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PubMed2004

A microelectrode/microelectronic hybrid device for brain implantable neuroprosthesis applications.

We have designed, fabricated, and characterized a microminiaturized "neuroport" for brain implantable neuroprosthesis applications, using an analog CMOS integrated circuit and a silicon based microelectrode array. An ultra-low power, low-noise CMOS preamplifier array with integral multiplexing was designed to accommodate stringent thermal and electrophysiological requirements for implantation in the brain, and a hybrid integration approach was developed to fabricate a functional microminiaturized neuroprobe device. Measurements showed that our fully scalable 16-channel CMOS amplifier chip had an average gain of 44 dB, bandwidth from 10 Hz to 7.3 kHz, and an equivalent input noise of approximately 9 microVrms with an average power consumption per preamplifier of 52 microW, which is consistent with simulation results. As a proof-of-concept demonstration, we have measured local field potentials from thalamocortical brain slices of rats, showing oscillatory behavior with an amplitude about 0.5 mV and a period ranging 80-120 ms. The results suggest that the hybrid integrated neuroport can form a prime platform for the development of a next level microminiaturized neural interface to the brain in a single implantable unit.

Action Potentials↗

PubMed2004

Visualization and analysis of microarray and gene ontology data with treemaps.

BACKGROUND: The increasing complexity of genomic data presents several challenges for biologists. Limited computer monitor views of data complexity and the dynamic nature of data in the midst of discovery increase the challenge of integrating experimental results with information resources. The use of Gene Ontology enables researchers to summarize results of quantitative analyses in this framework, but the limitations of typical browser presentation restrict data access. RESULTS: Here we describe extensions to the treemap design to visualize and query genome data. Treemaps are a space-filling visualization technique for hierarchical structures that show attributes of leaf nodes by size and color-coding. Treemaps enable users to rapidly compare sizes of nodes and sub-trees, and we use Gene Ontology categories, levels of RNA, and other quantitative attributes of DNA microarray experiments as examples. Our implementation of treemaps, Treemap 4.0, allows user-defined filtering to focus on the data of greatest interest, and these queried files can be exported for secondary analyses. Links to model system web pages from Treemap 4.0 enable users access to details about specific genes without leaving the query platform. CONCLUSIONS: Treemaps allow users to view and query the data from an experiment on a single computer monitor screen. Treemap 4.0 can be used to visualize various genome data, and is particularly useful for revealing patterns and details within complex data sets.

Animals↗

PubMed2005

Alkahest NuclearBLAST : a user-friendly BLAST management and analysis system.

BACKGROUND: Sequencing of EST and BAC end datasets is no longer limited to large research groups. Drops in per-base pricing have made high throughput sequencing accessible to individual investigators. However, there are few options available which provide a free and user-friendly solution to the BLAST result storage and data mining needs of biologists. RESULTS: Here we describe NuclearBLAST, a batch BLAST analysis, storage and management system designed for the biologist. It is a wrapper for NCBI BLAST which provides a user-friendly web interface which includes a request wizard and the ability to view and mine the results. All BLAST results are stored in a MySQL database which allows for more advanced data-mining through supplied command-line utilities or direct database access. NuclearBLAST can be installed on a single machine or clustered amongst a number of machines to improve analysis throughput. NuclearBLAST provides a platform which eases data-mining of multiple BLAST results. With the supplied scripts, the program can export data into a spreadsheet-friendly format, automatically assign Gene Ontology terms to sequences and provide bi-directional best hits between two datasets. Users with SQL experience can use the database to ask even more complex questions and extract any subset of data they require. CONCLUSION: This tool provides a user-friendly interface for requesting, viewing and mining of BLAST results which makes the management and data-mining of large sets of BLAST analyses tractable to biologists.

Algorithms↗

PubMed1990

High-resolution surface views of human lymphocytes during capping of CD4 and HLA antigens as revealed by immunogold fracture-flip.

