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Edison, NJ, United States

Crocker J.,Howard Hughes Medical Institute | Abe N.,Columbia University | Rinaldi L.,Columbia University | McGregor A.P.,Oxford Brookes University | And 12 more authors.
Cell | Year: 2015

In animals, Hox transcription factors define regional identity in distinct anatomical domains. How Hox genes encode this specificity is a paradox, because different Hox proteins bind with high affinity in vitro to similar DNA sequences. Here, we demonstrate that the Hox protein Ultrabithorax (Ubx) in complex with its cofactor Extradenticle (Exd) bound specifically to clusters of very low affinity sites in enhancers of the shavenbaby gene of Drosophila. These low affinity sites conferred specificity for Ubx binding in vivo, but multiple clustered sites were required for robust expression when embryos developed in variable environments. Although most individual Ubx binding sites are not evolutionarily conserved, the overall enhancer architecture - clusters of low affinity binding sites - is maintained and required for enhancer function. Natural selection therefore works at the level of the enhancer, requiring a particular density of low affinity Ubx sites to confer both specific and robust expression. © 2015 Elsevier Inc.

Ming X.,The New School | Ming X.,New Jersey Neuroscience Institute | Barnes V.,Colgate Palmolive | Rhodes N.,Metabolon | Guo L.,Metabolon
Journal of Proteome Research | Year: 2012

Autism spectrum disorders (ASD) are a group of biological disorders with associated metabolic derangement. This study aimed to identify a pattern of metabolic perturbance in ASD using metabolomics in urinary specimens from 48 children with ASD and 53 age matched controls. Using a combination of liquid- and gas-chromatography-based mass spectrometry, we detected the levels of 82 metabolites (53 of which were increased) that were significantly altered between the ASD and the control groups using osmolality normalized data. Pattern analysis showed that the levels of several amino acids such as glycine, serine, threonine, alanine, histidine, glutamyl amino acids and the organic acid, taurine were significantly (p ≤ 0.05) lower in ASD children. The levels of antioxidants such as carnosine were also reduced in ASD (p = 0.054). Furthermore, several gut bacterial metabolites were significantly altered in ASD children who had gastrointestinal dysfunction. Overall, this study detected abnormal amino acid metabolism, increased oxidative stress, and altered gut microbiomes in ASD. The relationship of altered gut microbial co-metabolism and the disrupted metabolisms requires further investigation. © 2012 American Chemical Society.

Leger D.,University of Paris Descartes | Partinen M.,Rinnekoti Research Center | Hirshkowitz M.,Sleep Disorders and Research Center | Chokroverty S.,New Jersey Neuroscience Institute | Hedner J.,Sahlgrenska University Hospital
Sleep Medicine | Year: 2010

Objective: To describe the characteristics of insomnia in primary care physicians' (PCPs') practices in 10 countries and to understand how the difficulty of maintaining sleep (DMS) was or was not associated with other insomnia symptoms such as difficulty initiating sleep (DIS), early morning awakenings (EMA) or nonrestorative sleep (NRS) in PCPs patients with insomnia. Methods: International, noninterventional, cross-sectional, observational survey conducted in a primary care setting in subjects complaining of sleep disturbances in 10 countries. A questionnaire based on DSM-IV and ICSD criteria was administered. Results: Thirteen thousand one hundred twenty-four subjects were enrolled by 647 physicians; 5293 of them (32.6%) had insomnia and were surveyed. The population was predominantly female (63.9%) with a mean age of 47.8 ± 15.3. years; 39.9% of these patients have already been treated for sleep difficulties. Combination of all types of insomnia symptoms (DIS. +. DMS. +. EMA. +. NRS) was the most frequently reported combination (38.6% of the subjects), while the percentage of subjects presenting with only one type of insomnia symptom (DIS, DMS, EMA or NRS) was very low: 3%, 1.8%, 0.9% and 1.4% respectively. DMS was on average the most commonly reported insomnia symptom (80.2%). Multiple logistic regression showed that DMS, EMA and NRS symptoms were significantly linked with each other and also to other insomnia criteria (sleep satisfaction, sleep quality, sleep duration, number of hours of sleep, frequency of insomnia symptoms, wake up rested / unrested and non restorative sleep). Conclusions: Patients visiting PCPs with insomnia are likely to present with severe and poly-symptomatic insomnia. © 2010 Elsevier B.V.

