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Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90091/1/22677_ftp.pd

Differential Regulation of Focal Adhesion Kinase and Mitogen-Activated Protein Kinase Tyrosine Phosphorylation During Insulin-Like Growth Factor-I-Mediated Cytoskeletal Reorganization

In SH-SY5Y human neuroblastoma cells, insulin-like growth factor (IGF)-I mediates membrane ruffling and growth cone extension. We have previously shown that IGF-I activates the tyrosine phosphorylation of focal adhesion kinase (FAK) and extracellular signal-regulated protein kinase (ERK) 2. In the current study, we examined which signaling pathway underlies IGF-I-mediated FAK phosphorylation and cytoskeletal changes and determined if an intact cytoskeleton was required for IGF-I signaling. Treatment of SH-SY5Y cells with cytochalasin D disrupted the actin cytoskeleton and prevented any morphological changes induced by IGF-I. Inhibitors of phosphatidylinositol 3-kinase (PI 3-K) blocked IGF-I-mediated changes in the actin cytoskeleton as measured by membrane ruffling. In contrast, PD98059, a selective inhibitor of ERK kinase, had no effect on IGF-I-induced membrane ruffling. In parallel with effects on the actin cytoskeleton, cytochalasin D and PI 3-K inhibitors blocked IGF-I-induced FAK tyrosine phosphorylation, whereas PD98059 had no effect. It is interesting that cytochalasin D did not block IGF-I-induced ERK2 tyrosine phosphorylation. Therefore, it is likely that FAK and ERK2 tyrosine phosphorylations are regulated by separate pathways during IGF-I signaling. Our study suggests that integrity as well as dynamic motility of the actin cytoskeleton mediated by PI 3-K is required for IGF-I-induced FAK tyrosine phosphorylation, but not for ERK2 activation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66347/1/j.1471-4159.1998.71031333.x.pd

Can Drug Screening Lead to Candidate Therapies for Testing in Diabetic Neuropathy?

A key mechanism of dorsal root ganglia (DRG) neuron injury in high glucose is mitochondrial overload leading to oxidative stress. We screened selected compounds for the ability to prevent hyperglycemia-induced mitochondrial superoxide in primary sensory DRG neurons. Twenty five out of 1,040 compounds decreased both mitochondrial superoxide and subsequent neuronal injury. These data both validate our screening strategy and indicate further mechanistic evaluation of drug hits and related compounds. Such studies may lead to the design of rational therapeutic approaches for this severe complication of diabetes.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63408/1/ars.2007.1815.pd

Reversibility of Serum Removal Effects on IGF-II mRNA in Human Neuroblastoma Cells

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73527/1/j.1749-6632.1993.tb26227.x.pd

Preferências nutricionais entre adolescentes da classe média de Manaus, AM (Brazil)

INTRODUÇÃO: O Brasil tem sido considerado um País em transição nutricional em razão dos recentes aumentos na prevalência de obesidade e doenças crônicas na classe média, sendo importante identificar os fatores que influenciam as preferências nutricionais desse grupo. Foi realizado estudo com estudantes de classe média de um colégio secundário, particular, em Manaus, AM, Brasil. Com o objetivo de determinar a disponibilidade e a acessibilidade das merendas e analisar as atitudes e preferências dos estudantes e a influência de vários fatores na escolha de merendas nutritivas. MÉTODOS: O estudo incluiu quatros fases: (a) discusão em um grupo de especialistas em nutrição sobre a disponibilidade e acessibilidade das merendas em Manaus; (b) inquérito junto a um grupo dos adolescentes (n=63) sobre suas preferências e hábitos nutricionais; (c) inquérito junto a supermercados selecionado para identificar a disponibilidade e acessibilidade das merendas preferidas; (d) um grupo acompanhado de uma subamostra dos adolescentes (n=55) para identificar a preferências e atitudes sobre o custo e disponibilidade das merendas. RESULTADOS: Foi constatado que os estudantes possuíam condições financeiras para comprar merendas e que as merendas nutritivas não custam mais do que as não nutritivas. A preferência dos adolescentes foi por merendas não nutritivas. Os fatores que, principalmente, influenciam na escolha originam-se da família e da televisão. CONCLUSÃO: As implicações para futuras pesquisas e programas nutricionais são discutidos, recomendando-se campanha de educação nutricional para famílias, visto a importância desta na escolha de merendas entre esses adolescentes.INTRODUCTION: Brazil has been called a nation in nutrition transitional because of recent increases in the prevalence of obesity and related chronic diseases. With overweight conditions already prevalent among middle-income populations, there exists a need to identify factors that influence nutrition behavior within this group. OBJECTIVE: To address this subject, a research study was implemented among middle-class adolescents attending a large private secondary school in Manaus, Amazonas, Brazil. The study determined the availability and accessibility of snack foods as well as subjects’ attitudes and preferences towards, and the influence of family and friends on healthy (high-nutrient density) snack choices. METHODS: The 4-stage process included: (a) a nutrition expert focus group discussion that reported local nutrition problems in general and factors related to adolescent nutrition, (b) an adolescent pilot survey (n=63) that solicited information about snacking preferences and habits as well as resources for nutrition information and snack money; (c) a survey of various area food market sources to determine the availability and accessibility of high nutrient density snacks; and (d) a follow-up adolescent survey (n=55) that measured snack food preferences and perceptions about their cost and availability. RESULTS: Results included the finding that, although affordable high nutrient density snacks were available, preferences for low nutrient density snacks prevailed. The adolescents were reportedly more likely to be influenced by and obtain nutrition information from family members than friends. CONCLUSION: From study results it is apparent that a focus on food availability will not automatically result in proper nutritional practices among adolescents. This fact and the parental influence detected are evidence of a need to involve adolescents and their parents in nutrition education campaigns to improve adolescent snack food choices

