What are the determinants of childhood infections in India’s peri-urban slums? A case study of eight cities

BACKGROUND: Respiratory Tract Infections (RTIs) and Gastro-Intestinal (GI) infections are the leading causes of child mortality and morbidity. This study investigates the associations between the individual, household and slum-level determinants of children’s health and vulnerability to RTIs and GI infections in peri-urban slums in India; an area of research interest at the Childhood Infections and Pollution Consortium. METHODS: The 2015–16 Indian National Family Health Survey was used for data analysis on children aged 0–5 years. NFHS-4 includes data on slums in eight Indian cities, including Delhi, Meerut, Kolkata, Indore, Mumbai, Nagpur, Hyderabad, Chennai. The outcome variables, having fever and cough (FeCo) and diarrhoea in the last two weeks, were used to define the phenotype of infections; for this analysis fever and cough were measures of RTIs and diarrhoea was used to measure GI infections. Exposures considered in this study include variables at the individual, household and slum level and were all informed by existing literature. Multilevel models were used to estimate the association between exposures and outcomes variables; a prior of Cauchy distribution with a scale of 2.5 was selected when building the multilevel logistic models. RESULTS: The total sample size of the number of children included in the analysis was n = 1,424. Data was imputed to account for missingness, and the original and imputed sample showing similar distributions. Results showed that diarrhoea and FeCo were both found to be more present in younger children than older children by a few months. In fixed effects, the odds of developing FeCo were higher if the mother perceives the child was born smaller than average (AOR 4.41, 1.13–17.17, P<0.05) at individual level. On the other hand, the odds of the diarrhoea outcome were lower if the child was older (AOR 0.97, 0.96–0.98, P<0.05) at individual level, and household’s water source was public tap or standpipe (AOR 0.54, 0.31–0.96, P<0.05) at household level. CONCLUSION: The determinants of health, both social and related to health care, at all levels demonstrated linkages to child morbidity in RTIs and GI infections. The empirical evidence highlights the need for contextualised ideas at each level, including one health approach when designing interventions to improve child health

Comparison of Circulating Concentrations of Reproductive Hormones in Boars of Lines Selected for Size of Testes or Number of Ovulations and Embryonal Survival to Concentrations in Respective Control Lines

The objectives of this study were to determine whether circulating concentrations of gonadotropins and gonadal hormones of boars were altered as a result of selection of pigs for size of testes or for embryonal survival and(or) number of ovulations. Included in Exp. 1 and 2 were boars with the greatest estimated paired weight of testes (TS) and boars from a control (C) line. Concentrations of FSH were similar ( P \u3e .10) in boars from the TS and C lines. In Exp. 3, 4, and 5, circulating concentrations of FSH and 17β-estradiol (E2) were evaluated in neonates, during pubertal development, and in mature boars of lines selected for an index of number of ovulations and embryonal survival ( I ) , and data were compared to those for boars from a respective C line. Concentrations of E2 were not different in boars from the I line and those from the C line during the early neonatal period but were greater ( P \u3c .05) in boars of the C line than in those from the I line during pubertal development. Concentrations of FSH were greater ( P \u3c .05) in mature boars from the I line than in those from the C line. In summary, selection for size of testes did not influence circulating concentrations of FSH in mature boars. The secretory pattern of E2 in boars before puberty changed as a result of selection for embryonal survival and number of ovulations in females of the I line, and the different patterns of circulating E2 early in life may result in enhanced circulating concentrations of FSH in adult boars of the I line compared with boars of the C line

Assessing the infection burden and associated risk factors in children under 5 across Jaipurs urban slums: A feasibility study using a One Health approach

Purpose: Infectious diseases are one of the leading causes of death among children under five (U5s) across both India & globally. This is worse in slum environments with poor access to water, sanitation & hygiene (WASH), good nutrition & a safe built environment. / Globally, a One Health (e.g. human, animal & environment) approach is increasingly advocated by WHO, FAO & OIE to reduce infections & antimicrobial resistance. As U5s living in peri-urban slums are exposed to household and community owned companion & livestock animals and pests, the CHIP Consortium hypothesized that utilizing a One Health approach to co-produce behavior change & slum upgrading interventions may reduce this burden where other WASH & nutrition interventions have failed. / This study aimed to assess the feasibility of utilising a One Health approach to assess U5 infection & risk factor prevalence in Jaipurs urban slums prior to undertaking prospective cohort studies involving culture and culture independent sampling of U5s and animals across our study sites in Jaipur, Jakarta & Antofagasta. / Methods: We administered a Rapid Household Survey to 25 purposely selected households across six slums. The questionnaire evaluated infection prevalence, health seeking behaviors, the built environment, presence of animals & pests, and individual to household-level demographics. Associations were calculated using correlations among continuous variables to show strength of significance between continuous variables. / Results: We found a high incidence of infections in children under five at 40%. This was most significantly correlated with accessibility of sanitary toilets (r = .62) and household expenditure. Vaccination coverage and child characteristics (such as size) were minimally correlated, while the presence of animals (pets or pests) was not correlated; the latter was likely due to the design of the survey. / Conclusion: This study found a higher infection prevalence than previous studies. We also found higher correlations with infection incidence among household-level characteristics, indicating that effective interventions need to address both the built and socio-economic environments. A pilot prospective cohort study, which includes researcher observations for the presence of animals to account for inconsistencies in the survey, is now underway

