Design,Synthesis, Antimicrobial Evaluation and in Silico Studies of Eugenol-Sulfonamide Hybrids

Using molecular hybridization, specific sulfonamide derivatives of eugenol were synthesized with subtle modifications in the allylic chain of the eugenol subunit (and also in the nature of the substituent group in the sulfonamide aromatic ring) which allowed us to study the influence of structural changes on the antimicrobial potential of the hybrids. Antimicrobial test results showed that most of the synthesized hybrid compounds showed good activity with better results than the parent compounds. Molecular docking studies of the hybrids with the essential bacterial enzyme DHPS showed complexes with low binding energies, suggesting that DHPS could be a possible target for the antibacterial sulfonamide-eugenol hybrids. Furthermore, most of the final compounds presented similar docking poses to that of the crystallographic ligand sulfamethoxazole. The results obtained allow us to conclude that these are promising compounds for use as new leads in the search for new antibacterial sulfonamides.     

Evaluation of the prevalence and economic burden of adverse drug reactions presenting to the medical emergency department of a tertiary referral centre: a prospective study

Background  

Adverse drug reactions (ADRs) are now recognized as an important cause of hospital admissions, with a proportion ranging from 0.9–7.9%. They also constitute a significant economic burden. We thus aimed at determining the prevalence and the economic burden of ADRs presenting to Medical Emergency Department (ED) of a tertiary referral center in India     

A novel mechanism of autophagic cell death in dystrophic muscle regulated by P2RX7 receptor large-pore formation and HSP90

P2RX7 is an ATP-gated ion channel, which can also exhibit an open state with a considerably wider permeation. However, the functional significance of the movement of molecules through the large pore (LP) and the intracellular signaling events involved are not known. Here, analyzing the consequences of P2RX7 activation in primary myoblasts and myotubes from the Dmd^mdx mouse model of Duchenne muscular dystrophy, we found ATP-induced P2RX7-dependent autophagic flux, leading to CASP3-CASP7-independent cell death. P2RX7-evoked autophagy was triggered by LP formation but not Ca²⁺ influx or MAPK1-MAPK3 phosphorylation, 2 canonical P2RX7-evoked signals. Phosphoproteomics, protein expression inference and signaling pathway prediction analysis of P2RX7 signaling mediators pointed to HSPA2 and HSP90 proteins. Indeed, specific HSP90 inhibitors prevented LP formation, LC3-II accumulation, and cell death in myoblasts and myotubes but not in macrophages. Pharmacological blockade or genetic ablation of p2rx7 also proved protective against ATP-induced death of muscle cells, as did inhibition of autophagy with 3-MA. The functional significance of the P2RX7 LP is one of the great unknowns of purinergic signaling. Our data demonstrate a novel outcome—autophagy—and show that molecules entering through the LP can be targeted to phagophores. Moreover, we show that in muscles but not in macrophages, autophagy is needed for the formation of this LP. Given that P2RX7-dependent LP and HSP90 are critically interacting in the ATP-evoked autophagic death of dystrophic muscles, treatments targeting this axis could be of therapeutic benefit in this debilitating and incurable form of muscular dystrophy.     

Influence of substrate concentration on the stability and yield of continuous biohydrogen production

The effect of substrate concentration (sucrose) on the stability and yield of a continuous fermentative process producing hydrogen was studied. High substrate concentrations are attractive from an energy standpoint as they would minimise the energy required for heating. The reactor was a CSTR; temperature was maintained at 35 degrees C; pH was controlled between 5.2 and 5.3, and the hydraulic retention time (HRT) was 12 h. Online measurements were taken for ORP, pH, temperature, %CO2, gas output and %H2, and data logged using a MatLAB data acquisition toolbox. Steady-state operation was obtained at 10, 20 and 40 g/L of sucrose in the influent, but a subsequent step change to 50 g/L was unsustainable. The hydrogen content ranged between 50% and 60%. The yield of hydrogen decreased as the substrate concentration increased from 1.7 +/- 0.2 mol/mol hexose added at 10 g/L, to 0.8 +/- 0.1 mol/mol at 50 g/L. Sparging with nitrogen improved the hydrogen yield by at least 35% at 40 g/L and at least 33% at 50 g/L sucrose. Sparging also enabled steady-state operation at 50 g/L sucrose. Addition of an extra 4 g/L of n-butyric acid to the reactor operating at 40 g/L sucrose increased the butyrate concentration from 9,830 to 18,900 mg/L, immediately stopping gas production and initiating the production of propionate, whilst the addition of 2 g/L taking the butyrate concentration to 12,200 mg/L did not do so. It was shown that operation at 50 g/L sucrose in a CSTR in butyrate fermentation is possible.     

Cyclohexanehexol inhibitors of Abeta aggregation prevent and reverse Alzheimer phenotype in a mouse model

When given orally to a transgenic mouse model of Alzheimer disease, cyclohexanehexol stereoisomers inhibit aggregation of amyloid beta peptide (Abeta) into high-molecular-weight oligomers in the brain and ameliorate several Alzheimer disease-like phenotypes in these mice, including impaired cognition, altered synaptic physiology, cerebral Abeta pathology and accelerated mortality. These therapeutic effects, which occur regardless of whether the compounds are given before or well after the onset of the Alzheimer disease-like phenotype, support the idea that the accumulation of Abeta oligomers has a central role in the pathogenesis of Alzheimer disease.     

Can multiple-copy sequences of prey DNA be detected amongst the gut contents of invertebrate predators?

The first experiments to clearly demonstrate that DNA techniques might be used to detect predator-prey interactions between arthropods are reported. The accurate modelling of such interactions has depended until now upon a mixture of laboratory experiments, population monitoring and biochemical tests. The latter involve gut-content analyses, and have most recently depended upon the development of prey-specific monoclonal antibodies. Although these are excellent for detecting predation on a target prey, they are impractical for analysing the prey range of a particular predator. Molecular detection depends upon the ability of DNA to resist digestion in the predator gut and of the polymerase chain reaction (PCR) to amplify prey-specific DNA from semidigested material. As a first step, experiments using carabid beetles, Pterostichus cupreus L., as predators and mosquitoes as prey are reported. The target sequences were fully characterized multiple-copy esterase genes from two laboratory strains of Culex quinquefasciatus Say. Although DNA was extracted from homogenates of whole beetles (minus appendages), a 146 bp product could be amplified from both mosquito strains digested in the beetle gut for 28 h. The larger, 263 bp product was detectable for 28 h in one mosquito strain, but could not be amplified after 5 h from the other. Whether the beetles had eaten one mosquito or six, digested for zero or 28 h, the prey were equally detectable. Having demonstrated that shorter, multiple-copy sequences survive digestion for a considerable period in the gut of a predator, the opportunity exists to develop new detection systems for studying predation in the field.     

Grandmothering and the evolution of homo erectus

Despite recent, compelling challenge, the evolution of Homo erectus is still commonly attributed to big game hunting and/or scavenging and family provisioning by men. Here we use a version of the "grandmother" hypothesis to develop an alternative scenario, that climate-driven adjustments in female foraging and food sharing practices, possibly involving tubers, favored significant changes in ancestral life history, morphology, and ecology leading to the appearance, spread and persistence of H. erectus. Available paleoclimatic, environmental, fossil and archaeological data are consistent with this proposition; avenues for further critical research are readily identified. This argument has important implications for widely-held ideas about the recent evolution of long human lifespans, the prevalence of male philopatry among ancestral hominids, and the catalytic role of big game hunting and scavenging in early human evolution.