Jayadev S.,University of Washington | Nochlin D.,New Jersey Neuroscience Institute | Poorkaj P.,Education Center | Steinbart E.J.,Education Center | And 8 more authors.
Annals of Neurology | Year: 2011

Objective To describe the Alzheimer disease (AD)-like clinical and pathological features, including marked neurofibrillary tangle (NFT) pathology, of a familial prion disease due to a rare nonsense mutation of the prion gene (PRNP). Methods Longitudinal clinical assessments were available for the proband and her mother. After death, both underwent neuropathological evaluation. PRNP was sequenced after failure to find immunopositive Aβ deposits in the proband and the documentation of prion protein (PrP) immunopositive pathology. Results The proband presented at age 42 years with a 3-year history of progressive short-term memory impairment and depression. Neuropsychological testing found impaired memory performance, with relatively preserved attention and construction. She was diagnosed with AD and died at age 47 years. Neuropathologic evaluation revealed extensive limbic and neocortical NFT formation and neuritic plaques consistent with a Braak stage of VI. The NFTs were immunopositive, with multiple tau antibodies, and electron microscopy revealed paired helical filaments. However, the neuritic plaques were immunonegative for Aβ, whereas immunostaining for PrP was positive. The mother of the proband had a similar presentation, including depression, and had been diagnosed clinically and pathologically as AD. Reevaluation of her brain tissue confirmed similar tau and PrP immunostaining findings. Genetic analysis revealed that both the proband and her mother had a rare PRNP mutation (Q160X) that resulted in the production of truncated PrP. Interpretation We suggest that PRNP mutations that result in a truncation of PrP lead to a prolonged clinical course consistent with a clinical diagnosis of AD and severe AD-like NFTs. © 2010 American Neurological Association.

Kang S.,University of Iowa | Wu C.,University of Iowa | Wu C.,University of Sichuan | Banik R.K.,University of Iowa | And 2 more authors.
Pain | Year: 2010

Dilute capsaicin produces a differential effect on incision-related pain behaviors depending upon the test; it reduces heat hyperalgesia and guarding pain but not mechanical hyperalgesia. This suggests that common mechanisms for heat hyperalgesia and guarding pain occur, and distinct mechanisms exist for mechanical hyperalgesia. The purpose of the present study was to evaluate the effect of capsaicin treatment on the activity of cutaneous nociceptors sensitized by incision to understand the mechanisms for the selective action of dilute capsaicin on incisional pain. We compared the effect of 0.05% capsaicin vs. vehicle treatment on pain behaviors after incision and on the activity of nociceptors from these same rats using the in vitro glabrous skin-nerve preparation. Immunohistochemical expression of protein gene product 9.5 (PGP9.5), neurofilament 200, calcitonin gene related peptide (CGRP) and isolectin B4 (IB4) in skin was also evaluated 1 week after 0.05% capsaicin infiltration. Infiltration of 0.05% capsaicin decreased CGRP and IB4/PGP9.5-immunoreactivity of nociceptors in skin. The same dose of capsaicin that inhibited heat hyperalgesia and guarding behavior interfered with chemo- and heat sensitivity of C-fibers. Neither mechanical hyperalgesia nor mechanosensitivity of nociceptors was affected by capsaicin, suggesting that the concentration of capsaicin used in this study did not cause fiber degeneration. These results demonstrate that nociceptors desensitized by capsaicin contribute to heat hyperalgesia and guarding pain after plantar incision. These putative TRPV1-expressing C-fibers are sensitized to heat and acid after incision, and the transduction of heat and chemical stimuli after plantar incision is impaired by dilute capsaicin. © 2009 International Association for the Study of Pain.

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