In-depth proteomic characterization of Schistosoma haematobium: Towards the development of new tools for elimination
Contributors: Sotillo, Javier, Pearson, Mark S, Becker, Luke, Mekonnen, Gebeyaw G, Amoah, Abena S, Dam, Govert van, Corstjens, Paul LAM, Murray, Janice, Mduluza, Takafira, Mutapi, Francisca
... Schistosomiasis is a neglected disease affecting hundreds of millions worldwide. Of the three main species affecting humans, Schistosoma haematobium is the most common, and is the leading cause of urogenital schistosomiasis. S. haematobium infection can cause different urogenital clinical complications, particularly in the bladder, and furthermore, this parasite has been strongly linked with squamous cell carcinoma. A comprehensive analysis of the molecular composition of its different proteomes will contribute to developing new tools against this devastating disease.
Contributors: Law, Philip J, Timofeeva, Maria, Fernandez-Rozadilla, Ceres, Broderick, Peter, Studd, James, Fernandez-Tajes, Juan, Farrington, Susan, Svinti, Victoria, Palles, Claire, Orlando, Giulia
... Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide, and has a strong heritable basis. We report a genome-wide association analysis of 34,627 CRC cases and 71,379 controls of European ancestry that identifies SNPs at 31 new CRC risk loci. We also identify eight independent risk SNPs at the new and previously reported European CRC loci, and a further nine CRC SNPs at loci previously only identified in Asian populations. We use in situ promoter capture Hi-C (CHi-C), gene expression, and in silico annotation methods to identify likely target genes of CRC SNPs. Whilst these new SNP associations implicate target genes that are enriched for known CRC pathways such as Wnt and BMP, they also highlight novel pathways with no prior links to colorectal tumourigenesis. These findings provide further insight into CRC susceptibility and enhance the prospects of applying genetic risk scores to personalised screening and prevention.
Burden of disease from inadequate water, sanitation and hygiene for selected adverse health outcomes: An updated analysis with a focus on low- and middle-income countries
Contributors: Prüss-Ustün, Annette, Wolf, Jennyfer, Bartram, Jamie, Clasen, Thomas, Cumming, Oliver, Freeman, Matthew C, Gordon, Bruce, Hunter, Paul R, Medlicott, Kate, Johnston, Richard
... To develop updated estimates in response to new exposure and exposure-response data of the burden of diarrhoea, respiratory infections, malnutrition, schistosomiasis, malaria, soil-transmitted helminth infections and trachoma from exposure to inadequate drinking-water, sanitation and hygiene behaviours (WASH) with a focus on low- and middle-income countries.
Mapping the medical outcomes study HIV health survey (MOS-HIV) to the EuroQoL 5 Dimension (EQ-5D-3 L) utility index
Contributors: Shi, Yuan, Thompson, Jennifer, Walker, A Sarah, Paton, Nicholas, Cheung, Yin Bun
... Mapping of health-related quality-of-life measures to health utility values can facilitate cost-utility evaluation. Regression-based methods tend to lead to shrinkage of variance. This study aims to map the Medical Outcomes Study HIV Health Survey (MOS-HIV) to EuroQoL 5 Dimensions (EQ-5D-3 L) utility index, and to characterize the performance of three mapping methods, including ordinary least squares (OLS), equi-percentile method (EPM), and a recently proposed method called Mean Rank Method (MRM).
Contributors: Obolski, Uri, Perez, Pablo N., Villabona Arenas, Julian, Thézé, Julien, Faria, Nuno R., Lourenço, José
... Viruses, such as dengue, Zika, yellow fever and chikungunya, depend on mosquitoes for transmission. Their epidemics typically present periodic patterns, linked to the underlying mosquito population dynamics, which are known to be driven by natural climate fluctuations. Understanding how climate dictates the timing and potential of viral transmission is essential for preparedness of public health systems and design of control strategies. While various alternative approaches have been proposed to estimate local transmission potential of such viruses, few open‐source, ready to use and freely available software tools exist. We developed the Mosquito‐borne Viral Suitability Estimator (MVSE) software package for the R programming environment. MVSE estimates the index P, a novel suitability index based on a climate‐driven mathematical expression for the basic reproductive number of mosquito‐borne viruses. By accounting for local humidity and temperature, as well as viral, vector and human priors, the index P can be estimated for specific host and viral species in different regions of the globe. We describe the background theory, empirical support and biological interpretation of the index P. Using real‐world examples spanning multiple epidemiological contexts, we further demonstrate MVSE's basic functionality, research and educational potentials.
