Biology subjects

Redmond, S.

Publications and source records attributed to Redmond, S..

6 recordsLinked to original sources

bioRxiv2024

Sequencing 1206 genomes reveals origin and movement of Aedes aegypti driving increased dengue risk

The number of dengue cases worldwide has increased ten-fold over the past decade as Aedes aegypti, the primary vector of this disease, thrives and expands its distribution, revealing limitations to current control methods. To better understand how Ae. aegypti evolved from a forest dwelling, generalist species to a highly anthropophilic urban species and the impact of contemporary gene flow on the future of dengue control, we sequenced 1,206 genomes from mosquitoes collected at 74 locations around the globe. Here we show that after evolving a preference for humans in the Sahel region of West Africa, the origin of the fully domesticated, anthropophilic subspecies Ae. aegypti aegypti (Aaa) occurred in the Americas during the Atlantic Slave Trade era and was followed by its explosive expansion around the globe. In recent decades, Aaa has invaded coastal Africa, the ancestral home range, introducing insecticide resistance mutations and an affinity for human hosts. Evidence of back-to-Africa migration is found in regions with recent dengue outbreaks, raising concern that global movement of Aaa could increase transmission risk of arboviruses including dengue in urban Africa. These data provide a platform to further study this important mosquito vector species and underscore developing complexity in the fight to limit the spread of dengue, Zika, and chikungunya diseases.

genomics↗

bioRxiv2024

Deep Learning Analysis on Images of iPSC-derived Motor Neurons Carrying fALS-genetics Reveals Disease-Relevant Phenotypes

Amyotrophic lateral sclerosis (ALS) is a devastating condition with very limited treatment options. It is a heterogeneous disease with complex genetics and unclear etiology, making the discovery of disease-modifying interventions very challenging. To discover novel mechanisms underlying ALS, we leverage a unique platform that combines isogenic, induced pluripotent stem cell (iPSC)-derived models of disease-causing mutations with rich phenotyping via high-content imaging and deep learning models. We introduced eight mutations that cause familial ALS (fALS) into multiple donor iPSC lines, and differentiated them into motor neurons to create multiple isogenic pairs of healthy (wild-type) and sick (mutant) motor neurons. We collected extensive high-content imaging data and used machine learning (ML) to process the images, segment the cells, and learn phenotypes. Self-supervised ML was used to create a concise embedding that captured significant, ALS-relevant biological information in these images. We demonstrate that ML models trained on core cell morphology alone can accurately predict TDP-43 mislocalization, a known phenotypic feature related to ALS. In addition, we were able to impute RNA expression from these image embeddings, in a way that elucidates molecular differences between mutants and wild-type cells. Finally, predictors leveraging these embeddings are able to distinguish between mutant and wild-type both within and across donors, defining cellular, ML-derived disease models for diverse fALS mutations. These disease models are the foundation for a novel screening approach to discover disease-modifying targets for familial ALS.

neuroscience↗

bioRxiv2019

Temporal trends in incidence of childhood cancer in Switzerland, 1985-2014

STRUCTURED ABSTRACTO_ST_ABSBackgroundC_ST_ABSIncidence of childhood cancer increased in most countries worldwide, but the reasons are unclear. This study investigates trends in childhood cancer incidence in Switzerland from 1985 to 2014.\n\nMethodsWe extracted data on all childhood cancer cases diagnosed at ages 0-14 years in Switzerland from the Swiss Childhood Cancer Registry. We included ICCC-3 main groups I-XII and calculated age-standardised, cumulative, and age-specific incidence for different diagnostic groups. We analysed trends in annual age-standardised incidence using JoinPoint regression models.\n\nResultsOver the study period from 1985-2014, 5104 of 5486 cancer diagnoses (93%) were microscopically verified. The proportion of children treated in paediatric cancer centres increased from 84% during 1985-1994 to 93% in 1995-2004 and 98% in 2005-2014 (p<0.001). Using the 2010 European standard population, age-standardised incidence was 143 in 1985-1994, 154 in 1995-2004, and 162 per million in 2005-2014. Over the period 1985-2014, incidence for all cancers increased by 0.7% (95% confidence interval [CI] 0.5-1.0) per year, 0.8% (95% CI 0.2%-1.4%) for leukaemias, 3.8% (95% CI 1.7%-6.0%) for epithelial neoplasms and melanomas, and 3.0% (95% CI 1.3%-4.6%) for CNS tumours for the period 1985-2002.\n\nConclusionTrends in incidence were driven mostly by increases among leukaemias and CNS tumours. For CNS tumours, observed trends may be explained at least partially by diagnostic changes and improved registration. For leukaemias, rising incidence may be real and at least partly due to changes in risk factors.\n\nHighlightsO_LIIn Switzerland, incidence of childhood cancer increased by 18% from 1985-2014.\nC_LIO_LIIncrease in incidence was mainly caused by brain tumours and leukaemias.\nC_LIO_LIImproved registration and diagnostics may have increased brain tumour incidence.\nC_LIO_LIIncreasing trend for leukaemias may be real, but reasons remain elusive.\nC_LI

