Genome-wide association study of Alzheimer's disease with psychotic symptoms

Psychotic symptoms occur in ~40% of subjects with Alzheimer's disease (AD) and are associated with more rapid cognitive decline and increased functional deficits. They show heritability up to 61% and have been proposed as a marker for a disease subtype suitable for gene mapping efforts. We undertook a combined analysis of three genome-wide association studies (GWASs) to identify loci that (1) increase susceptibility to an AD and subsequent psychotic symptoms; or (2) modify risk of psychotic symptoms in the presence of neurodegeneration caused by AD. In all, 1299 AD cases with psychosis (AD+P), 735 AD cases without psychosis (AD-P) and 5659 controls were drawn from Genetic and Environmental Risk in AD Consortium 1 (GERAD1), the National Institute on Aging Late-Onset Alzheimer's Disease (NIA-LOAD) family study and the University of Pittsburgh Alzheimer Disease Research Center (ADRC) GWASs. Unobserved genotypes were imputed to provide data on >1.8 million single-nucleotide polymorphisms (SNPs). Analyses in each data set were completed comparing (1) AD+P to AD-P cases, and (2) AD+P cases with controls (GERAD1, ADRC only). Aside from the apolipoprotein E (APOE) locus, the strongest evidence for association was observed in an intergenic region on chromosome 4 (rs753129; 'AD+PvAD-P' P=2.85 × 10(-7); 'AD+PvControls' P=1.11 × 10(-4)). SNPs upstream of SLC2A9 (rs6834555, P=3.0 × 10(-7)) and within VSNL1 (rs4038131, P=5.9 × 10(-7)) showed strongest evidence for association with AD+P when compared with controls. These findings warrant further investigation in larger, appropriately powered samples in which the presence of psychotic symptoms in AD has been well characterized.Molecular Psychiatry advance online publication, 18 October 2011; doi:10.1038/mp.2011.125.

Association between tortilla consumption and human urinary fumonisin B1 levels in a Mexican population

Fumonisins are mycotoxins produced by Fusarium spp. and commonly contaminate maize and maize products worldwide. Fumonisins are rodent carcinogens and have been associated with human esophageal cancer. However, the lack of a valid exposure biomarker has hindered both the assessment of human exposure and the evaluation of disease risk. A sensitive liquid chromatography-mass spectrometry method to measure urinary fumonisin B1 (FB1) following extraction on Oasis MAX cartridges was established and applied to urine samples from women in a cohort recruited in Morelos County, Mexico. Urinary FB1 was compared with dietary information on tortilla consumption. FB1 recovery in spiked samples averaged 94% as judged by deuterium-labeled FB1 internal standard. Urinary FB1 was determined in 75 samples from women selected based on low, medium, or high consumption of maize-based tortillas. The geometric mean (95% confidence interval) of urinary FB1 was 35.0 (18.8-65.2), 63.1 (36.8-108.2), and 147.4 (87.6-248.0) pg/mL and the frequency of samples above the detection limit (set at 20 pg FB1/mL urine) was 45%, 80%, and 96% for the low, medium, and high groups, respectively. Women with high intake had a 3-fold higher average FB1 levels compared with the "low intake" group (F = 7.3; P = 0.0015). Urinary FB1 was correlated with maize intake (P-trend = 0.001); the correlation remained significant after adjusting for age, education, and place of residence. This study suggests that measurement of urinary FB1 is sufficiently sensitive for fumonisin exposure assessment in human populations and could be a valuable tool in investigating the associated health effects of exposure.

Pre-storage of gelified reagents in a lab-on-a-foil system for rapid nucleic acid analysis

Reagent pre-storage in a microfluidic chip can enhance operator convenience, simplify the system design, reduce the cost of storage and shipment, and avoid the risk of cross-contamination. Although dry reagents have long been used in lateral flow immunoassays, they have rarely been used for nucleic acid-based point-of-care (POC) assays due to the lack of reliable techniques to dehydrate and store fragile molecules involved in the reaction. In this study, we describe a simple and efficient method for prolonged on-chip storage of PCR reagents. The method is based on gelification of all reagents required for PCR as a ready-to-use product. The approach was successfully implemented in a lab-on-a-foil system, and the gelification process was automated for mass production. Integration of reagents on-chip by gelification greatly facilitated the development of easy-to-use lab-on-a-chip (LOC) devices for fast and cost-effective POC analysis.

The water-gas shift reaction over CeO/CuO:Operando SSITKA-DRIFTS-mass spectrometry study of low temperature mechanism

An inverse CeO2/CuO catalyst has been investigated by operando steady-state isotopic transient kinetic analysis (SSITKA) in combination with diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS) under 3% CO +3% H2O reactant mixture at 473 K with the aim of determining intermediates involved in the water gas shift reaction at relatively low temperatures. Among the various species detected in the infrared spectra which may be involved in the reaction, i.e. formates, copper carbonyls and carbonates, a particular type of carbonate species is identified as a reaction intermediate on the basis of detailed analysis of the spectra during isotopic exchange in comparison with the change in the corresponding isotopically labelled CO2 product. 

