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Hayward, CA, United States

Boccuto L.,Greenwood Genetic Center | Chen C.-F.,Greenwood Genetic Center | Pittman A.R.,Greenwood Genetic Center | Skinner C.D.,Greenwood Genetic Center | And 5 more authors.
Molecular Autism | Year: 2013

Background: Autism spectrum disorders (ASDs) are relatively common neurodevelopmental conditions whose biological basis has been incompletely determined. Several biochemical markers have been associated with ASDs, but there is still no laboratory test for these conditions. Methods. We analyzed the metabolic profile of lymphoblastoid cell lines from 137 patients with neurodevelopmental disorders with or without ASDs and 78 normal individuals, using Biolog Phenotype MicroArrays. Results: Metabolic profiling of lymphoblastoid cells revealed that the 87 patients with ASD as a clinical feature, as compared to the 78 controls, exhibited on average reduced generation of NADH when tryptophan was the sole energy source. The results correlated with the behavioral traits associated with either syndromal or non-syndromal autism, independent of the genetic background of the individual. The low level of NADH generation in the presence of tryptophan was not observed in cell lines from non-ASD patients with intellectual disability, schizophrenia or conditions exhibiting several similarities with syndromal autism except for the behavioral traits. Analysis of a previous small gene expression study found abnormal levels for some genes involved in tryptophan metabolic pathways in 10 patients. Conclusions: Tryptophan is a precursor of important compounds, such as serotonin, quinolinic acid, and kynurenic acid, which are involved in neurodevelopment and synaptogenesis. In addition, quinolinic acid is the structural precursor of NAD§ssup§+§esup§, a critical energy carrier in mitochondria. Also, the serotonin branch of the tryptophan metabolic pathway generates NADH. Lastly, the levels of quinolinic and kynurenic acid are strongly influenced by the activity of the immune system. Therefore, decreased tryptophan metabolism may alter brain development, neuroimmune activity and mitochondrial function. Our finding of decreased tryptophan metabolism appears to provide a unifying biochemical basis for ASDs and perhaps an initial step in the development of a diagnostic assay for ASDs. © 2013 Boccuto et al.; licensee BioMed Central Ltd. Source


The present invention is related to compositions and methods to treat, ameliorate and/or prevent morbidity and/or mortality from microbial infections. In particular, bacterial infections that are associated with the production and release of bacterial toxins. For example, many Clostridia bacteria, such as


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 2.56M | Year: 2004

DESCRIPTION (provided by applicant): In this Phase II SBIR grant, we propose to develop our Phenotype MicroArray (PM) technology into a high throughput screening (HTS) assay for drug toxicity. The proposal addresses a key need in drug discovery for fas


Grant
Agency: Department of Health and Human Services | Branch: | Program: STTR | Phase: Phase I | Award Amount: 276.98K | Year: 2004

DESCRIPTION (provided by applicant): The principal goal of this project is to adapt the "Phenotype MicroArray[TM]" ("PM") technology of Biolog, Inc (Hayward, CA) for fastidious and microaerophilic bacterial species, with special emphasis on those important in human disease. PM technology allows efficient, sensitive characterization of thousands of physiologic and phenotypic properties of microbial cells. The Phase I studies proposed here will focus on strains of the gastric pathogen Helicobacter pylori (Hp) (implicated in peptic ulcer disease and gastric cancer), and the intestinal pathogen Campylobacter jejuni (Cj) (a very common cause of gastroenteritis, and rheumatoid arthritis, and also (with some strains) of an autoimmune induced peripheral nerve degeneration and paralysis - Guillain Barre syndrome). Cj and Hp are each genetically diverse. Cj is weakly clonal in population genetic structure, whereas Hp is considered non-clonal, but exhibits striking geographic differences in gene pools, especially with strains of East Asia vs. Europe and the Americas. This Phase I STTR project has two experimental Aims. First: To refine, optimize, and implement a PM technology testing protocol for robust analysis of representative Hp and Cj strains. This will make testing of Hp and Cj strains available to the scientific research community, either through PM Kits or PM Services. Second: To transfer this technology to Berg's lab, where it will be beta site tested and used to study a range of Hp and Cj strains chosen primarily for their particular disease associations and to assess if such disease associations are linked to metabolic differences or other PM-detected phenotypic traits. With Hp, the effects of human gastrin (a reported stimulator of Hp growth, and possible signal of Hp entry into the gastric mucosa) on PM profiles will be determined. With Cj, PM profiles of representative strains will be scored at 37C vs. 42C, to assess if thermal signaling might be used by Cj to adapt to different hosts (human vs. chicken). In Phase II the PM methodology will be implemented for representative strains of other Helicobacter and Campylobacter species, and also for other genera of fastidious pathogens.


Grant
Agency: Department of Health and Human Services | Branch: | Program: STTR | Phase: Phase II | Award Amount: 467.18K | Year: 2007

DESCRIPTION (provided by applicant): Mycobacterium tuberculosis and other Mycobacterium species are major pathogens around the world. They are part of a larger group of so-called fastidious pathogens that are difficult to study because, for a wide range of reasons, they are difficult to culture. Phenotype MicroArrayTM (PM) technology is a tool that can aid in understanding the physiological and metabolic properties of fastidious pathogens. It enables a scientist to scan nearly 2,000 phenotypes of a microbial cell line in a single experiment. This technology can now be used with most aerobic gram negative/positive species of interest in human health and more than 70 scientific publications and presentations demonstrate how it can be applied in a wide range of scientific investigations. However, a number of fastidious genera are currently not amenable to PM analysis. One principal goal for this STTR project is to adapt PM technology for these fastidious aerobic, microaerophilic, and anaerobic bacterial species, with special emphasis on those important in human disease and/or biodefense considerations. The genera we will focus on include agents of lung, cutaneous, and tissue infections (Mycobacterium, Nocardia, Legionella), microaerophilic gastro-intestinal pathogens (Helicobacter, Campylobacter, Arcobacter, Wolinella), and important colonizers of the colon and vagina (Bacteroides, Clostridium, Lactobacillus, Escherichia). These were selected as highest priority because we have received requests from more than 40 scientists seeking to utilize PM technology in their studies of these microorganisms. This level of scientific interest documents the need and potential for commercialization of the technology that we are proposing to develop. A second goal is to expand the capabilities of the Biolog Microbial Identification System, which is now installed in about half of US State Public Health Labs and is frequently used to identify less common or unusual microbial pathogens. Most of these genera are also not currently included in Biolog's Identification Database. However, with success in development efforts proposed here, the Database will be expanded to include these important fastidious species. As a third goal, our collaborator at Texas A&M University will focus on the most important genus, Mycobacterium, and use knockout strains with PM technology to study the function of genes that are unique to the metabolism and drug resistance of this genus. If successful, this aspect of the project will aid efforts toward the development of new or more effective anti-mycobacterial drug therapies. This project will directly benefit public health by providing a technology for efficient simultaneous testing of hundreds to thousands of cellular phenotypes. It will be applied in hospital diagnostic work, environmental diagnostic work, bioterrorism monitoring, new drug development, toxicology studies, and in many areas of basic biology research.

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