New InhA Inhibitors Based on Expanded Triclosan and Di-Triclosan Analogues to Develop a New Treatment for Tuberculosis

The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) has reinforced the need for the development of new anti-TB drugs. The first line drug isoniazid inhibits InhA. This is a prodrug requiring activation by the enzyme KatG. Mutations in KatG have largely contributed to clinical isoniazid resistance. We aimed to design new ‘direct’ InhA inhibitors that obviate the need for activation by KatG, circumventing pre-existing resistance. In silico molecular modelling was used as part of a rational structure-based drug-design approach involving inspection of protein crystal structures of InhA:inhibitor complexes, including the broad spectrum antibiotic triclosan (TCS). One crystal structure exhibited the unusual presence of two triclosan molecules within the Mycobacterium tuberculosis InhA binding site. This became the basis of a strategy for the synthesis of novel inhibitors. A series of new, flexible ligands were designed and synthesised, expanding on the triclosan structure. Low Minimum Inhibitory Concentrations (MICs) were obtained for benzylphenyl compounds (12, 43 and 44) and di-triclosan derivative (39), against Mycobacterium bovis BCG although these may also be inhibiting other enzymes. The ether linked di-triclosan derivative (38) displayed excellent in vitro isolated enzyme inhibition results comparable with triclosan, but at a higher MIC (125 µg mL−1). These compounds offer good opportunities as leads for further optimisation

Microclimate variables of the ambient environment deliver the actual estimates of the extrinsic incubation period of Plasmodium vivax and Plasmodium falciparum : A study from a malaria-endemic urban setting, Chennai in India

Background: Environmental factors such as temperature, relative humidity and their daily variation influence a range of mosquito life history traits and hence, malaria transmission. The standard way of characterizing environmental factors with meteorological station data need not be the actual microclimates experienced by mosquitoes within local transmission settings. Methods: A year-long study was conducted in Chennai, India to characterize local temperature and relative humidity (RH). Data loggers (Hobos) were placed in a range of probable indoor and outdoor resting sites of Anopheles stephensi. Recordings were taken hourly to estimate mean temperature and RH, together with daily temperature range (DTR) and daily relative humidity range. The temperature data were used to explore the predicted variation in extrinsic incubation period (EIP) of Plasmodium falciparum and Plasmodium vivax between microhabitats and across the year. Results: Mean daily temperatures within the indoor settings were significantly warmer than those recorded outdoors. DTR in indoor environments was observed to be modest and ranged from 2 to 6 °C. Differences in EIP between microhabitats were most notable during the hottest summer months of April-June, with parasite development predicted to be impaired for tiled houses and overhead tanks. Overall, the prevailing warm and stable conditions suggest rapid parasite development rate regardless of where mosquitoes might rest. Taking account of seasonal and local environmental variation, the predicted EIP of P. falciparum varied from a minimum of 9.1 days to a maximum of 15.3 days, while the EIP of P. vivax varied from 8.0 to 24.3 days. Conclusions: This study provides a detailed picture of the actual microclimates experienced by mosquitoes in an urban slum malaria setting. The data indicate differences between microhabitats that could impact mosquito and parasite life history traits. The predicted effects for EIP are often relatively subtle, but variation between minimum and maximum EIPs can play a role in disease transmission, depending on the time of year and where mosquitoes rest. Appropriate characterization of the local microclimate conditions would be the key to fully understand the effects of environment on local transmission ecology

Overhead tank is the potential breeding habitat of Anopheles stephensi in an urban transmission setting of Chennai, India

Background: Wells and overhead tanks (OHT) are the major breeding sources of the local malaria vector, Anopheles stephensi in the Indian city of Chennai; they play a significant role in vector breeding, and transmission of urban malaria. Many other man-made breeding habitats, such as cemented cisterns/containers, barrels or drums, sumps or underground tanks, and plastic pots/containers are maintained to supplement water needs, temporarily resulting in enhanced mosquito/vector breeding. Correlating breeding habitats with immature vector abundance is important in effective planning to strengthen operational execution of vector control measures. Methods: A year-long, weekly study was conducted in Chennai to inspect available clear/clean water mosquito breeding habitats. Different breeding features, such as instar-wise, immature density and co-inhabitation with other mosquito species, were analysed. The characteristics of breeding habitats, i.e., type of habitat, water temperature and presence of aquatic organisms, organic matter and green algal remnants on the water surface at the time of inspection, were also studied. Immature density of vector was correlated with presence of other mosquito species, malaria prevalence, habitat characteristics and monthly/seasonal fluctuations. All the data collected from field observations were analysed using standard statistical tools. Results: When the immature density of breeding habitats was analysed, using one-way ANOVA, it was observed that the density did not change in a significant way either across seasons or months. OHTs contributed significantly to the immature population when compared to wells and other breeding habitats of the study site. The habitat positivity of wells and OHTs was significantly associated with the presence of aquatic organisms, organic matter and algal remnants. Significant correlations of malaria prevalence with monthly immature density, as well as number of breeding habitats with immature vector mosquitoes, were also observed. Conclusions: The findings that OHTs showed fairly high and consistent immature density of An. stephensi irrespective of seasons indicates the potentiality of the breeding habitat in contributing to vector density. The correlation between vector breeding habitats, immature density and malaria prevalence indicates the proximity of these habitats to malaria cases, proving its role in vector abundance and local malaria transmission. The preference of An. stephensi to breed in OHTs calls for intensified, appropriate and sustained intervention measures to curtail vector breeding and propagation to shrink malaria to pre-elimination level and beyond

6TiSCH Operation Sublayer (6top) implementation on Contiki OS

The Internet Engineering Task Force (IETF) has set up the 6TiSCH Working Group (WG) to focus on enabling IPv6 over the Time Slotted Channel Hoping (TSCH) mode of the IEEE 802.15.4-2015 standard. This paper describes our Contiki implementation of the 6TiSCH operation sublayer, 6top, which is used for dynamic scheduling of bandwidth between the neighboring sensor nodes and facilitate the On the Fly (OTF) scheduling

Isolated bilateral pleural effusion as the sole manifestation of late onset ovarian hyperstimulation syndrome

To report a case of late onset ovarian hyperstimulation with bilateral pleural effusion and respiratory distress as the sole manifestation after embryo transfer

Rural Electricity Demand in India (REDI)

Data from the Rural Electricity Demand in India (REDI) survey by SPI-ISEP. The dataset contains detailed information on electricity demand in rural India. The dataset covers 10,000 households and 2,000 rural enterprises across 200 villages in Bihar, Uttar Pradesh, Odisha, and Rajasthan