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Huang S.-H.,University of Southern California | Wu C.-H.,University of Southern California | Jiang S.,Fudan University | Bahner I.,Florida Southern College | And 2 more authors.
Biochemical Journal | Year: 2011

Cryptococcus neoformans causes life-threatening meningoencephalitis, particularly prevalent in AIDS patients. The interrelationship between C. neoformans and HIV-1 is intriguing, as both pathogens elicit severe neuropathological complications. We have previously demonstrated that the HIV-1 gp41 ectodomain fragments gp41-I33 (amino acids 579-611) and gp41-I90 (amino acids 550-639) can enhance C. neoformans binding to HBMECs (human brain microvascular endothelial cells). Both peptides contain the loop region of gp41. In the present study, we used immunofluorescence microscopy and transmission and scanning electron microscopy to explore the underlying mechanisms. Our findings indicated that both C. neoformans and gp41-I90 up-regulated ICAM-1 (intercellular adhesion molecule 1) on the HBMECs and elicited membrane ruffling on the surface of HBMECs. The HIV-1 gp41 ectodomain could also induce CD44 and β-actin redistribution to the membrane lipid rafts, but it could not enhance PKCα (protein kinase Cα) phosphorylation like C. neoformans. Instead, gp41-I90 was able to induce syncytium formation on HBMECs. The results of the present study suggest HIV-1 gp41-enhanced C. neoformans binding to HBMECs via gp41 core domain-induced membrane activities, revealing a potential mechanism of invasion for this pathogenic fungus into the brain tissues of HIV-1-infected patients. ©The Authors Journal compilation © 2011 Biochemical Society. Source


Wang X.,New Hill | Wang X.,Huazhong University of Science and Technology | Blanchard J.,New Hill | Grundke-Iqbal I.,New Hill | And 4 more authors.
Acta Neuropathologica | Year: 2014

The etiopathogenesis of neither the sporadic form of Alzheimer disease (AD) nor of amyotrophic lateral sclerosis (ALS) is well understood. The activity of protein phosphatase-2A (PP2A), which regulates the phosphorylation of tau and neurofilaments, is negatively regulated by the myeloid leukemia-associated protein SET, also known as inhibitor-2 of PP2A, I 2 PP2A. In AD brain, PP2A activity is compromised, probably because I 2 PP2A is overexpressed and is selectively cleaved at asparagine 175 into an N-terminal fragment, I2NTF, and a C-terminal fragment, I 2CTF, and both fragments inhibit PP2A. Here, we analyzed the spinal cords from ALS and control cases for I 2 PP2A cleavage and PP2A activity. As observed in AD brain, we found a selective increase in the cleavage of I 2 PP2A into I2NTF and I 2CTF and inhibition of the activity and not the expression of PP2A in the spinal cords of ALS cases. To test the hypothesis that both AD and ALS could be triggered by I2CTF, a cleavage product of I 2 PP2A, we transduced by intracerebroventricular injections newborn rats with adeno-associated virus serotype 1 (AAV1) containing human I 2CTF. AAV1-I2CTF produced reference memory impairment and tau pathology, and intraneuronal accumulation of Aβ by 5-8 months, and motor deficit and hyperphosphorylation and proliferation of neurofilaments, tau and TDP-43 pathologies, degeneration and loss of motor neurons and axons in the spinal cord by 10-14 months in rats. These findings suggest a previously undiscovered etiopathogenic relationship between sporadic forms of AD and ALS that is linked to I 2 PP2A and the potential of I 2 PP2A -based therapeutics for these diseases. © 2013 Springer-Verlag Berlin Heidelberg. Source


Skinner M.C.,University of Washington | Kiselev A.O.,University of Washington | Isaacs C.E.,New York State Institute for Basic Research | Mietzner T.A.,University of Pittsburgh | And 2 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2010

Topical microbicides for prevention of sexually transmitted diseases (STDs) would be especially useful for women who are not able to persuade their partner(s) to take precautions. Many topical microbicides are in various stages of development, based on a variety of active ingredients. We investigated the in vitro activity of an engineered antimicrobial peptide (WLBU2) and a lipid (3-O-octyl-sn-glycerol [3-OG]) which could potentially be used as active ingredients in such a product. Using commercially available cytotoxicity reagents [Alamar Blue, 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT), and lactate dehydrogenase (LDH)], we first determined the toxicity of WLBU2 and 3-OG to the host cells in our assay procedure and excluded toxic concentrations from further testing. To determine activity against Chlamydia trachomatis, we used an assay previously developed by our laboratory in which chlamydial elementary bodies (EBs) were exposed to microbicides prior to contact with epithelial cells: the minimum (microbi)cidal concentration (MCC) assay. To further simulate conditions of transmission, we carried out the same assay in the presence of a simulated vaginal fluid, a simulated seminal fluid, human serum albumin, and a range of pH values which might be found in the human vagina at the time of exposure. Last, we tested WLBU2 and 3-OG in combination to determine if adding them together resulted in synergistic activity. We found that WLBU2 and 3-OG both have excellent activity in vitro against C. trachomatis and significantly more activity when added together. The simulated fluids reduced activity, but the synergy seen is good evidence that they would be effective when combined in a microbicide formulation. Copyright © 2010, American Society for Microbiology. All Rights Reserved. Source