epidemiology↗

bioRxiv2019

Tumor Necrosis Factor induces pathogenic programmed macrophage necrosis in tuberculosis through a mitochondrial-lysosomal-endoplasmic reticulum circuit

Necrosis of infected macrophages constitutes a critical pathogenetic event in tuberculosis releasing mycobacteria into the extracellular environment where they can grow unrestricted. In zebrafish infected with Mycobacterium marinum, a close relative of Mycobacterium tuberculosis, excess Tumor Necrosis Factor triggers programmed necrosis of infected macrophages through the production of mitochondrial reactive oxygen species (ROS) and the participation of cyclophilin D, a component of the mitochondrial permeability transition pore. Here we show that this necrosis pathway is not mitochondrion-intrinsic but rather results from an interorganellar circuit initiating and culminating in the mitochondrion. Mitochondrial ROS induce production of lysosomal ceramide which ultimately activates the cytosolic protein BAX. BAX promotes calcium flow from the endoplasmic reticulum into the mitochondrion through ryanodine receptors. The resultant mitochondrial calcium overload triggers cyclophilin D-mediated necrosis. We identify ryanodine receptors and plasma membrane L-Type calcium channels as specific druggable targets to intercept mitochondrial calcium overload so as to inhibit macrophage necrosis.

cell biology↗

bioRxiv2018

A chromosome-scale assembly of the major African malaria vector Anopheles funestus

BackgroundAnopheles funestus is one of the three most consequential and widespread vectors of human malaria in tropical Africa. However, the lack of a high-quality reference genome has hindered the association of phenotypic traits with their genetic basis in this important mosquito.\n\nFindingsHere we present a new high-quality An. funestus reference genome (AfunF3) assembled using 240x coverage of long-read single-molecule sequencing for contigging, combined with 100x coverage of short-read Hi-C data for chromosome scaffolding. The assembled contigs total 446 Mbp of sequence and contain substantial duplication due to alternative alleles present in the sequenced pool of mosquitos from the FUMOZ colony. Using alignment and depth-of-coverage information, these contigs were deduplicated to a 211 Mbp primary assembly, which is closer to the expected haploid genome size of 250 Mbp. This primary assembly consists of 1,053 contigs organized into 3 chromosome-scale scaffolds with an N50 contig size of 632 kbp and an N50 scaffold size of 93.811 Mbp, representing a 100-fold improvement in continuity versus the current reference assembly, AfunF1.\n\nConclusionThis highly contiguous and complete An. funestus reference genome assembly will serve as an improved basis for future studies of genomic variation and organization in this important disease vector.

bioinformatics↗

bioRxiv2016

Natural diversity of the malaria vector Anopheles gambiae

The sustainability of malaria control in Africa is threatened by rising levels of insecticide resistance, and new tools to prevent malaria transmission are urgently needed. To gain a better understanding of the mosquito populations that transmit malaria, we sequenced the genomes of 765 wild specimens of Anopheles gambiae and Anopheles coluzzii sampled from 15 locations across Africa. The data reveal high levels of genetic diversity, with over 50 million single nucleotide polymorphisms across the 230 Mbp genome. We observe complex patterns of population structure and marked variations in local population size, some of which may be due at least in part to malaria control interventions. Insecticide resistance genes show strong signatures of recent selection associated with multiple independent mutations spreading over large geographical distances and between species. The genetic variability of natural populations substantially reduces the target space for novel gene-drive strategies for mosquito control. This large dataset provides a foundation for tracking the emergence and spread of insecticide resistance and developing new vector control tools.

genomics↗