Synthesis and evaluation of 7-chloro-4-(piperazin-1-yl)quinoline-sulfonamide as hybrid antiprotozoal agents

A new series of 4-aminochloroquinoline based sulfonamides were synthesized and evaluated for antiamoebic and antimalarial activities. Out of the eleven compounds evaluated (F1–F11), two of them (F3 and F10) showed good activity against Entamoeba histolytica (IC₅₀ <5 μM). Three of the compounds (F5, F7 and F8) also displayed antimalarial activity against the chloroquine-resistant (FCR-3) strain of Plasmodium falciparum with IC₅₀ values of 2 μM. Compound F7, whose crystal structure was also determined, inhibited β-haematin formation more potently than quinine. To further understand the action of hybrid molecules F7 and F8, molecular docking was carried out against the homology model of P. falciparum enzyme dihydropteroate synthase (PfDHPS). The complexes showed that the inhibitors place themselves nicely into the active site of the enzyme and exhibit interaction energy which is in accordance with our activity profile data. Application of Lipinski ‘rule of five’ on all the compounds (F1–F11) suggested high drug likeness of F7 and F8, similar to quinine.     

Child Centred Approach to Climate Change and Health Adaptation through Schools in Bangladesh: A Cluster Randomised Intervention Trial

Background

Bangladesh is one of the most vulnerable countries to climate change. People are getting educated at different levels on how to deal with potential impacts. One such educational mode was the preparation of a school manual, for high school students on climate change and health protection endorsed by the National Curriculum and Textbook Board, which is based on a 2008 World Health Organization manual. The objective of this study was to test the effectiveness of the manual in increasing the knowledge level of the school children about climate change and health adaptation.

Methods

This cluster randomized intervention trial involved 60 schools throughout Bangladesh, with 3293 secondary school students participating. School upazilas (sub-districts) were randomised into intervention and control groups, and two schools from each upazila were randomly selected. All year seven students from both groups of schools sat for a pre-test of 30 short questions of binary response. A total of 1515 students from 30 intervention schools received the intervention through classroom training based on the school manual and 1778 students of the 30 control schools did not get the manual but a leaflet on climate change and health issues. Six months later, a post-intervention test of the same questionnaire used in the pre-test was performed at both intervention and control schools. The pre and post test scores were analysed along with the demographic data by using random effects model.

Results

None of the various school level and student level variables were significantly different between the control and intervention group. However, the intervention group had a 17.42% (95% CI: 14.45 to 20.38, P = <0.001) higher score in the post-test after adjusting for pre-test score and other covariates in a multi-level linear regression model.

Conclusions

These results suggest that school-based intervention for climate change and health adaptation is effective for increasing the knowledge level of school children on this topic.     

Phylogenetic and Molecular Clock Analysis of Dengue Serotype 1 and 3 from New Delhi,India

Dengue fever is the most prevalent arboviral disease in the tropical and sub-tropical regions of the world. The present report describes molecular detection and serotyping of dengue viruses in acute phase blood samples collected from New Delhi, India. Phylogenetic and molecular clock analysis of dengue virus serotype 1 and 3 strains were also investigated. Dengue virus infection was detected in 68.87% out of 604 samples tested by RT-PCR between 2011 & 2014. Dengue serotype 1 was detected in 25.48% samples, dengue serotype 2 in 79.56% samples and dengue serotype 3 in 11.29% samples. Dengue serotype 4 was not detected. Co-infection by more than one dengue serotype was detected in 18.26% samples. Envelope gene of 29 DENV-1 and 14 DENV-3 strains were sequenced in the study. All the DENV-1 strains grouped with the American African genotype. All DENV-3 strains were found to belong to Genotype III. Nucleotide substitution rates of dengue 1 and 3 viruses were determined in the study. Time to the most recent common ancestor (TMRCA) of dengue 1 viruses was determined to be 132 years. TMRCA of DENV-3 viruses was estimated to be 149 years. Bayesian skyline plots were constructed for Indian DENV-1 and 3 strains which showed a decrease in population size since 2005 in case of DENV- 1 strains while no change was observed in recent years in case of DENV-3 strains. The study also revealed a change in the dominating serotype in Delhi, India in recent years. The study will be helpful in formulating control strategies for the outbreaks. In addition, it will also assist in tracking the movement and evolution of this emerging virus.     