News Article
Site: http://www.biosciencetechnology.com/rss-feeds/all/rss.xml/all

The risk of Alzheimer’s disease—the most common cause of dementia—increases as a person ages. But the risk of Alzheimer’s is increased dramatically for adults with Down syndrome. At age 40, individuals with Down syndrome already have the neuropathological changes of Alzheimer’s disease, including the telltale buildup of amyloid plaques and tau tangles that precede symptoms. The early buildup occurs because people with Down syndrome carry an extra copy of chromosome 21, which contains a gene that produces a protein that is a precursor for amyloid. Ninety percent of individuals with Down syndrome will have developed Alzheimer’s disease by age 70 (in the general population, 11 percent of people over age 65 and 32 percent of people over age 85 have Alzheimer’s). However, there is wide variation in age at onset of dementia, ranging from under 40 to over 70 years of age, suggesting that additional genetic, biological, and environmental factors may be important modifiers of risk that accelerate or slow disease progression. New studies at Columbia are designed to explain why some people with Down syndrome develop Alzheimer’s disease earlier than others and why some people with Down syndrome may never develop the disease. With funding from the NIH, Nicole Schupf, Ph.D., DrPH, will identify biomarkers for Alzheimer’s disease in people with Down syndrome, which may help researchers predict who will develop Alzheimer’s in all groups of people. Dr. Schupf is professor of epidemiology at CUMC in Columbia’s Taub Institute for Research on Alzheimer’s Disease and the Aging Brain and the Departments of Neurology and Psychiatry. Many researchers believe that future Alzheimer’s disease treatments may be most effective in the early stages of the disease, before the onset of symptoms and before irreversible neuron loss has occurred. Dr. Schupf’s work will identify biomarkers that can predict the risk of developing Alzheimer’s disease in people with Down syndrome with no symptoms of the degenerative disease. The study focuses on a longitudinal and multidisciplinary determination of key biomarkers that are likely to define the progression from normal aging to onset of dementia, including levels and rates of change in blood-based biomarkers such as b-amyloid peptides, protein, inflammatory and lipid profiles, measures of amyloid and tau concentration in cerebrospinal fluid, neuroimaging-based changes, PET studies of brain amyloid uptake, and genetic polymorphisms. These biomarkers will be combined to develop the most valid indicators of preclinical and early stages of Alzheimer’s. The goal is to develop a noninvasive test to detect Alzheimer’s disease in individuals with Down syndrome and in the broader population. The grant for this prospective study is part of an NIH initiative, Biomarkers of Alzheimer’s Disease in Adults with Down Syndrome, that supports two collaborative teams seeking Alzheimer’s Disease biomarkers in people with Down syndrome. Dr. Schupf leads a team of investigators from Columbia University Medical Center, the University of California, Irvine, Kennedy Krieger Institute/Johns Hopkins University, Massachusetts General Hospital/Harvard, the New York State Institute for Basic Research in Developmental Disabilities, and the University of North Texas Health Sciences Center. The second team is headed by Benjamin Handen, PhD, from the University of Pittsburgh. The two projects will share $37 million in funding over the next five years.


Gordon L.B.,Brown University | Gordon L.B.,Harvard University | Massaro J.,Boston University | D'Agostino Sr. R.B.,Boston University | And 5 more authors.
Circulation | Year: 2014

Background - Hutchinson-Gilford progeria syndrome is an ultrarare segmental premature aging disease resulting in early death from heart attack or stroke. There is no approved treatment, but starting in 2007, several recent single-arm clinical trials administered inhibitors of protein farnesylation aimed at reducing toxicity of the disease-producing protein progerin. No study assessed whether treatments influence patient survival. The key elements necessary for this analysis are a robust natural history of survival and comparison with a sufficiently large patient population that has been treated for a sufficient time period with disease-targeting medications. Methods and Results - We generated Kaplan-Meier survival analyses for the largest untreated Hutchinson-Gilford progeria syndrome cohort to date. Mean survival was 14.6 years. Comparing survival for treated versus age- and sex-matched untreated cohorts, hazard ratio was 0.13 (95% confidence interval, 0.04-0.37; P<0.001) with median follow-up of 5.3 years from time of treatment initiation. There were 21 of 43 deaths in untreated versus 5 of 43 deaths among treated subjects. Treatment increased mean survival by 1.6 years. Conclusions - This study provides a robust untreated disease survival profile that can be used for comparisons now and in the future to assess changes in survival with treatments for Hutchinson-Gilford progeria syndrome. The current comparisons estimating increased survival with protein farnesylation inhibitors provide the first evidence of treatments influencing survival for this fatal disease. © 2014 American Heart Association, Inc. Source

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