The surface ultrastructure of lymphocytes during capping of two transmembrane proteins is shown. As seen by fracture-flip the plasma membranes of human lymphocytes are covered by a high density of surface particles. Incubation in 30% glycerol leads to aggregation of these surface particles. Immunogold labelling shows that the transmembrane proteins bearing HLA class I and CD4 antigens are confined to the particle aggregates. These results indicate that surface particles revealed by fracture-flip represent surface protrusions of integral membrane proteins seen as intramembrane particles in freeze-fractured lymphocytes. During capping HLA or CD4 antigens aggregate into progressively larger patches and, finally, into single caps. As revealed by fracture-flip the patches/caps are seen as clearly differentiated raised platforms that are clearly and sharply demarcated relative to contiguous areas of the surface. In non-patched (non-capped) regions, the pattern of distribution and apparent density of surface particles remain unaltered. Immunogold labelling clearly demarcates patches and caps, and shows that virtually no antigen molecules remain dispersed over the non-patched (non-capped) regions. Estimates of the surface density of either HLA or CD4 antigens over the capped areas point to high planar concentrations of the transmembrane proteins that bear these antigens.

Antigens, Surface↗

PubMed2002

Rubicon Genomics, Inc.

Rubicon Genomics, Inc. is a leader in development and application of effective methods to analyze human DNA for genome-wide genotyping and haplotyping. The company is developing its proprietary OmniPlex technology as an integrated platform for archiving, amplifying and analyzing patient DNA for drug target discovery, pharmacogenomics and diagnostics. Single-site, multiple-site or whole genome amplification can be done using small samples of DNA that have been archived as OmniPlex DNA. Rubicon technology will make genome-wide SNP scoring faster, more accurate, more robust and less expensive. Rubicon will partner with pharmaceutical and diagnostic companies, as well as the makers of instruments and reagents to bring OmniPlex technology to the widest market - increasing the pipeline of more effective and safer drugs and ushering in the practice of gene-based medicine.

DNA↗

PubMed2001

Emerging homogeneous DNA-based technologies in the clinical laboratory.

BACKGROUND: Advances in molecular diagnostic technologies have enabled genetic testing in single closed-tube reactions. The purpose of this review is to highlight some of the platforms and technologies currently available for the homogeneous detection of targets and the application of the technologies in the clinical setting. Validation issues surrounding the technologies, which may need to be addressed before they can become widely accepted, will also be discussed. APPROACH: This review discusses the principles of several of the major technologies available for performing homogeneous genetic analyses. Publications arising from the application of the technologies in a wide range of clinical areas are used to highlight and compare the potential advantages and shortcomings of the various technologies. CONTENT: This review is descriptive and focuses on three areas: the technologies available for performing homogeneous analysis, the clinical applications where the technologies are being used, and validation issues surrounding the acceptance of the technologies in the general clinical setting. SUMMARY: This review intends to give the reader a greater understanding of the various technologies available for performing homogeneous genetic testing in the clinical laboratory. Through insight into the principles and performance characteristics underlying these technologies, the end user can evaluate their value and limitations in the clinical diagnostic setting.

Clinical Laboratory Techniques↗

PubMedDate not supplied

Lighting the circle of life: fluorescent sensors for covert surveillance of the cell cycle.

The cell cycle is the collective mechanism through which all of us develop, exist and in many cases, when it goes wrong, die. Despite enormous progress in unravelling the complexity of the cell cycle through intensive study over the past 100 years, development of new tools to analyse the process and associated cellular events has not kept pace. All standard cell cycle analysis methods preclude real time dynamic analysis of the cell cycle in live cells at single cell resolution. To address the needs of cell cycle investigations across a range of analysis platforms we are currently developing a range of cell cycle phase markers based on GFP expression controlled by well characterised cell cycle components to allow covert surveillance of the cell cycle in living cells.

Biomarkers↗

PubMed2005

Single molecule fluorescence control for nanotechnology.

