An integrated semiconductor device enabling non-optical genome sequencing

The seminal importance of DNA sequencing to the life sciences, biotechnology and medicine has driven the search for more scalable and lower-cost solutions. Here we describe a DNA sequencing technology in which scalable, low-cost semiconductor manufacturing techniques are used to make an integrated circuit able to directly perform non-optical DNA sequencing of genomes. Sequence data are obtained by directly sensing the ions produced by template-directed DNA polymerase synthesis using all-natural nucleotides on this massively parallel semiconductor-sensing device or ion chip. The ion chip contains ion-sensitive, field-effect transistor-based sensors in perfect register with 1.2 million wells, which provide confinement and allow parallel, simultaneous detection of independent sequencing reactions. Use of the most widely used technology for constructing integrated circuits, the complementary metal-oxide semiconductor (CMOS) process, allows for low-cost, large-scale production and scaling of the device to higher densities and larger array sizes. We show the performance of the system by sequencing three bacterial genomes, its robustness and scalability by producing ion chips with up to 10 times as many sensors and sequencing a human genome.     

The molecular mechanisms of congenital hypofibrinogenaemia

Congenital hypofibrinogenaemia is characterized by abnormally low levels of fibrinogen and is usually caused by heterozygous mutations in the fibrinogen chain genes (, and ). However, it does not usually result in a clinically significant condition unless inherited in a homozygous or compound heterozygous state, where it results in a severe bleeding disorder, afibrinogenaemia. Various protein and expression studies have improved our understanding of how mutations causing hypo- and afibrinogenaemia affect secretion of the mature fibrinogen molecule from the hepatocyte. Some mutations can perturb chain assembly as in the 153 Cys Arg case, while others such as the B Leu Arg and the B414 Gly Ser mutations allow intracellular hexamer assembly but inhibit protein secretion. An interesting group of mutations, such as 284 Gly Arg and 375 Arg Trp, not only cause hypofibrinogenaemia but are also associated with liver disease. The nonexpression of these variant chains in plasma fibrinogen is due to retention in the endoplasmic reticulum, which in turn leads to hypofibrinogenaemia.Received 17 December 2003; received after revision 19 January 2004; accepted 21 January 2004     

The influence of pH on the sex-related differences in renal organic ion transport.

The stimulating effects of elevated medium pH and androgen on in vitro transport of p-aminohippurate and N-methylnicotinamide (NMN) were additive, although the androgenic effect was pH-dependent only in the case of NMN. The similarity of response of the 2 systems supports the idea of a common passive efflux pathway for organic anions and cations.     

Common sequence variants on 20q11.22 confer melanoma susceptibility

We conducted a genome-wide association pooling study for cutaneous melanoma and performed validation in samples totaling 2,019 cases and 2,105 controls. Using pooling, we identified a new melanoma risk locus on chromosome 20 (rs910873 and rs1885120), with replication in two further samples (combined P < 1 x 10(-15)). The per allele odds ratio was 1.75 (1.53, 2.01), with evidence for stronger association in early-onset cases.     

Terrain imaging using a SAR system based on reflected GPS signals

This paper describes a 3D multi-static synthetic aperture radar (SAR) imaging system which utilises reflected GPS signals from moving objects on the Earth's surface. The principle of bi-static radar is used to model the reflected GPS signals. The movement of a visible GPS satellite serves as a base for a synthetic aperture over an observation time period. As an example, a MATLAB simulation has been carried out in order to detect the movement of imaged object sunder the assumption of one static GPS receiver with two targets which move with different speeds. The influence of the visible satellite'sposition and velocity on the spatial resolution of such a SAR system isdiscussed. Simulation results show that by measuring the cross-correlation of the reflected GPS signal from the terrain and objects on it,the detection of the objects can enjoy a good spatial resolution for thecase of moving objects and a moving GPS receiver. Furthermore, thespatial resolution is also related to the selection of visible GPS satelliteswith respect to their azimuths, elevations and velocities. This systemhas the following useful features: (a) no dedicated signal transmitter is required; (b) the GPS signal frequency is reused; (c) GPS operates round-the-clock and its signals cover the entire Earth's surface; (d) low power consumption; and (e) known GPS signal structure.     

Evaluating lek occupancy of Greater Sage-Grouse in relation to landscape cultivation in the Dakotas

Greater Sage-Grouse ( Centrocercus urophasianus ) have been declining in many states and provinces of North America, and North and South Dakota hold no exception to these declines. We studied effects of cultivated land on Greater Sage-Grouse lek abandonment in North and South Dakota. Landscape-level data were assessed using satellite imagery within a geographic information system. Comparisons were made of 1972-1976 and 1999-2000 percent cultivated and noncultivated land. These comparisons were made between land uses surrounding active leks versus inactive leks, active leks versus random locations, and abandoned regions versus active regions. The 1999-2000 imagery illustrated that percent cultivated land was greater near abandoned leks (4-km buffers) than near active leks in North Dakota or random sites, but this did not hold true in South Dakota. Comparison of an extensive region of abandoned leks with a region of active leks in North Dakota illustrated a similar increase as well as dispersion of cultivation within the abandoned region. However, 1972-1976 imagery revealed that this relationship between percentage of cultivated land and lek activity in North Dakota has been static over the last 30 years. Thus, if the decline of Greater Sage-Grouse is the result of cultivated land infringements, it occurred prior to 1972 in North Dakota.     

The influence of pH on the sex-related differences in renal organic ion transport

Summary The stimulating effects of elevated medium pH and androgen on in vitro transport of p-aminohippurate and N-methylnicotinamide (NMN) were additive, although the androgenic effect was pH-dependent only in the case of NMN. The similarity of response of the 2 systems supports the idea of a common passive efflux pathway for organic anions and cations.Naval Medical Research and Development Command, Research Task No. MS04101.0160. The opinions and assertions contained herein are the private ones of the authors and are not to be construed as official or reflecting the views of the Navy Department or the naval service at large. The experiments reported herein were conducted according to the principles set forth in the Guide for the Care and Use of Laboratory Animals, Institute of Laboratory Animal Resources, National Research Council, DHEW Pub. No. (NIH) 74-23.