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121.
A genomewide linkage-disequilibrium scan localizes the Saguenay-Lac-Saint-Jean cytochrome oxidase deficiency to 2p16 下载免费PDF全文
Lee N Daly MJ Delmonte T Lander ES Xu F Hudson TJ Mitchell GA Morin CC Robinson BH Rioux JD 《American journal of human genetics》2001,68(2):397-409
Leigh syndrome (LS) affects 1/40,000 newborn infants in the worldwide population and is characterized by the presence of developmental delay and lactic acidosis and by a mean life expectancy variously estimated at 3-5 years. Saguenay-Lac-Saint-Jean (SLSJ) cytochrome oxidase (COX) deficiency (LS French-Canadian type [LSFC] [MIM 220111]), an autosomal recessive form of congenital lactic acidosis, presents with developmental delay and hypotonia. It is an LS variant that is found in a geographically isolated region of Quebec and that occurs in 1/2,178 live births. Patients with LSFC show a phenotype similar to that of patients with LS, but the two groups differ in clinical presentation. We studied DNA samples from 14 patients with LSFC and from their parents, representing a total of 13 families. Because of founder effects in the SLSJ region, considerable linkage disequilibrium (LD) was expected to surround the LSFC mutation. We therefore performed a genomewide screen for LD, using 290 autosomal microsatellite markers. A single marker, D2S1356, located on 2p16, showed significant (P < 10(-5)) genomewide LD. Using high-resolution genetic mapping with additional markers and four additional families with LSFC, we were able to identify a common ancestral haplotype and to limit the critical region to approximately 2 cM between D2S119 and D2S2174. COX7AR, a gene encoding a COX7a-related protein, had previously been mapped to this region. We determined the genomic structure and resequenced this gene in patients with LSFC and in controls but found no functional mutations. Although the LSFC gene remains to be elucidated, the present study demonstrates the feasibility of using a genomewide LD strategy to localize the critical region for a rare genetic disease in a founder population. 相似文献
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John Baeten Amritha Suresh Alexander Johnson Ketan Patel Moni Kuriakose Anita Flynn Deepak Kademani 《Translational oncology》2014,7(2):213-220
Aberrant glycosylation during carcinogenesis results in altered glycan expression on oral cancer cells. The objective of this study was to detect this atypical glycosylation via imaging of fluorophore-conjugated lectins. Paired normal and tumor tissue from seven patients with oral squamous cell carcinoma were investigated for sialic acid expression via the legume protein wheat germ agglutinin (WGA). Fluorophore (Alexa Fluor 350 and Alexa Fluor 647) conjugated WGA was topically applied to the tissue samples and imaged using a custom wide-field fluorescence imaging system. All seven patients had histologically confirmed disease with 6/7 exhibiting squamous cell carcinoma and 1/7 exhibiting dysplasia. Fluorescent data collected from all patients demonstrated that fluorophore conjugated WGA could distinguish between pathologically normal and diseased tissue with the average signal-to-noise ratio (SNR) among all patients being 5.88 (P = .00046). This SNR was statistically significantly higher than the SNR from differences in tissue autofluorescence (P = .0049). A lectin inhibitory experiment confirmed that lectin binding is molecularly specific to overexpressed tumor glycans and that fluorescence is not due to tissue optical properties or tissue diffusion differences. These results illustrate that changes in tumor glycan content of oral neoplasms can be detected with optical imaging using topically applied fluorescently labeled WGA. Lectin targeting of oral lesions using optical imaging may provide a new avenue for the early detection of oral cancers. 相似文献
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Renee Heffron Craig R. Cohen Kenneth Ngure Elizabeth Bukusi Edwin Were James Kiarie Nelly Mugo Connie Celum Jared M. Baeten Partners PrEP Study the Partners in Prevention HSV/HIV Transmission Study and the Partners Demonstration Project Teams 《PloS one》2015,10(12)
Introduction
HIV-1 prevention programs targeting HIV-1 serodiscordant couples need to identify couples that are likely to become pregnant to facilitate discussions about methods to minimize HIV-1 risk during pregnancy attempts (i.e. safer conception) or effective contraception when pregnancy is unintended. A clinical prediction tool could be used to identify HIV-1 serodiscordant couples with a high likelihood of pregnancy within one year.Methods
Using standardized clinical prediction methods, we developed and validated a tool to identify heterosexual East African HIV-1 serodiscordant couples with an increased likelihood of becoming pregnant in the next year. Datasets were from three prospectively followed cohorts, including nearly 7,000 couples from Kenya and Uganda participating in HIV-1 prevention trials and delivery projects.Results
The final score encompassed the age of the woman, woman’s number of children living, partnership duration, having had condomless sex in the past month, and non-use of an effective contraceptive. The area under the curve (AUC) for the probability of the score to correctly predict pregnancy was 0.74 (95% CI 0.72–0.76). Scores ≥7 predicted a pregnancy incidence of >17% per year and captured 78% of the pregnancies. Internal and external validation confirmed the predictive ability of the score.Discussion
A pregnancy likelihood score encompassing basic demographic, clinical and behavioral factors defined African HIV-1 serodiscordant couples with high one-year pregnancy incidence rates. This tool could be used to engage African HIV-1 serodiscordant couples in counseling discussions about fertility intentions in order to offer services for safer conception or contraception that align with their reproductive goals. 相似文献125.