Nanoscience and nanotechnology are providing fresh approaches to engineer materials with practical applications such as molecular-sized therapeutic and diagnostic devices, drug delivery vehicles, environmental sensors, high-rate manufacturing platforms, and self-assembling nanomachines. In many cases, researchers are mimicking biological systems that easily achieve molecular scale control through directed self-assembly. In parallel, a revolution has occurred in the basic sciences, which utilizes recent advances in fluorescence microscopy to achieve single molecule detection capability. The future will see a merger of these two separate research thrusts, as single molecule detection will afford optimal control over the assembly and performance of individual nanoscale devices.

Fluorescence↗

PubMed2005

Comparative linkage analysis and visualization of high-density oligonucleotide SNP array data.

BACKGROUND: The identification of disease-associated genes using single nucleotide polymorphisms (SNPs) has been increasingly reported. In particular, the Affymetrix Mapping 10 K SNP microarray platform uses one PCR primer to amplify the DNA samples and determine the genotype of more than 10,000 SNPs in the human genome. This provides the opportunity for large scale, rapid and cost-effective genotyping assays for linkage analysis. However, the analysis of such datasets is nontrivial because of the large number of markers, and visualizing the linkage scores in the context of genome maps remains less automated using the current linkage analysis software packages. For example, the haplotyping results are commonly represented in the text format. RESULTS: Here we report the development of a novel software tool called CompareLinkage for automated formatting of the Affymetrix Mapping 10 K genotype data into the "Linkage" format and the subsequent analysis with multi-point linkage software programs such as Merlin and Allegro. The new software has the ability to visualize the results for all these programs in dChip in the context of genome annotations and cytoband information. In addition we implemented a variant of the Lander-Green algorithm in the dChipLinkage module of dChip software (V1.3) to perform parametric linkage analysis and haplotyping of SNP array data. These functions are integrated with the existing modules of dChip to visualize SNP genotype data together with LOD score curves. We have analyzed three families with recessive and dominant diseases using the new software programs and the comparison results are presented and discussed. CONCLUSIONS: The CompareLinkage and dChipLinkage software packages are freely available. They provide the visualization tools for high-density oligonucleotide SNP array data, as well as the automated functions for formatting SNP array data for the linkage analysis programs Merlin and Allegro and calling these programs for linkage analysis. The results can be visualized in dChip in the context of genes and cytobands. In addition, a variant of the Lander-Green algorithm is provided that allows parametric linkage analysis and haplotyping.

Family Health↗

PubMed2003

A novel polyacrylamide magnetic nanoparticle contrast agent for molecular imaging using MRI.

A novel polyacrylamide superparamagnetic iron oxide nanoparticle platform is described which has been synthetically prepared such that multiple crystals of iron oxide are encapsulated within a single polyacrylamide matrix (PolyAcrylamide Magnetic [PAM] nanoparticles). This formulation provides for an extremely large T2 and T2* relaxivity of between 620 and 1140 sec(-1) mM(-1). Administration of PAM nanoparticles into rats bearing orthotopic 9L gliomas allowed quantitative pharmacokinetic analysis of the uptake of nanoparticles in the vasculature, brain, and glioma. Addition of polyethylene glycol of varying sizes (0.6, 2, and 10 kDa) to the surface of the PAM nanoparticles resulted in an increase in plasma half-life and affected tumor uptake and retention of the nanoparticles as quantified by changes in tissue contrast using MRI. The flexible formulation of these nanoparticles suggests that future modifications could be accomplished allowing for their use as a targeted molecular imaging contrast agent and/or therapeutic platform for multiple indications.

Acrylic Resins↗

PubMed2004

Development of a rapid genotyping method for single nucleotide polymorphisms and its application in cancer studies.

