Molecular diagnosis for heterogeneous genetic diseases with high-throughput DNA sequencing applied to retinitis pigmentosa

BACKGROUND:
The genetic heterogeneity of many Mendelian disorders, such as retinitis pigmentosa which results from mutations in over 40 genes, is a major obstacle to obtaining a molecular diagnosis in clinical practice. Targeted high-throughput DNA sequencing offers a potential solution and was used to develop a molecular diagnostic screen for patients with retinitis pigmentosa.
METHODS:
A custom sequence capture array was designed to target the coding regions of all known retinitis pigmentosa genes and used to enrich these sequences from DNA samples of five patients. Enriched DNA was subjected to high-throughput sequencing singly or in pools, and sequence variants were identified by alignment of up to 10 million reads per sample to the normal reference sequence. Potential pathogenicity was assessed by functional predictions and frequency in controls.
RESULTS AND CONCLUSIONS:
Known homozygous PDE6B and compound heterozygous CRB1 mutations were detected in two patients. A novel homozygous missense mutation (c.2957A?T; p.N986I) in the cyclic nucleotide gated channel ß1 (CNGB1) gene predicted to have a deleterious effect and absent in 720 control chromosomes was detected in one case in which conventional genetic screening had failed to detect mutations. The detection of known and novel retinitis pigmentosa mutations in this study establishes high-throughput DNA sequencing with DNA pooling as an effective diagnostic tool for heterogeneous genetic diseases.

Phase-Transfer Catalysis in Segmented Flow in a Microchannel: Fluidic Control of Selectivity and Productivity

Precise control over the interfacial area of aqueous and organic slugs in segmented flow in a microchannel reactor provides an attractive means to optimize the yield and productivity of a phase-transfer-catalyzed reaction. Herein, we report the selective alkylation of phenylacetonitrile to the monoalkylated product in a microchannel of 250-mu m internal diameter operated in a continuous and solvent-free manner in the slug-flow regime. The conversion of phenylacetonitrile increased from 40% to 99% as a result of a 97% larger slug surface-to-volume ratio when the volumetric aqueous-to-organic phase flow ratio was raised from 1.0 to 6.1 at the same residence time. The larger surface-to-volume ratio significantly promoted catalyst phase transfer but decreased selectivity because of the simultaneous increase of the rate of the consecutive reaction to the dialkylated product. There exists all Optimum flow ratio with a maximum productivity. Conversion and selectivity in the microchannel reactor were both found to be significantly larger than in a stirred reactor.

TESTING FOR STATIONARITY IN HETEROGENEOUS PANEL DATA IN THE CASE OF MODEL MISSPECIFICATION

This paper investigates the performance of the tests proposed by Hadri and by Hadri and Larsson for testing for stationarity in heterogeneous panel data under model misspecification. The panel tests are based on the well known KPSS test (cf. Kwiatkowski et al.) which considers two models: stationarity around a deterministic level and stationarity around a deterministic trend. There is no study, as far as we know, on the statistical properties of the test when the wrong model is used. We also consider the case of the simultaneous presence of the two types of models in a panel. We employ two asymptotics: joint asymptotic, T, N -> infinity simultaneously, and T fixed and N allowed to grow indefinitely. We use Monte Carlo experiments to investigate the effects of misspecification in sample sizes usually used in practice. The results indicate that the assumption that T is fixed rather than asymptotic leads to tests that have less size distortions, particularly for relatively small T with large N panels (micro-panels) than the tests derived under the joint asymptotics. We also find that choosing a deterministic trend when a deterministic level is true does not significantly affect the properties of the test. But, choosing a deterministic level when a deterministic trend is true leads to extreme over-rejections. Therefore, when unsure about which model has generated the data, it is suggested to use the model with a trend. We also propose a new statistic for testing for stationarity in mixed panel data where the mixture is known. The performance of this new test is very good for both cases of T asymptotic and T fixed. The statistic for T asymptotic is slightly undersized when T is very small (

On the function of the internal cavity of histone deacetylase protein 8: R37 is a crucial residue for catalysis

Biochemical studies reveal that a conserved arginine residue (R37) at the centre of the 14 angstrom internal cavity of histone deacetylase (HDAC) 8 is important for catalysis and acetate affinity. Computational studies indicate that R37 forms multiple hydrogen bonding interactions with the backbone carbonyl oxygen atoms of two conserved glycine residues, G303 and G305, resulting in a 'closed' form of the channel. One possible rationale for these data is that water or product (acetate) transit through the catalytically crucial internal channel of HDAC8 is regulated by a gating interaction between G139 and G303 tethered in position by the conserved R37. (C) 2011 Elsevier Ltd. All rights reserved.

Combining bio- and chemo-catalysis: from enzymes to cells, from petroleum to biomass

In the future, biomass will continue to emerge as a viable source of chemicals. The development of new industries that utilize bio-renewables provides opportunities for innovation. For example, bio- and chemo-catalysts can be combined in 'one pot' to prepare chemicals of commercial value. This has been demonstrated using isolated enzymes and whole cells for a variety of chemical transformations. The one-pot approach has been successfully adopted to convert chemicals derived from biomass, and, in our opinion, it has an important role to play in the design of a more sustainable chemical industry. To implement new one-pot bio- and chemo-catalytic processes, issues of incompatibility must be overcome; the strategies for which are discussed in this opinion article.

A Pipeline Interleaved Heterogeneous SIMD Soft Processor Array Architecture for MIMO-OFDM Detection

The most promising way to maintain reliable data transfer across the rapidly fluctuating channels used by next generation multiple-input multiple-output communications schemes is to exploit run-time variable modulation and antenna configurations. This demands that the baseband signal processing architectures employed in the communications terminals must provide low cost and high performance with runtime reconfigurability. We present a softcore-processor based solution to this issue, and show for the first time, that such programmable architectures can enable real-time data operation for cutting-edge standards
such as 802.11n; furthermore, by exploiting deep processing pipelines and interleaved task execution, the cost and performance of these architectures is shown to be on a par with traditional dedicated circuit based solutions. We believe this to be the first such programmable architecture to achieve this, and the combination of implementation efficiency and programmability makes this implementation style the most promising approach for hosting such dynamic architectures.