidade, adsorção, encapsulação e liberação de substâncias ativas

Biodegradable microspheres used as controlled release systems are important in pharmaceutics. Chitosan biopolymer represents an attractive biomaterial alternative because of its physicochemical and biological characteristics. Chitosan microspheres are expected to become promising carrier systems for drug and vaccine delivery, especially for non-invasive ways oral, mucosal and transdermal routes. Controlling the swelling rate and swelling capacity of the hydrogel and improving the fragile nature of microspheres under acidic conditions are the key challenges that need to be overcomed in order to enable the exploration of the full pharmaceutical potential use of these microparticles. Many studies have focused on the modification of chitosan microsphere structures with cross-linkers, various polymers blends and new organic-inorganic hybrid systems in order to obtain improved properties. In this work, microspheres made of chitosan and nanosized hydrophobic silica (Aerosil R972) were produced by a method consisting of two steps. First, a preparation of a macroscopically homogeneous chitosan-hydrophobic silica dispersion was prepared followed by spray drying. FTIR spectroscopy, X-ray powder diffraction, differential scanning calorimetry, thermal gravimetric analysis, scanning electron microscopy (SEM) and high-resolution transmission electron microscopy (TEM) were used to characterize the microspheres. Also, the were conducted acid stability, moisture sorption capacity, release properties and biological assays. The chitosan-hydrophobic silica composite microspheres showed improved thermal degradation, lower water affinity, better acid stability and ability to retard rifampicin and propranolol hydrochloride (drug models) release under simulated physiological conditions. In vitro biocompatibility studies indicated low cytotoxicity and low capacity to activate cell production of the pro-inflammatory mediator nitric oxide. The results show here encourage further studies on the use of the new chitosan-hydrophobic silica composite microspheres as drug carrier systems via oral or nasal routes.

Seawater carbonate chemistry and sperm swimming speed, fertilization success of the Australasian sea urchin Heliocidaris erythrogramma in lab experiment

Background: Climate change will lead to intense selection on many organisms, particularly during susceptible early life stages. To date, most studies on the likely biotic effects of climate change have focused on the mean responses of pooled groups of animals. Consequently, the extent to which inter-individual variation mediates different selection responses has not been tested. Investigating this variation is important, since some individuals may be preadapted to future climate scenarios. Methodology/Principal Findings: We examined the effect of CO2-induced pH changes ("ocean acidification") in sperm swimming behaviour on the fertilization success of the Australasian sea urchin Heliocidaris erythrogramma, focusing on the responses of separate individuals and pairs. Acidification significantly decreased the proportion of motile sperm but had no effect on sperm swimming speed. Subsequent fertilization experiments showed strong inter-individual variation in responses to ocean acidification, ranging from a 44% decrease to a 14% increase in fertilization success. This was partly explained by the significant relationship between decreases in percent sperm motility and fertilization success at delta pH = 0.3, but not at delta pH = 0.5. Conclusions and Significance: The effects of ocean acidification on reproductive success varied markedly between individuals. Our results suggest that some individuals will exhibit enhanced fertilization success in acidified oceans, supporting the concept of 'winners' and 'losers' of climate change at an individual level. If these differences are heritable it is likely that ocean acidification will lead to selection against susceptible phenotypes as well as to rapid fixation of alleles that allow reproduction under more acidic conditions. This selection may ameliorate the biotic effects of climate change if taxa have sufficient extant genetic variation upon which selection can act.