Host Reproductive Phenology Drives Seasonal Patterns of Host Use in Mosquitoes

Seasonal shifts in host use by mosquitoes from birds to mammals drive the timing and intensity of annual epidemics of mosquito-borne viruses, such as West Nile virus, in North America. The biological mechanism underlying these shifts has been a matter of debate, with hypotheses falling into two camps: (1) the shift is driven by changes in host abundance, or (2) the shift is driven by seasonal changes in the foraging behavior of mosquitoes. Here we explored the idea that seasonal changes in host use by mosquitoes are driven by temporal patterns of host reproduction. We investigated the relationship between seasonal patterns of host use by mosquitoes and host reproductive phenology by examining a seven-year dataset of blood meal identifications from a site in Tuskegee National Forest, Alabama USA and data on reproduction from the most commonly utilized endothermic (white-tailed deer, great blue heron, yellow-crowned night heron) and ectothermic (frogs) hosts. Our analysis revealed that feeding on each host peaked during periods of reproductive activity. Specifically, mosquitoes utilized herons in the spring and early summer, during periods of peak nest occupancy, whereas deer were fed upon most during the late summer and fall, the period corresponding to the peak in births for deer. For frogs, however, feeding on early- and late-season breeders paralleled peaks in male vocalization. We demonstrate for the first time that seasonal patterns of host use by mosquitoes track the reproductive phenology of the hosts. Peaks in relative mosquito feeding on each host during reproductive phases are likely the result of increased tolerance and decreased vigilance to attacking mosquitoes by nestlings and brooding adults (avian hosts), quiescent young (avian and mammalian hosts), and mate-seeking males (frogs)

Metabolomics-Based Discovery of Diagnostic Biomarkers for Onchocerciasis

Onchocerciasis, caused by the filarial parasite Onchocerca volvulus, afflicts millions of people, causing such debilitating symptoms as blindness and acute dermatitis. There are no accurate, sensitive means of diagnosing O. volvulus infection. Clinical diagnostics are desperately needed in order to achieve the goals of controlling and eliminating onchocerciasis and neglected tropical diseases in general. In this study, a metabolomics approach is introduced for the discovery of small molecule biomarkers that can be used to diagnose O. volvulus infection. Blood samples from O. volvulus infected and uninfected individuals from different geographic regions were compared using liquid chromatography separation and mass spectrometry identification. Thousands of chromatographic mass features were statistically compared to discover 14 mass features that were significantly different between infected and uninfected individuals. Multivariate statistical analysis and machine learning algorithms demonstrated how these biomarkers could be used to differentiate between infected and uninfected individuals and indicate that the diagnostic may even be sensitive enough to assess the viability of worms. This study suggests a future potential of these biomarkers for use in a field-based onchocerciasis diagnostic and how such an approach could be expanded for the development of diagnostics for other neglected tropical diseases

Structural Basis for Fe–S Cluster Assembly and tRNA Thiolation Mediated by IscS Protein–Protein Interactions

Crystal structures reveal how distinct sites on the cysteine desulfurase IscS bind two different sulfur-acceptor proteins, IscU and TusA, to transfer sulfur atoms for iron-sulfur cluster biosynthesis and tRNA thiolation

Functional genomics of the horn fly, Haematobia irritans (Linnaeus, 1758)

<p>Abstract</p> <p>Background</p> <p>The horn fly, <it>Haematobia irritans </it>(Linnaeus, 1758) (Diptera: Muscidae) is one of the most important ectoparasites of pastured cattle. Horn flies infestations reduce cattle weight gain and milk production. Additionally, horn flies are mechanical vectors of different pathogens that cause disease in cattle. The aim of this study was to conduct a functional genomics study in female horn flies using Expressed Sequence Tags (EST) analysis and RNA interference (RNAi).</p> <p>Results</p> <p>A cDNA library was made from whole abdominal tissues collected from partially fed adult female horn flies. High quality horn fly ESTs (2,160) were sequenced and assembled into 992 unigenes (178 contigs and 814 singlets) representing molecular functions such as serine proteases, cell metabolism, mitochondrial function, transcription and translation, transport, chromatin structure, vitellogenesis, cytoskeleton, DNA replication, cell response to stress and infection, cell proliferation and cell-cell interactions, intracellular trafficking and secretion, and development. Functional analyses were conducted using RNAi for the first time in horn flies. Gene knockdown by RNAi resulted in higher horn fly mortality (protease inhibitor functional group), reduced oviposition (vitellogenin, ferritin and vATPase groups) or both (immune response and 5'-NUC groups) when compared to controls. Silencing of ubiquitination ESTs did not affect horn fly mortality and ovisposition while gene knockdown in the ferritin and vATPse functional groups reduced mortality when compared to controls.</p> <p>Conclusions</p> <p>These results advanced the molecular characterization of this important ectoparasite and suggested candidate protective antigens for the development of vaccines for the control of horn fly infestations.</p

