New York State Institute for Basic Research

New York City, NY, United States

New York State Institute for Basic Research

New York City, NY, United States
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Wang L.,Magee Womens Research Institute | Sassi A.B.,Magee Womens Research Institute | Sassi A.B.,University of Pittsburgh | Patton D.,University of Washington | And 6 more authors.
Drug Development and Industrial Pharmacy | Year: 2012

The feasibility of using a liposome drug delivery system to formulate octylglycerol (OG) as a vaginal microbicide product was explored. A liposome formulation was developed containing 1% OG and phosphatidyl choline in a ratio that demonstrated in vitro activity against Neisseria gonorrhoeae, HSV-1, HSV-2 and HIV-1 while sparing the innate vaginal flora, Lactobacillus. Two conventional gel formulations were prepared for comparison. The OG liposome formulation with the appropriate OG/lipid ratio and dosing level had greater efficacy than either conventional gel formulation and maintained this efficacy for at least 2 months. No toxicity was observed for the liposome formulation in ex vivo testing in a human ectocervical tissue model or in vivo testing in the macaque safety model. Furthermore, minimal toxicity was observed to lactobacilli in vitro or in vivo safety testing. The OG liposome formulation offers a promising microbicide product with efficacy against HSV, HIV and N. gonorrhoeae. © 2012 Informa Healthcare USA, Inc.

Weidner K.L.,CUNY - College of Staten Island | Goodman J.H.,New York State Institute for Basic Research | Goodman J.H.,SUNY Downstate Medical Center | Chadman K.K.,New York State Institute for Basic Research | McCloskey D.P.,CUNY - College of Staten Island
Aging and Disease | Year: 2011

Aging confers an increased risk for developing seizure activity, especially within brain regions that mediate learning and synaptic plasticity. Brain derived neurotrophic factor (BDNF) is a member of the neurotrophin family that has an important role in regulating growth and development of the nervous system. BDNF is upregulated after pharmacological seizure induction and this upregulation contributes to enhanced excitability of the hippocampal mossy fiber-CA3 pathway, which is accompanied by neuropeptide Y (NPY) upregulation. Mice overexpressing a BDNF transgene in forebrain neurons provide an avenue for understanding the role of neurotrophic support in the aged hippocampus. In this study BDNF transgenic (TG) mice were utilized to determine whether increased BDNF expression through genetic manipulation resulted in age-related changes in hippocampal excitability and NPY expression. Spontaneous behavioral seizures were observed in TG mice, but not WT mice, past 5 months of age and the severity of behavioral seizures increased with age. Electrophysiological investigation of hippocampal CA3 activity indicated that slices from aged TG mice (86%), but not age-matched WT mice, or young TG mice, showed epileptiform activity in response to either repeated paired pulse or high frequency (tetanic) stimulation. Electrophysiological results were supported by the observation of robust ectopic NPY immunoreactivity in hippocampal mossy fibers of most aged TG mice (57%), which was absent in age-matched WT mice and young TG mice. The results from this study indicate that forebrain restricted BDNF overexpression produces age-related changes in hyperexcitability and NPY immunoreactivity in mossy fiber-CA3 pathway. Together, these data suggest that the capability for BDNF to promote epileptogenesis is maintained, and may be enhanced, in the aging hippocampus.

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.

Cosentino S.A.,Columbia University Medical Center | Cosentino S.A.,Columbia University | Stern Y.,Columbia University Medical Center | Stern Y.,Columbia University | And 13 more authors.
Archives of Neurology | Year: 2010

Objectives: To determine if plasma β-amyloid (Aβ) levels (1) can be linked to specific cognitive changes that constitute conversion to Alzheimer disease (AD) and (2) correspond to cognitive change independent of dementia. Design: Longitudinal study including 3 visits during approximately 4 1/2 years (2000-2006). Setting: Northern Manhattan community. Participants: Eight hundred eighty individuals from a population-based and ethnically diverse sample who had 2 plasma Aβ measurements and were dementia free at the time of the first Aβ sample; 481 remained cognitively healthy, 329 were cognitively or functionally impaired but not demented at any point, and 70 developed AD. Main Outcome Measures: General estimating equations tested the association between plasma Aβ (baseline and change in values) and cognitive change (composite score and memory, language, and visuospatial indices). Results: High baseline plasma Aβ42 (P=.01) and Aβ40 (P=.01) and decreasing/relatively stable Aβ42 (P=.01) values were associated with faster decline in multiple cognitive domains. In those who remained cognitively healthy, high baseline plasma Aβ42 (P=.01) and decreasing/relatively stable plasma Aβ42 (P=.01) was associated with faster cognitive decline, primarily in memory. Conclusions: The association between plasma Aβ and multiple aspects of cognition more clearly specifies the previously documented downward trajectory of plasma Aβ with AD onset. The predominant association with memory seen only in healthy elderly individuals also suggests that plasma Aβ is linked with even earlier neurologic changes that may or may not culminate in dementia. ©2010 American Medical Association. All rights reserved.

