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

Resting and feeding preferences of Anopheles stephensi in an urban setting, perennial for malaria

Background: The Indian city of Chennai is endemic for malaria and the known local malaria vector is Anopheles stephensi. Plasmodium vivax is the predominant malaria parasite species, though Plasmodium falciparum is present at low levels. The urban ecotype of malaria prevails in Chennai with perennial transmission despite vector surveillance by the Urban Malaria Scheme (UMS) of the National Vector Borne Disease Control Programme (NVBDCP). Understanding the feeding and resting preferences, together with the transmission potential of adult vectors in the area is essential in effective planning and execution of improved vector control measures. Methods: A yearlong survey was carried out in cattle sheds and human dwellings to check the resting, feeding preferences and transmission potential of An. stephensi. The gonotrophic status, age structure, resting and host seeking preferences were studied. The infection rate in An. stephensi and Anopheles subpictus were analysed by circumsporozoite ELISA (CS-ELISA). Results: Adult vectors were found more frequently and at higher densities in cattle sheds than human dwellings. The overall Human Blood Index (HBI) was 0.009 indicating the vectors to be strongly zoophilic. Among the vectors collected from human dwellings, 94.2% were from thatched structures and the remaining 5.8% from tiled and asbestos structures. 57.75% of the dissected vectors were nulliparous whereas, 35.83% were monoparous and the rest 6.42% biparous. Sporozoite positivity rate was 0.55% (4/720) and 1.92% (1/52) for An. stephensi collected from cattle sheds and human dwellings, respectively. One adult An. subpictus (1/155) was also found to be infected with P. falciparum. Conclusions: Control of the adult vector populations can be successful only by understanding the resting and feeding preferences. The present study indicates that adult vectors predominantly feed on cattle and cattle sheds are the preferred resting place, possibly due to easy availability of blood meal source and lack of any insecticide or repellent pressure. Hence targeting these resting sites with cost effective, socially acceptable intervention tools, together with effective larval source management to reduce vector breeding, could provide an improved integrated vector management strategy to help drive down malaria transmission and assist in India's plan to eliminate malaria by 2030

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

Towards work life fulfilment: Scale development and validation

This research aimed to develop and validate a multidimensional reflective-reflective measure of work-life fulfilment (WLF) through four studies. In study 1, spread across three phases, the researchers identified relevant dimensions and the nomological network of WLF using the Antecedents-Dimensions-Outcomes systematic review framework, further cross-validated with focus group discussions. Items were generated in the second phase and assessed for face validity by a focus group. Content validity indices (CVI) at item-level (I-CVI) and scale-level (S-CVI) and modified kappa were estimated in the third phase to select final items for pilot testing in study 2. Responses from 100 professionals from the IT/ITeS sector were subjected to exploratory factor analysis upon testing for the factorability of data. In study 3, confirmatory factor analysis was conducted on an additional sample of 564 IT/ITeS professionals, and the latent structure was validated through reliability analyses, discriminant and convergent validity assessments, and tetrad analysis. The presence of common method bias was also checked and invalidated. Study 4, conducted on an additional sample of 621 IT/ITeS and BFSI professionals, tested the relationship of WLF with three antecedents, namely resonant leadership, relational civility and psychological capital, to establish its nomological validity and outcome variable burnout, to establish predictive validity. The scale was further cross-validated on 325 professionals from the BFSI sector in the fifth study to test generalizability. The results confirm work prowess, work-life balance, rewards and recognition, healthy lifestyle, relationship management, and self-transcendence as the distinct dimensions of WLF. The study contributes to the literature with a unique, six-dimensional, 26-item, second-order, reflective-reflective measurement model of WLF that is psychometrically fit for use on samples across diverse contexts

Synthesis, molecular structure and emission properties of benzoato-bridged lanthanide complexes with hydrotris(pyrazolyl)borate

Reaction of GdCl3 and TbCl3 with one equivalent of the potassium salt of the tridentate ligand hydrotris(pyrazol-1- yl)borate [K(tp)] and two equivalents of sodium p-X-benzoate (X = H, Cl, Br and NO2) yielded the complexes 1-6 of composition [(tp)Ln(mu-p-X-OBz)(2)}(2)] (Ln = Gd, Tb) whereas the reaction of TbCl3 with 2 equivalents of [K(tp)] and one equivalent of sodium azide, gave the tetranuclear complex [{tp)(2)Tb(mu-N- 3)}(4)] (7). The crystal structures of the benzoate complexes (X = H) of Gd (1) and Tb (2) and their analogous p-Cl-benzoate derivatives with Gd (3) and Tb (4) have been determined. The compounds consist of a seven-coordinate tetrakis carboxylato bridged dimetal unit with two capping hydrotris(pyrazolyl)borate ligands. Unit cell determinations suggested that [{tp)Tb(mu-p-Cl-OBZ)(2)}(2)] (5), and [{(tp)Tb(mu-p-NO2-OBz)(2)}(2)] (6), are isostructural with (3) and (4). Single crystal X-Ray analysis of (7) revealed its tetranuclear structure comprising a cyclic 16-membered Tb-4(mu- N-3)(4)-unit with two hydrotris(pyrazol-1-yl)borate ligands bound to each of the terbium ions resulting in a tetragonal antiprismatic N-8-coordination sphere. The luminescence properties of the unsubstituted and para-substituted Gd and Tb benzoate complexes have been studied in solution at room temperature

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

Socio-demographic and household attributes may not necessarily influence malaria: evidence from a cross sectional study of households in an urban slum setting of Chennai, India

Abstract Background Household and environmental factors are reported to influence the malaria endemicity of a place. Hence, a careful assessment of these factors would, potentially help in locating the possible areas under risk to plan and adopt the most suitable and appropriate malaria control strategies. Methods A cross-sectional household survey was carried out in the study site, Besant Nagar, Chennai, through random sampling method from February 2014 to February 2015. A structured interviewer-administered questionnaire was used to assess selected variables of demography, structural particulars of a household, usage of repellents, animals on site, presence of breeding habitats and any mosquito/vector breeding in the household, malaria/vector control measures undertaken by government in each houses. The data was collected through one to one personal interview method, statistically analysed overall and compared between the households/people infected with malaria within a period of 1 year and their non-infected counterparts of the same area. Results Presence of malaria was found to be significantly associated with the occupation, number of inhabitants, presence of a separate kitchen, availability of overhead tanks and cisterns, immatures of vector mosquitoes, presence of mosquito breeding and type of roof structures (p < 0.05). However, age, gender, usage of repellents, animals on site, number of breeding habitats or detection of vector breeding did not significantly associate with the malaria incidence/prevalence. Conclusions The survey revealed various demographic, household and environmental factors likely to associate with the malaria incidence/prevalence in an urban slum of Chennai. The socio-demographic and household variables have revealed disparities in malaria infection from the present cross sectional study. The absence of significant association with many parameters indicates the probable role of other confounding factors which influence the malaria prevalence