(Table II, page 668-669) Distribution of elements between minerals soluble in 1M Hydroxylamine hydrochloride (Reducible); in 1m HCL (Acid-soluble) and in the insoluble residue of manganese nodules

Attempts to classify pelagic sediments have been based either on appearance and composition, or on the ultimate origin of the components. In particular it appears feasible to distinguish minerals which crystallized in sea-water from those which formed in magmas, in hydrothermal solution, or by weathering under acidic conditions. It is the case of iron and manganese oxide mineral aggregates which constitute one of the major types of rock encountered on the ocean floor; according to Menard (unpublished) about 10% of the pelagic area of the Pacific is covered by such nodules. The nodules consist of intimately intergrown crystallites of different minerals among those identified, besides detrital minerals and organic matter, are opal, goethite, rutile, anatase, barite, nontronite, and at least three manganese oxide minerals of major importance. Arrhenius and Korkisch (1959) have attempted to separate from each other the different minerals constituting the nodules, in order to establish the details of their structure and the localization of the heavy metal ions. The results demonstrate (Table II) that copper and nickel are concentrated in the manganese oxide phases concentrated in the reducible fraction. Cobalt, part of the nickel and most of the chromium are distributed between these and the acid-soluble group of the non-manganese minerals, dominated by goethite and disordered FeOOH.

Microbial phylogenetic and functional responses within acidified wastewater communities exhibiting enhanced phosphate uptake

Acid stimulated accumulation of insoluble phosphorus within microbial cells is highly beneficial to wastewater treatment but remains largely unexplored. Using single cell analyses and next generation sequencing, the response of active polyphosphate accumulating microbial communities under conditions of enhanced phosphorus uptake under both acidic and aerobic conditions was characterised. Phosphorus accumulation activities were highest under acidic conditions (pH 5.5 > 8.5), where a significant positive effect on bioaccumulation was observed at pH 5.5 when compared to pH 8.5. In contrast to the Betaproteobacteria and Actinobacteria dominated enhanced biological phosphorus removal process, the functionally active polyP accumulators at pH 5.5 belonged to the Gammaproteobacteria, with key accumulators identified as members of the families Aeromonadaceae and Enterobacteriaceae. This study demonstrated a significant enrichment of key polyphosphate kinase and exopolyphosphatase genes within the community metagenome after acidification, concomitant with an increase in P accumulation kinetics.

Design and stability study of a paediatric oral solution of methotrexate 2mg/ml

International audience

Synthesis, characterization, and preliminary application of new biocompatible nanogels useful as anticancer drug delivery systems

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Ferrous iron sensing and responding in Pseudomonas aeruginosa

Controlling iron distribution is important for all organisms, and is key in bacterial pathogenesis. It has long been understood that cystic fibrosis (CF) patient sputum contains elevated iron concentrations. However, anaerobic bacteria have been isolated from CF sputum and hypoxic zones in sputum have been measured. Because ferrous iron [Fe(II)] is stable in reducing, acidic conditions, it could exist in the CF lung. I show that a two-component system, BqsRS, specifically responds to Fe(II) in the CF pathogen, Pseudomonas aeruginosa. Concurrently, a clinical study found that Fe(II) is present in CF sputum at all stages of lung function decline. Fe(II), not Fe(III) correlates with patients in the most severe disease state. Furthermore, transcripts of the newly identified BqsRS were detected in sputum. Two component systems are the main method bacteria interact with their extracellular environment. A typical two-component system contains a sensor histidine kinase, which upon activation phosphorylates a response regulator that then acts as a transcription factor to elicit a cellular response to stimuli. To explore the mechanism of BqsRS, I describe the Fe(II)-sensing RExxE motif in the sensor BqsS and determine the consensus DNA sequence BqsR binds. With the BqsR binding sequence, I identify novel regulon members through bioinformatic and molecular biology techniques. From the predicted function of new BqsR regulon members, I find that Fe(II) elicits a response that globally protects the cells against cationic stressors, including clinically relevant antibiotics. Subsequently, I use BqsR as a case study to determine if promoter outputs can accurately be predicted based only on a deep understanding of a transcriptional activator’s operator or if a broader regulatory context is required for accurate predictions at all genomic loci. This work highlights the importance of Fe(II) as a (micro)environmental factor, even in conditions typically thought of as aerobic. Since the presence of Fe(II) can alter P. aeruginosa’s antibiotic susceptibility, combining the current strategy of targeting Fe(III) with a new approach targeting Fe(II) may help eradicate infections in the CF lung in the future.