Insulin-like Growth Factor Binding Protein Expression in Human Retinal Pigment Epithelial Cells

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73426/1/j.1749-6632.1993.tb26229.x.pd

Concise Review: Stem Cell Therapies for Amyotrophic Lateral Sclerosis: Recent Advances and Prospects for the Future

Amyotrophic lateral sclerosis (ALS) is a lethal disease involving the loss of motor neurons. Although the mechanisms responsible for motor neuron degeneration in ALS remain elusive, the development of stem cell‐based therapies for the treatment of ALS has gained widespread support. Here, we review the types of stem cells being considered for therapeutic applications in ALS, and emphasize recent preclinical advances that provide supportive rationale for clinical translation. We also discuss early trials from around the world translating cellular therapies to ALS patients, and offer important considerations for future clinical trial design. Although clinical translation is still in its infancy, and additional insight into the mechanisms underlying therapeutic efficacy and the establishment of long‐term safety are required, these studies represent an important first step toward the development of effective cellular therapies for the treatment of ALS. S tem C ells 2014;32:1099–1109Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/106861/1/stem1628.pd

Ontology-based Brucella vaccine literature indexing and systematic analysis of gene-vaccine association network

<p>Abstract</p> <p>Background</p> <p>Vaccine literature indexing is poorly performed in PubMed due to limited hierarchy of Medical Subject Headings (MeSH) annotation in the vaccine field. Vaccine Ontology (VO) is a community-based biomedical ontology that represents various vaccines and their relations. SciMiner is an in-house literature mining system that supports literature indexing and gene name tagging. We hypothesize that application of VO in SciMiner will aid vaccine literature indexing and mining of vaccine-gene interaction networks. As a test case, we have examined vaccines for <it>Brucella</it>, the causative agent of brucellosis in humans and animals.</p> <p>Results</p> <p>The VO-based SciMiner (VO-SciMiner) was developed to incorporate a total of 67 <it>Brucella </it>vaccine terms. A set of rules for term expansion of VO terms were learned from training data, consisting of 90 biomedical articles related to <it>Brucella </it>vaccine terms. VO-SciMiner demonstrated high recall (91%) and precision (99%) from testing a separate set of 100 manually selected biomedical articles. VO-SciMiner indexing exhibited superior performance in retrieving <it>Brucella </it>vaccine-related papers over that obtained with MeSH-based PubMed literature search. For example, a VO-SciMiner search of "live attenuated <it>Brucella </it>vaccine" returned 922 hits as of April 20, 2011, while a PubMed search of the same query resulted in only 74 hits. Using the abstracts of 14,947 <it>Brucella</it>-related papers, VO-SciMiner identified 140 <it>Brucella </it>genes associated with <it>Brucella </it>vaccines. These genes included known protective antigens, virulence factors, and genes closely related to <it>Brucella </it>vaccines. These VO-interacting <it>Brucella </it>genes were significantly over-represented in biological functional categories, including metabolite transport and metabolism, replication and repair, cell wall biogenesis, intracellular trafficking and secretion, posttranslational modification, and chaperones. Furthermore, a comprehensive interaction network of <it>Brucella </it>vaccines and genes were identified. The asserted and inferred VO hierarchies provide semantic support for inferring novel knowledge of association of vaccines and genes from the retrieved data. New hypotheses were generated based on this analysis approach.</p> <p>Conclusion</p> <p>VO-SciMiner can be used to improve the efficiency for PubMed searching in the vaccine domain.</p

Computational methods for identifying a layered allosteric regulatory mechanism for ALS-causing mutations of Cu-Zn superoxide dismutase 1

The most prominent form of familial amyotrophic lateral sclerosis (fALS, Lou Gehrig's Disease) is caused by mutations of Cu-Zn superoxide dismutase 1 (SOD1). SOD1 maintains antioxidant activity under fALS causing mutations, suggesting that the mutations introduce a new, toxic, function. There are 100+ such known mutations that are chemically diverse and spatially distributed across the structure. The common phenotype leads us to propose an allosteric regulatory mechanism hypothesis: SOD1 mutants alter the correlated dynamics of the structure and differentially signal across an inherent allosteric network, thereby driving the disease mechanism at varying rates of efficiency. Two recently developed computational methods for identifying allosteric control sites are applied to the wild type crystal structure, 4 fALS mutant crystal structures, 20 computationally generated fALS mutants and 1 computationally generated non-fALS mutant. The ensemble of mutant structures is used to generate an ensemble of dynamics, from which two allosteric control networks are identified. One network is connected to the catalytic site and thus may be involved in the natural antioxidant function. The second allosteric control network has a locus bordering the dimer interface and thus may serve as a mechanism to modulate dimer stability. Though the toxic function of mutated SOD1 is unknown and likely due to several contributing factors, this study explains how diverse mutations give rise to a common function. This new paradigm for allostery controlled function has broad implications across allosteric systems and may lead to the identification of the key chemical activity of SOD1-linked ALS. Proteins 2011. © 2010 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/79415/1/22892_ftp.pd

Intraspinal stem cell transplantation for amyotrophic lateral sclerosis

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/134502/1/ana24584_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/134502/2/ana24584.pd