Pressure gradients along whole culms and leaf sheaths, and other aspects of humidity-induced gas transport in Phragmites australis

Emergent aquatic macrophytes growing in waterlogged anaerobic sediments overlain by deep water require particularly efficient ventilating systems. In Phragmites australis (Cav.) Trin. ex Steud, pressurized gas flows, generated by humidity-induced diffusion of air into leaf sheaths, enhance oxygen transport to below-ground parts and aid in the removal of respiratory CO2 and sediment-generated CO2 and methane. Although modelling and flow measurements have pointed to the probable involvement of all leaf sheaths in the flow process and the development of pressure gradients along the whole lengths of living culm and leaf sheaths, direct measurements of pressure gradients have never been reported. The aim of this study was to search for pressure gradient development in Phragmites culms and leaf sheaths and to determine their magnitudes and distribution. In addition, dynamic (with gas flow) and static pressures (no flow condition) and their relationship to flows, leaf sheath areas, and living-to-dead culm ratios were further investigated. Dynamic pressures (DeltaPd) recorded in the pith cavities of intact (non-excised) leafy culms, pneumatically isolated from the below-ground parts and venting through an artificial bore-hole near the base, revealed a curvilinear gradient of pressure 'asymptoting' towards the tips of the culms. Similarly, DeltaPd in upper and lower parts of leaf sheaths increased with distance from the base of the culm, with values in the upper parts always being greater. Curvilinear gradients of pressure were also found along pneumatically isolated individual leaf sheaths, but radial channels linking the leaf sheath aerenchyma with the pith cavity of the culm appeared to offer little resistance to flow. In keeping with predictions, static pressure differentials (DeltaPs) achieved in intact and excised culms and single leaf sheaths on intact culms proved to be relatively independent of leaf sheath area, whereas the potential for developing convective flows (pressure-driven flows) increased with increasing leaf sheath area. As measured by the ventilating coefficient [1-(DeltaPd/(DeltaPs)] the old dead (efflux) to living (influx) culm ratio of 1:12 compared with 1:25 raised ventilating efficiency from 31% to 71%, giving flows per tall culm into the rhizome system of c. 2.8 cm3 and 6.5 cm3 min-1, respectively. It was concluded that dynamic pressure gradients probably extend along the whole length of the leafy culms and leaf sheaths of Phragmites and that all leaf sheaths and all exposed points along the leaf sheaths can contribute convective gas-flow to the rhizome system.     

Is Content Really King? An Objective Analysis of the Public's Response to Medical Videos on YouTube

Medical educators and patients are turning to YouTube to teach and learn about medical conditions. These videos are from authors whose credibility cannot be verified & are not peer reviewed. As a result, studies that have analyzed the educational content of YouTube have reported dismal results. These studies have been unable to exclude videos created by questionable sources and for non-educational purposes. We hypothesize that medical education YouTube videos, authored by credible sources, are of high educational value and appropriately suited to educate the public. Credible videos about cardiovascular diseases were identified using the Mayo Clinic''s Center for Social Media Health network. Content in each video was assessed by the presence/absence of 7 factors. Each video was also evaluated for understandability using the Suitability Assessment of Materials (SAM). User engagement measurements were obtained for each video. A total of 607 videos (35 hours) were analyzed. Half of all videos contained 3 educational factors: treatment, screening, or prevention. There was no difference between the number of educational factors present & any user engagement measurement (p NS). SAM scores were higher in videos whose content discussed more educational factors (p<0.0001). However, none of the user engagement measurements correlated with higher SAM scores. Videos with greater educational content are more suitable for patient education but unable to engage users more than lower quality videos. It is unclear if the notion “content is king” applies to medical videos authored by credible organizations for the purposes of patient education on YouTube.     