Single nucleotide polymorphisms (SNPs) in cancer-related genes can act as low risk genetic factors for the development of this disease. SNPs have also been shown to influence the efficacy and toxicity of various cytotoxic agents used in the treatment of cancer. Progress in these important areas of cancer research relies upon rapid, inexpensive and accurate means of SNP genotyping. In the present study we describe a fluorescent PCR-based method that utilizes single strand conformation polymorphism (SSCP) analysis to distinguish between different alleles. A real-time DNA fragment analysis platform and ultra-thin, re-useable gels allow short run times and hence a relatively high throughput to be achieved. A standardised procedure for the identification of optimal running conditions for each SNP is presented. We used this fluorescent-SSCP method to genotype SNPs in the MTHFR, p21, cyclin D1, MMP-2, vitamin D receptor, TNF-alpha and IL-6 genes. Multiplex PCR of two SNPs allows up to 500 genotypes per day to be evaluated with 100% accuracy. The low start-up and running costs make this method particularly well suited for SNP genotyping studies that involve up to 1,000 DNA samples.

Base Sequence↗

PubMed1994

A three-dimensional microelectrode array for chronic neural recording.

This paper describes a 3-D microelectrode array for the chronic recording of single-unit activity in the central nervous system. The array is formed by a microassembly of planar silicon multishank microprobes, which are precisely positioned in a micromachined platform that resides on the surface of the cortex. Interconnects between the probes and the platform are formed using electroplated nickel lead transfers, implemented using automated computer control. All dimensions are controlled to +/- 1 micron and sank/probe separations as small as 100 microns are possible. Four-probe 16-shank prototype arrays have been tested chronically in guinea pig cortex. After three months in vivo, no significant tissue reaction has been observed surrounding these structures when they remain free to move with the brain, with normal appearing tissue between shanks spaced at 150 microns to 200 microns intervals. The array structure is compatible with the use of signal processing circuitry both on the probes and on the platform. A platform-based signal processing system has been designed to interface with several active probes, providing direct analog access to the recording sites, performing on-chip analog-to-digital conversion of neural activity, and providing simple binary-output recognition of single-unit spike events using a user-input threshold voltage.

Animals↗

PubMed2002

Kinetic polymerase chain reaction on pooled DNA: a high-throughput, high-efficiency alternative in genetic epidemiological studies.

The ideal technology for screening single-nucleotide polymorphisms requires high throughput with minimal cost per sample, minimal usage of valuable DNA resources, and maximal flexibility for assessment of new polymorphisms. We demonstrate here the feasibility of kinetic allele-specific PCR with DNA pooling (S. Germer et al., Genome Res., 10: 258-266, 2000) in a population study that satisfies all of the mentioned criteria and offers a powerful new tool for detecting meaningful polymorphic differences in candidate gene association studies and genome-wide linkage dysequilibrium scans. Three individuals prepared pooled DNA samples from 269 individuals separated into three racial/ethnic groups: Caucasians (n = 56), African-Americans (n = 86), and Hispanics (n = 127). We used kinetic allele-specific PCR to determine the allele frequencies of the common paraoxonase 1 polymorphism, PON1 Q191R, in these pools. Paraoxonase 1 is a critical enzyme for inactivating neurotoxic intermediates in the metabolism of organophosphates. In a blinded test of the technology, these nine pooled DNA samples were sent to Roche for genotyping by kinetic allele-specific PCR. The allele frequencies found were 0.266 +/- 0.011, 0.386 +/- 0.011, and 0.617 +/- 0.010, respectively, which were comparable to the frequencies of 0.269, 0.403, and 0.622 determined by PCR-restriction fragment length polymorphism analysis. These same samples were genotyped on two kinetic PCR platforms from different manufacturers, using three different DNA polymerases. The results were comparable between both platforms and among all three polymerases. The results demonstrate a powerful new technology for determining frequencies of single-nucleotide polymorphisms in an epidemiological study.

Alleles↗

PubMed1995

Intertester reliability of assessing postural sway using the chattecx balance system.

