Disease-specific, neurosphere-derived cells as models for brain disorders

There is a pressing need for patient-derived cell models of brain diseases that are relevant and robust enough to produce the large quantities of cells required for molecular and functional analyses. We describe here a new cell model based on patient-derived cells from the human olfactory mucosa, the organ of smell, which regenerates throughout life from neural stem cells. Olfactory mucosa biopsies were obtained from healthy controls and patients with either schizophrenia, a neurodevelopmental psychiatric disorder, or Parkinson's disease, a neurodegenerative disease. Biopsies were dissociated and grown as neurospheres in defined medium. Neurosphere-derived cell lines were grown in serum-containing medium as adherent monolayers and stored frozen. By comparing 42 patient and control cell lines we demonstrated significant disease-specific alterations in gene expression, protein expression and cell function, including dysregulated neurodevelopmental pathways in schizophrenia and dysregulated mitochondrial function, oxidative stress and xenobiotic metabolism in Parkinson's disease. The study has identified new candidate genes and cell pathways for future investigation. Fibroblasts from schizophrenia patients did not show these differences. Olfactory neurosphere-derived cells have many advantages over embryonic stem cells and induced pluripotent stem cells as models for brain diseases. They do not require genetic reprogramming and they can be obtained from adults with complex genetic diseases. They will be useful for understanding disease aetiology, for diagnostics and for drug discovery

History of malaria treatment as a predictor of subsequent subclinical parasitaemia: A cross-sectional survey and malaria case records from three villages in Pailin, western Cambodia

Background: Treatment of the sub-clinical reservoir of malaria, which may maintain transmission, could be an important component of elimination strategies. The reliable detection of asymptomatic infections with low levels of parasitaemia requires high-volume quantitative polymerase chain reaction (uPCR), which is impractical to conduct on a large scale. It is unknown to what extent sub-clinical parasitaemias originate from recent or older clinical episodes. This study explored the association between clinical history of malaria and subsequent sub-clinical parasitaemia. Methods: In June 2013 a cross-sectional survey was conducted in three villages in Pailin, western Cambodia. Demographic and epidemiological data and blood samples were collected. Blood was tested for malaria by high-volume qP

String kernels of imperfect matches for offtarget detection in RNA interference

Abstract. RNA interference (RNAi) is a posttranscriptional gene silencing mechanism frequently used to study gene functions and knock down viral genes. RNAi has been regarded as a highly effective means of gene repression. However, an “off-target effect ” deteriorates its specificity and applicability. The complete off-target effects can only be characterized by examining all factors through systematic investigation of each gene in a genome. However, this complete investigation is too expensive to conduct experimentally which motivates a computational study. The sequence matching between an siRNA and its target mRNA allows for mismatches, G-U wobbles, and the secondary structure bulges, in addition to exact matches. To simulate these matching features, we propose string kernels measuring the similarity between two oligonucleotides and develop novel efficient implementations for RNAi off-target detection. We apply the algorithms for off-target errors in C. elegans and human.

The impact of targeted malaria elimination with mass drug administrations on falciparum malaria in southeast Asia: A cluster randomised trial

10.1371/journal.pmed.1002745PLoS Medicine162e100274