Contributors: Patel, Avnish, Perrin, Abigail J, Flynn, Helen R, Bisson, Claudine, Withers-Martinez, Chrislaine, Treeck, Moritz, Flueck, Christian, Nicastro, Giuseppe, Martin, Stephen R, Ramos, Andres
... Cyclic AMP (cAMP) is an important signalling molecule across evolution, but its role in malaria parasites is poorly understood. We have investigated the role of cAMP in asexual blood stage development of Plasmodium falciparum through conditional disruption of adenylyl cyclase beta (ACβ) and its downstream effector, cAMP-dependent protein kinase (PKA). We show that both production of cAMP and activity of PKA are critical for erythrocyte invasion, whilst key developmental steps that precede invasion still take place in the absence of cAMP-dependent signalling. We also show that another parasite protein with putative cyclic nucleotide binding sites, Plasmodium falciparum EPAC (PfEpac), does not play an essential role in blood stages. We identify and quantify numerous sites, phosphorylation of which is dependent on cAMP signalling, and we provide mechanistic insight as to how cAMP-dependent phosphorylation of the cytoplasmic domain of the essential invasion adhesin apical membrane antigen 1 (AMA1) regulates erythrocyte invasion.
Contributors: Walker, Dominic
... Spreadsheet containing information on applications for open access Article Processing Charges (APCs) made through the Research Councils UK (RCUK) block grant between 1 April 2018 and 31 March 2019 at the London School of Hygiene and Tropical Medicine. Information collected by the Open Access team in LSHTM's Library & Archives Service.
Identification of regulatory variants associated with genetic susceptibility to meningococcal disease
Contributors: Borghini, Lisa, Png, Eileen, Binder, Alexander, Wright, Victoria J, Pinnock, Ellie, de Groot, Ronald, Hazelzet, Jan, Emonts, Marieke, Van der Flier, Michiel, Schlapbach, Luregn J
... Non-coding genetic variants play an important role in driving susceptibility to complex diseases but their characterization remains challenging. Here, we employed a novel approach to interrogate the genetic risk of such polymorphisms in a more systematic way by targeting specific regulatory regions relevant for the phenotype studied. We applied this method to meningococcal disease susceptibility, using the DNA binding pattern of RELA – a NF-kB subunit, master regulator of the response to infection – under bacterial stimuli in nasopharyngeal epithelial cells. We designed a custom panel to cover these RELA binding sites and used it for targeted sequencing in cases and controls. Variant calling and association analysis were performed followed by validation of candidate polymorphisms by genotyping in three independent cohorts. We identified two new polymorphisms, rs4823231 and rs11913168, showing signs of association with meningococcal disease susceptibility. In addition, using our genomic data as well as publicly available resources, we found evidences for these SNPs to have potential regulatory effects on ATXN10 and LIF genes respectively. The variants and related candidate genes are relevant for infectious diseases and may have important contribution for meningococcal disease pathology. Finally, we described a novel genetic association approach that could be applied to other phenotypes.
Contributors: Ashton, PM, Thanh, LT, Trieu, PH, Van Anh, D, Trinh, NM, Beardsley, J, Kibengo, F, Chierakul, W, Dance, DAB, Rattanavong, S
... Cryptococcus neoformans (C. neoformans var. grubii) is an environmentally acquired pathogen causing 181,000 HIV-associated deaths each year. We sequenced 699 isolates, primarily C. neoformans from HIV-infected patients, from 5 countries in Asia and Africa. The phylogeny of C. neoformans reveals a recent exponential population expansion, consistent with the increase in the number of susceptible hosts. In our study population, this expansion has been driven by three sub-clades of the C. neoformans VNIa lineage; VNIa-4, VNIa-5 and VNIa-93. These three sub-clades account for 91% of clinical isolates sequenced in our study. Combining the genome data with clinical information, we find that the VNIa-93 sub-clade, the most common sub-clade in Uganda and Malawi, was associated with better outcomes than VNIa-4 and VNIa-5, which predominate in Southeast Asia. This study lays the foundation for further work investigating the dominance of VNIa-4, VNIa-5 and VNIa-93 and the association between lineage and clinical phenotype.
Contributors: Miller, Lori, Chaudhri, Shahana, Beaumont, Danielle, Kayani, Aasia, Javaid, Kiran, Chaudhri, Rizwana, Edwards, Phil, Brenner, Amy, Roberts, Ian, Shakur-still, Haleema
... Data and supporting material produced as part of a pilot study to test outcome questions for the WOMAN-2 trial of tranexamic acid for the prevention of postpartum haemorrhage. This pilot study was conducted in one hospital which will also be conducting the WOMAN-2 Trial in Pakistan. The pilot study population included participants similar to those to be included in the WOMAN-2 Trial: women who are anaemic, and having given birth. Participants took part in an interview which included answering questions from the draft participant reported outcomes questionnaire. A small subset of participants enrolled in this pilot study also took part in a cognitive interview directly following the questionnaire to learn how they understood the questions. Each row of the dataset table represents data for an individual participant.