In this study, we examined intertester reliability of dynamic and static balance using the Chattecx Dynamic Balance System. Ten female and two male subjects were randomly assigned to two testers and completed ten, 10-second preprogrammed double- and single-leg test conditions. Balance was measured as postural sway in centimeters by the Chattecx Dynamic Balance System. Static balance consisted of the platform remaining stable, whereas dynamic balance consisted of the platform tilting in an anterior and posterior direction during testing. The protocols and average postural sway values were:1. Double-Leg Static Eyes Open ([unk] = .28 cm)2. Double-Leg Static Eyes Closed ([unk] = .37 cm)3. Double-Leg Dynamic Eyes Open ([unk] = .86 cm)4. Double-Leg Dynamic Eyes Closed ([unk] = 1.72 cm)5. Single-Leg Static Dominant Eyes Open ([unk] = .99 cm)6. Single-Leg Static Dominant Eyes Closed ([unk] = 1.70 cm)7. Single-Leg Static Nondominant Eyes Open ([unk] = .65 cm)8. Single-Leg Static Nondominant Eyes Closed ([unk] = 1.48 cm)9. Single-Leg Dynamic Dominant Eyes Open ([unk] = .99cm)10. Single-Leg Dynamic Nondominant Eyes Open ([unk] = .91 cm).The mean values of postural sway ranged from .28 cm to 1.72 cm for double-leg stance measures and from .65 cm to 1.70 cm for the single-leg stance measures. The intraclass correlations (ICCs)(2,1) ranged from poor to excellent (ICCs = .06 to .90) and the standard error of measurement (SEM) ranged from .06 to .34 for the 10 trials. We feel that variability exists between subjects and/or testers between trials. The wide range of reliability values suggests that further research should determine both intratester and intertester reliability using a variety of protocols for assessment of static and dynamic balance.

Journal Article↗

PubMed2002

Pyrosequencing for detection of mutations in the connexin 26 (GJB2) and mitochondrial 12S RNA (MTRNR1) genes associated with hereditary hearing loss.

Hereditary hearing loss (HHL) is one of the most common congenital disorders and is highly heterogeneous. Mutations in the connexin 26 (CX26) gene (GJB2) account for about 20% of all cases of childhood deafness, and approach 50% in documented recessive cases of non-syndromic hearing loss. In addition, a single mitochondrial DNA mutation, mt1555A>G, in the 12S rRNA gene (MTRNR1), is associated with familial cases of progressive deafness. Effective screening of populations for HHL necessitates rapid assessment of several of these potential mutation sites. Pyrosequencing links a DNA synthesis protocol for determining sequence to an enzyme cascade that generates light whenever pyrophosphate is released during primer strand elongation. We assessed the ability of Pyrosequencing to detect common mutations causing HHL. Detection of the most common CX26 mutations in individuals of Caucasian (35delG), Ashkenazi (167delT), and Asian (235delC, V37I) descent was confirmed by Pyrosequencing. A total of 41 different mutations in the CX26 gene and the mitochondrial mt1555A>G mutation were confirmed. Genotyping of up to six different adjacent mutations was achieved, including simultaneous detection of 35delG and 167delT. Accurate and reproducible results were achieved taking advantage of assay flexibility and experimental conditions easily optimized for a high degree of standardization and cost-effectiveness. The standardized sample preparation steps, including target amplification by PCR and preparation of single-stranded template combined with automated sequence reaction and automated genotype scoring, positions this approach as a potentially high throughput platform for SNP/mutation genotyping in a clinical laboratory setting. .

Amino Acid Substitution↗

PubMed2004

Three-dimensional microarray compared with PCR-single-strand conformation polymorphism analysis/DNA sequencing for mutation analysis of K-ras codons 12 and 13.