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Yimer Wasihun Kifle Nele Goeyvaerts Kim Van Kerckhove Lander Willem Christel Faes Herwig Leirs Niel Hens Philippe Beutels 《PloS one》2015,10(7)
Many human infectious diseases originate from animals or are transmitted through animal vectors. We aimed to identify factors that are predictive of ownership and touching of animals, assess whether animal ownership influences social contact behavior, and estimate the probability of a major zoonotic outbreak should a transmissible influenza-like pathogen be present in animals, all in the setting of a densely populated European country. A diary-based social contact survey (n = 1768) was conducted in Flanders, Belgium, from September 2010 until February 2011. Many participants touched pets (46%), poultry (2%) or livestock (2%) on a randomly assigned day, and a large proportion of participants owned such animals (51%, 15% and 5%, respectively). Logistic regression models indicated that larger households are more likely to own an animal and, unsurprisingly, that animal owners are more likely to touch animals. We observed a significant effect of age on animal ownership and touching. The total number of social contacts during a randomly assigned day was modeled using weighted-negative binomial regression. Apart from age, household size and day type (weekend versus weekday and regular versus holiday period), animal ownership was positively associated with the total number of social contacts during the weekend. Assuming that animal ownership and/or touching are at-risk events, we demonstrate a method to estimate the outbreak potential of zoonoses. We show that in Belgium animal-human interactions involving young children (0–9 years) and adults (25–54 years) have the highest potential to cause a major zoonotic outbreak. 相似文献
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Lander Willem Sean Stijven Ekaterina Vladislavleva Jan Broeckhove Philippe Beutels Niel Hens 《PLoS computational biology》2014,10(4)
Modeling plays a major role in policy making, especially for infectious disease interventions but such models can be complex and computationally intensive. A more systematic exploration is needed to gain a thorough systems understanding. We present an active learning approach based on machine learning techniques as iterative surrogate modeling and model-guided experimentation to systematically analyze both common and edge manifestations of complex model runs. Symbolic regression is used for nonlinear response surface modeling with automatic feature selection. First, we illustrate our approach using an individual-based model for influenza vaccination. After optimizing the parameter space, we observe an inverse relationship between vaccination coverage and cumulative attack rate reinforced by herd immunity. Second, we demonstrate the use of surrogate modeling techniques on input-response data from a deterministic dynamic model, which was designed to explore the cost-effectiveness of varicella-zoster virus vaccination. We use symbolic regression to handle high dimensionality and correlated inputs and to identify the most influential variables. Provided insight is used to focus research, reduce dimensionality and decrease decision uncertainty. We conclude that active learning is needed to fully understand complex systems behavior. Surrogate models can be readily explored at no computational expense, and can also be used as emulator to improve rapid policy making in various settings. 相似文献
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Lander Baeten Kris Verheyen Christian Wirth Helge Bruelheide Filippo Bussotti Leena Finér Bogdan Jaroszewicz Federico Selvi Fernando Valladares Eric Allan Evy Ampoorter Harald Auge Daniel Avăcăriei Luc Barbaro Ionu Bărnoaiea Cristina C. Bastias Jürgen Bauhus Carsten Beinhoff Michael Scherer-Lorenzen 《Perspectives in Plant Ecology, Evolution and Systematics》2013,15(5):281-291
One of the current advances in functional biodiversity research is the move away from short-lived test systems towards the exploration of diversity-ecosystem functioning relationships in structurally more complex ecosystems. In forests, assumptions about the functional significance of tree species diversity have only recently produced a new generation of research on ecosystem processes and services. Novel experimental designs have now replaced traditional forestry trials, but these comparatively young experimental plots suffer from specific difficulties that are mainly related to the tree size and longevity. Tree species diversity experiments therefore need to be complemented with comparative observational studies in existing forests. Here we present the design and implementation of a new network of forest plots along tree species diversity gradients in six major European forest types: the FunDivEUROPE Exploratory Platform. Based on a review of the deficiencies of existing observational approaches and of unresolved research questions and hypotheses, we discuss the fundamental criteria that shaped the design of our platform. Key features include the extent of the species diversity gradient with mixtures up to five species, strict avoidance of a dilution gradient, special attention to community evenness and minimal covariation with other environmental factors. The new European research platform permits the most comprehensive assessment of tree species diversity effects on forest ecosystem functioning to date since it offers a common set of research plots to groups of researchers from very different disciplines and uses the same methodological approach in contrasting forest types along an extensive environmental gradient. 相似文献
130.
Elinor K Karlsson Snaevar Sigurdsson Emma Ivansson Rachael Thomas Ingegerd Elvers Jason Wright Cedric Howald Noriko Tonomura Michele Perloski Ross Swofford Tara Biagi Sarah Fryc Nathan Anderson Celine Courtay-Cahen Lisa Youell Sally L Ricketts Sarah Mandlebaum Patricio Rivera Henrik von Euler William C Kisseberth Cheryl A London Eric S Lander Guillermo Couto Kenine Comstock Mike P Starkey Jaime F Modiano Matthew Breen Kerstin Lindblad-Toh 《Genome biology》2013,14(12):1-16