Simukunin from the Salivary Glands of the Black Fly Simulium vittatum Inhibits Enzymes That Regulate Clotting and Inflammatory Responses

BACKGROUND: Black flies (Diptera: Simuliidae) feed on blood, and are important vectors of Onchocerca volvulus, the etiolytic agent of River Blindness. Blood feeding depends on pharmacological properties of saliva, including anticoagulation, but the molecules responsible for this activity have not been well characterized. METHODOLOGY/PRINCIPAL FINDINGS: Two Kunitz family proteins, SV-66 and SV-170, were identified in the sialome of the black fly Simulium vittatum. As Kunitz proteins are inhibitors of serine proteases, we hypothesized that SV-66 and/or -170 were involved in the anticoagulant activity of black fly saliva. Our results indicated that recombinant (r) SV-66 but not rSV-170 inhibited plasma coagulation. Mutational analysis suggested that SV-66 is a canonical BPTI-like inhibitor. Functional assays indicated that rSV66 reduced the activity of ten serine proteases, including several involved in mammalian coagulation. rSV-66 most strongly inhibited the activity of Factor Xa, elastase, and cathepsin G, exhibited lesser inhibitory activity against Factor IXa, Factor XIa, and plasmin, and exhibited no activity against Factor XIIa and thrombin. Surface plasmon resonance studies indicated that rSV-66 bound with highest affinity to elastase (K(D) = 0.4 nM) and to the active site of FXa (K(D) = 3.07 nM). We propose the name "Simukunin" for this novel protein. CONCLUSIONS: We conclude that Simukunin preferentially inhibits Factor Xa. The inhibition of elastase and cathepsin G further suggests this protein may modulate inflammation, which could potentially affect pathogen transmission

An insight into the sialome of Simulium guianense (DIPTERA:SIMulIIDAE), the main vector of River Blindness Disease in Brazil

<p>Abstract</p> <p>Background</p> <p>Little is known about the composition and function of the saliva in black flies such as <it>Simulium guianense</it>, the main vector of river blindness disease in Brazil. The complex salivary potion of hematophagous arthropods counteracts their host's hemostasis, inflammation, and immunity.</p> <p>Results</p> <p>Transcriptome analysis revealed ubiquitous salivary protein families--such as the Antigen-5, Yellow, Kunitz domain, and serine proteases--in the <it>S. guianense </it>sialotranscriptome. Insect-specific families were also found. About 63.4% of all secreted products revealed protein families found only in <it>Simulium</it>. Additionally, we found a novel peptide similar to kunitoxin with a structure distantly related to serine protease inhibitors. This study revealed a relative increase of transcripts of the SVEP protein family when compared with <it>Simulium vittatum </it>and <it>S. nigrimanum </it>sialotranscriptomes. We were able to extract coding sequences from 164 proteins associated with blood and sugar feeding, the majority of which were confirmed by proteome analysis.</p> <p>Conclusions</p> <p>Our results contribute to understanding the role of <it>Simulium </it>saliva in transmission of <it>Onchocerca volvulus </it>and evolution of salivary proteins in black flies. It also consists of a platform for mining novel anti-hemostatic compounds, vaccine candidates against filariasis, and immuno-epidemiologic markers of vector exposure.</p

Hsp70 chaperones: Cellular functions and molecular mechanism

Hsp70 proteins are central components of the cellular network of molecular chaperones and folding catalysts. They assist a large variety of protein folding processes in the cell by transient association of their substrate binding domain with short hydrophobic peptide segments within their substrate proteins. The substrate binding and release cycle is driven by the switching of Hsp70 between the low-affinity ATP bound state and the high-affinity ADP bound state. Thus, ATP binding and hydrolysis are essential in vitro and in vivo for the chaperone activity of Hsp70 proteins. This ATPase cycle is controlled by co-chaperones of the family of J-domain proteins, which target Hsp70s to their substrates, and by nucleotide exchange factors, which determine the lifetime of the Hsp70-substrate complex. Additional co-chaperones fine-tune this chaperone cycle. For specific tasks the Hsp70 cycle is coupled to the action of other chaperones, such as Hsp90 and Hsp100