BACKGROUND: We developed a rapid, precise, and accurate microarray-based method that uses a three-dimensional platform for detection of mutations. METHODS: We used the PamChip microarray to detect mutations in codons 12 and 13 of K-ras in 15 cell lines and 81 gastric or colorectal cancer tissues. Fluorescein isothiocyanate-labeled PCR products were analyzed with the microarray. We confirmed the microarray results with PCR-single-strand conformation polymorphism (SSCP) analysis and DNA sequencing. RESULTS: We could correctly identify wild-type, heterozygous, and homozygous mutant genotypes with the PamChip microarray in <3.5 h. The array data were consistent with those of PCR-SSCP analysis and DNA sequencing. All 15 cell lines and 80 of 81 clinical cancer specimens (98.8%; 95% confidence interval, 96.4-100%) were genotyped accurately with the microarray, a rate better than that of direct DNA sequencing (38.9%) or SSCP (93.8%). Only one clinical specimen was misdiagnosed as homozygous for the wild-type allele. Densitometric analysis of SSCP bands indicated that the content of the mutant allele in the specimen was approximately 16%. The PamChip microarray could detect mutant alleles representing more than 25% of the SSCP band proportions. Therefore, the limit for detection of mutant alleles by the PamChip microarray was estimated to be 16-25% of the total DNA. CONCLUSIONS: The PamChip microarray is a novel three-dimensional microarray system and can be used to analyze K-ras mutations quickly and accurately. The mutation detection rate was nearly 100% and was similar to that of PCR-SSCP together with sequencing analysis, but the microarray analysis was faster and easier.

Cell Line, Tumor↗

PubMed2002

The spectrin repeat: a structural platform for cytoskeletal protein assemblies.

Spectrin repeats are three-helix bundle structures which occur in a large number of diverse proteins, either as single copies or in tandem arrangements of multiple repeats. They can serve structural purposes, by coordination of cytoskeletal interactions with high spatial precision, as well as a 'switchboard' for interactions with multiple proteins with a more regulatory role. We describe the structure of the alpha-actinin spectrin repeats as a prototypical example, their assembly in a defined antiparallel dimer, and the interactions of spectrin repeats with multiple other proteins. The alpha-actinin rod domain shares several features common to other spectrin repeats. (1) The rod domain forms a rigid connection between two actin-binding domains positioned at the two ends of the alpha-actinin dimer. The exact distance and rigidity are important, for example, for organizing the muscle Z-line and maintaining its architecture during muscle contraction. (2) The spectrin repeats of alpha-actinin have evolved to make tight antiparallel homodimer contacts. (3) The spectrin repeats are important interaction sites for multiple structural and signalling proteins. The interactions of spectrin repeats are, however, diverse and defy any simple classification of their preferred interaction sites, which is possible for other domains (e.g. src-homology domains 3 or 2). Nevertheless, the binding properties of the repeats perform important roles in the biology of the proteins where they are found, and lead to the assembly of complex, multiprotein structures involved both in cytoskeletal architecture as well as in forming large signal transduction complexes.

Actinin↗

PubMed2004

Electrochemical biosensing platforms using platinum nanoparticles and carbon nanotubes.

Platinum nanoparticles with a diameter of 2-3 nm were prepared and used in combination with single-wall carbon nanotubes (SWCNTs) for fabricating electrochemical sensors with remarkably improved sensitivity toward hydrogen peroxide. Nafion, a perfluorosulfonated polymer, was used to solubilize SWCNTs and also displayed strong interactions with Pt nanoparticles to form a network that connected Pt nanoparticles to the electrode surface. TEM and AFM micrographs illustrated the deposition of Pt nanoparticles on carbon nanotubes whereas cyclic voltammetry confirmed an electrical contact through SWCNTs between Pt nanoparticles and the glassy carbon (GC) or carbon fiber backing. With glucose oxidase (GOx) as an enzyme model, we constructed a GC or carbon fiber microelectrode-based biosensor that responds even more sensitively to glucose than the GC/GOx electrode modified by Pt nanoparticles or CNTs alone. The response time and detection limit (S/N = 3) of this biosensor was determined to be 3 s and 0.5 microM, respectively.

Aspergillus niger↗