GELIFICATION - A SIMPLE AND EFFICIENT METHOD FOR ON-CHIP STORAGE OF REAGENTS: TOWARDS LAB-ON-A-CHIP SYSTEMS FOR POINT-OF-CARE DIAGNOSTICS

In this study, we describe a simple and efficient method for on-chip storage of reagents for point-of-care (POC) diagnostics. The method is based on gelification of all reagents required for on-chip PCR-based diagnostics as a ready-to-use product. The result reported here is a key step towards the development of a ready and easy to use fully integrated Lab-on-a-chip (LOC) system for fast, cost-effective and efficient POC diagnostics analysis.

Next generation sequencing-based molecular diagnosis of retinitis pigmentosa: identification of a novel genotype-phenotype correlation and clinical refinements

Retinitis pigmentosa (RP) is a devastating form of retinal degeneration, with significant social and professional consequences. Molecular genetic information is invaluable for an accurate clinical diagnosis of RP due to its high genetic and clinical heterogeneity. Using a gene capture panel that covers 163 of the currently known retinal disease genes, including 48 RP genes, we performed a comprehensive molecular screening in a collection of 123 RP unsettled probands from a wide variety of ethnic backgrounds, including 113 unrelated simplex and 10 autosomal recessive RP (arRP) cases. As a result, 61 mutations were identified in 45 probands, including 38 novel pathogenic alleles. Interestingly, we observed that phenotype and genotype were not in full agreement in 21 probands. Among them, eight probands were clinically reassessed, resulting in refinement of clinical diagnoses for six of these patients. Finally, recessive mutations in CLN3 were identified in five retinal degeneration patients, including four RP probands and one cone-rod dystrophy patient, suggesting that CLN3 is a novel non-syndromic retinal disease gene. Collectively, our results underscore that, due to the high molecular and clinical heterogeneity of RP, comprehensive screening of all retinal disease genes is effective in identifying novel pathogenic mutations and provides an opportunity to discover new genotype-phenotype correlations. Information gained from this genetic screening will directly aid in patient diagnosis, prognosis, and treatment, as well as allowing appropriate family planning and counseling.

Literature Focus

Literature focus is a feature consisting of short abstracts highlighting recent developments of interest in the literature selected
by postgraduate researchers.

The Kepler-10 Planetary System Revisited by HARPS-N: A Hot Rocky World and a Solid Neptune-Mass Planet

Kepler-10b was the first rocky planet detected by the Kepler satellite and confirmed with radial velocity follow-up observations from Keck-HIRES. The mass of the planet was measured with a precision of around 30%, which was
insufficient to constrain models of its internal structure and composition in detail. In addition to Kepler-10b, a second planet transiting the same star with a period of 45 days was statistically validated, but the radial velocities were only
good enough to set an upper limit of 20 M⊕ for the mass of Kepler-10c. To improve the precision on the mass for planet b, the HARPS-N Collaboration decided to observe Kepler-10 intensively with the HARPS-N spectrograph
on the Telescopio Nazionale Galileo on La Palma. In total, 148 high-quality radial-velocity measurements were obtained over two observing seasons. These new data allow us to improve the precision of the mass determination for Kepler-10b to 15%. With a mass of 3.33 ± 0.49 M⊕ and an updated radius of 1.47+0.03 −0.02 R⊕, Kepler-10b has a density of 5.8 ± 0.8 g cm−3, very close to the value predicted by models with the same internal structure and composition as the Earth. We were also able to determine a mass for the 45-day period planet Kepler-10c, with an even better precision of 11%. With a mass of 17.2 ± 1.9 M⊕ and radius of 2.35+0.09 −0.04 R⊕, Kepler-10c has a density of 7.1 ± 1.0 g cm−3. Kepler-10c appears to be the first strong evidence of a class of more massive solid planets with longer orbital periods

Characterization of the Kepler-101 planetary system with HARPS-N. A hot super-Neptune with an Earth-sized low-mass companion

We characterize the planetary system Kepler-101 by performing a combined differential evolution Markov chain Monte Carlo analysisof Kepler data and forty radial velocities obtained with the HARPS-N spectrograph. This system was previously validated and iscomposed of a hot super-Neptune, Kepler-101b, and an Earth-sized planet, Kepler-101c. These two planets orbit the slightly evolvedand metal-rich G-type star in 3.49 and 6.03 days, respectively. With mass Mp = 51.1+5.1−4.7 M⊕, radius Rp = 5.77+0.85−0.79 R⊕, and density ρp = 1.45+0.83 −0.48 g cm−3, Kepler-101b is the first fully characterized super-Neptune, and its density suggests that heavy elements makeup a significant fraction of its interior; more than 60% of its total mass. Kepler-101c has a radius of 1.25+0.19−0.17 R⊕, which implies theabsence of any H/He envelope, but its mass could not be determined because of the relative faintness of the parent star for highly precise radial-velocity measurements (Kp = 13.8) and the limited number of radial velocities. The 1σ upper limit, Mp < 3.8 M⊕, excludes a pure iron composition with a probability of 68.3%. The architecture of the planetary system Kepler-101 − containing aclose-in giant planet and an outer Earth-sized planet with a period ratio slightly larger than the 3:2 resonance − is certainly of interest for scenarios of planet formation and evolution. This system does not follow the previously reported trend that the larger planet has the longer period in the majority of Kepler systems of planet pairs with at least one Neptune-sized or larger planet.