New antiprotozoal agents: Synthesis and biological evaluation of different 4-(7-chloroquinolin-4-yl) piperazin-1-yl)pyrrolidin-2-yl)methanone derivatives

In an endeavor to develop efficacious antiprotozoal agents 4-(7-chloroquinolin-4-yl) piperazin-1-yl)pyrrolidin-2-yl)methanone derivatives (5–14) were synthesized, characterized and biologically evaluated for antiprotozoal activity. The compounds were screened in vitro against the HM1: IMSS strain of Entamoeba histolytica and NF54 chloroquine-sensitive strain of Plasmodium falciparum. Among the synthesized compounds six exhibited promising antiamoebic activity with IC₅₀ values (0.14–1.26 μM) lower than the standard drug metronidazole (IC₅₀ 1.80 μM). All nine compounds exhibited antimalarial activity (IC₅₀ range: 1.42–19.62 μM), while maintaining a favorable safety profile to host red blood cells. All the compounds were less effective as an antimalarial and more toxic (IC₅₀ range: 14.67–81.24 μM) than quinine (IC₅₀: 275.6 ± 16.46 μM) against the human kidney epithelial cells. None of the compounds exhibited any inhibitory effect on the viability of Anopheles arabiensis mosquito larvae.     

Temperature stress can alter the photosynthetic efficiency and secondary metabolite concentrations in St. John's wort.

Temperature stress is known to cause many physiological, biochemical and molecular changes in plant metabolism and possibly alter the secondary metabolite production in plants. The hypothesis of the current study was that temperature stress can increase the secondary metabolite concentrations in St. John's wort. Plants were grown under controlled environments with artificial light using cool white fluorescent lamps and CO2 enrichment and 70-day-old plants were subjected for 15 days to different temperature treatments of 15, 20, 25, 30 and 35 degrees C before harvested. Major aim of the study was to increase the major secondary metabolites in St. John's wort by applying temperature stress and to evaluate the physiological status of the plant especially the photosynthetic efficiency and peroxidase activity of the leaf tissues exposed to different temperatures under precisely controlled environmental factors. Results revealed that relatively high (35 degrees C) or low (15 degrees C) temperatures reduced the photosynthetic efficiency of the leaves of St. John's wort plants and resulted in low CO2 assimilation. Net photosynthetic rates and the maximal quantum efficiency of PSII photochemistry of the dark adopted leaves (phi(p)max) decreased significantly in the leaves of plants grown under 35 or 15 degrees C temperature treatments. High temperature (35 degrees C) treatment increased the leaf total peroxidase activity and also increased the hypericin, pseudohypericin and hyperforin concentrations in the shoot tissues. These results provide the first indication that temperature is an important environmental factor to optimize the secondary metabolite production in St. John's wort and controlled environment technology can allow the precise application of such specific stresses.     

Extracellular laccase production and its optimization from Arthrospira maxima catalyzed decolorization of synthetic dyes

In the present study laccase production potential of a photosynthetic, non nitrogen fixing cyanobacteria Arthrospira maxima (SAE-25780) was investigated for their probable use in synthetic dye decolorization which poses environmental pollution problem in aquatic bodies. A. maxima (SAE-25780) showed a constitutive production of laccase which increased up to 80% in the presence of inducer guaiacol. The optimal condition for laccase was 30 °C, 10 mM sucrose as a carbon source, 10 mM sodium nitrate as a nitrogen source, and 2 mM copper as metal activator. The partially purified laccase showed 84% and 49% decolorization potential for the two anthroquinonic dyes-Reactive Blue 4 and Remazol Brilliant Blue R, respectively (RBBR) within 96 h without any mediator. Therefore the laccase extracted from A. maxima (SAE-25780) can be used efficiently in bioremediation of synthetic dyes from paper, pulp and textile industries.     

Conserved Amphipathic Helices Mediate Lipid Droplet Targeting of Perilipins 1–3

Perilipins (PLINs) play a key role in energy storage by orchestrating the activity of lipases on the surface of lipid droplets. Failure of this activity results in severe metabolic disease in humans. Unlike all other lipid droplet-associated proteins, PLINs localize almost exclusively to the phospholipid monolayer surrounding the droplet. To understand how they sense and associate with the unique topology of the droplet surface, we studied the localization of human PLINs in Saccharomyces cerevisiae, demonstrating that the targeting mechanism is highly conserved and that 11-mer repeat regions are sufficient for droplet targeting. Mutations designed to disrupt folding of this region into amphipathic helices (AHs) significantly decreased lipid droplet targeting in vivo and in vitro. Finally, we demonstrated a substantial increase in the helicity of this region in the presence of detergent micelles, which was prevented by an AH-disrupting missense mutation. We conclude that highly conserved 11-mer repeat regions of PLINs target lipid droplets by folding into AHs on the droplet surface, thus enabling PLINs to regulate the interface between the hydrophobic lipid core and its surrounding hydrophilic environment.