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.

Nolin S.L.,New York State Institute for Basic Research | Glicksman A.,New York State Institute for Basic Research | Ersalesi N.,New York State Institute for Basic Research | Dobkin C.,New York State Institute for Basic Research | And 6 more authors.
Genetics in Medicine | Year: 2015

Fragile X CGG repeat alleles often contain one or more AGG interruptions that influence allele stability and risk of a full mutation transmission from parent to child. We have examined transmissions of maternal and paternal alleles with 45-90 repeats to quantify the effect of AGG interruptions on fragile X repeat instability.Methods:A novel FMR1 polymerase chain reaction assay was used to determine CGG repeat length and AGG interruptions for 1,040 alleles from 705 families.Results:We grouped transmissions into nine categories of five repeats by parental size and found that in every size category, alleles with no AGGs had the greatest risk for instability. For maternal alleles <75 repeats, 89% (24/27) that expanded to a full mutation had no AGGs. Two contractions in maternal transmission were accompanied by loss of AGGs, suggesting a mechanism for generating alleles that lack AGG interruptions. Maternal age was examined as a factor in full mutation expansions using prenatal samples to minimize ascertainment bias, and a possible effect was observed though it was not statistically significant (P = 0.06).Conclusion:These results strengthen the association of AGG repeats with CGG repeat stability and provide more accurate risk estimates of full mutation expansions for women with 45-90 repeat alleles. © American College of Medical Genetics and Genomics.

Vasquez K.,CUNY - College of Staten Island | Vasquez K.,New York University | Vasquez K.,New York State Institute for Basic Research | Kuizon S.,New York State Institute for Basic Research | And 3 more authors.
Advances in Experimental Medicine and Biology | Year: 2013

Autism contains a spectrum of behavioral and cognitive disturbances of childhood development that is manifested by deficits in social interaction, impaired communication, repetitive behavior, and/or restricted interest. Much research has been dedicated to finding the genes that are responsible for autism, but less than 10% of the cases can be attributed to one gene. Autism prevalence has increased in the last decade and there may be environmental components that are leading to this increase. There are reports of disruption of epigenetic mechanisms controlling the regulation of gene expression as probable cause for autism. Folic acid (FA) is prescribed to women during pregnancy, and can cause epigenetic changes. GABAergic pathway is involved in inhibitory neurotransmission in the central nervous system and plays a crucial role during early embryonic development. Autism may entail defect or deregulation of the GABAergic receptor pathway in the brain. Gamma-aminobutyric acid (type A) beta 1 receptor (GABRB1) disruption has been implicated in autism. In the present study, we investigated GABRB1 expression in response to FA supplementation in neuronal cells. Western blot analysis showed GABRB1 protein levels increased in the FA-treated cells in a concentration-dependent manner. FA-dependent increased expression of GABRB1 was further confirmed at the mRNA level using quantitative RT-PCR. These results suggest that epigenetic control of gene expression may affect the expression of GABRB1 and disrupt inhibitory synaptic transmission during embryonic development. © Springer Science+Business Media New York 2013.

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.

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.

Karmel B.Z.,New Hill | Karmel B.Z.,New York State Institute for Basic Research | Gardner J.M.,New Hill | Gardner J.M.,New York State Institute for Basic Research | And 10 more authors.
Pediatrics | Year: 2010

OBJECTIVES: Recent evidence suggests higher prevalence of autism spectrum disorder (ASD) in NICU graduates. This aim of this study was to identify retrospectively early behaviors found more frequently in NICU infants who went on to develop ASD. METHODS: Twenty-eight NICU graduates who later received a diagnosis of ASD were compared with 2169 other NICU graduates recruited from 1994 to 2005. They differed in gender, gestational age, and birth cohort. These characteristics were used to draw a matched control sample (n = 112) to determine which, if any, early behaviors discriminated subsequent ASD diagnosis. Behavioral testing at targeted ages (adjusted for gestation) included the Rapid Neonatal Neurobehavioral Assessment (hospital discharge, 1 month), Arousal-Modulated Attention (hospital discharge, 1 and 4 months), and Bayley Scales of Infant Development (multiple times, 4-25 months). RESULTS: At 1 month, children with ASD but not control children had persistent neurobehavioral abnormalities and higher incidences of asymmetric visual tracking and arm tone deficits. At 4 months, children with ASD had continued visual preference for higher amounts of stimulation than did control children, behaving more like newborns. Unlike control children, children with ASD had declining mental and motor performance by 7 to 10 months, resembling infants with severe central nervous system involvement. CONCLUSIONS: Differences in specific behavior domains between NICU graduates who later receive a diagnosis of ASD and matched NICU control children may be identified in early infancy. Studies with this cohort may provide insights to help understand and detect early disabilities, including ASD. Copyright © 2010 by the American Academy of Pediatrics.

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