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  • 1
    Language: English
    In: The Journal of biological chemistry, 10 August 2012, Vol.287(33), pp.27290-301
    Description: Diverse stresses including starvation and muscle disuse cause skeletal muscle atrophy. However, the molecular mechanisms of muscle atrophy are complex and not well understood. Here, we demonstrate that growth arrest and DNA damage-inducible 45a protein (Gadd45a) is a critical mediator of muscle atrophy. We identified Gadd45a through an unbiased search for potential downstream mediators of the stress-inducible, pro-atrophy transcription factor ATF4. We show that Gadd45a is required for skeletal muscle atrophy induced by three distinct skeletal muscle stresses: fasting, muscle immobilization, and muscle denervation. Conversely, forced expression of Gadd45a in muscle or cultured myotubes induces atrophy in the absence of upstream stress. We show that muscle-specific ATF4 knock-out mice have a reduced capacity to induce Gadd45a mRNA in response to stress, and as a result, they undergo less atrophy in response to fasting or muscle immobilization. Interestingly, Gadd45a is a myonuclear protein that induces myonuclear remodeling and a comprehensive program for muscle atrophy. Gadd45a represses genes involved in anabolic signaling and energy production, and it induces pro-atrophy genes. As a result, Gadd45a reduces multiple barriers to muscle atrophy (including PGC-1α, Akt activity, and protein synthesis) and stimulates pro-atrophy mechanisms (including autophagy and caspase-mediated proteolysis). These results elucidate a critical stress-induced pathway that reprograms muscle gene expression to cause atrophy.
    Keywords: Gene Expression Regulation ; Stress, Physiological ; Cell Cycle Proteins -- Metabolism ; Cell Nucleus -- Metabolism ; Muscle Proteins -- Metabolism ; Muscle, Skeletal -- Metabolism ; Muscular Atrophy -- Metabolism ; Nuclear Proteins -- Metabolism
    E-ISSN: 1083-351X
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  • 2
    In: Diabetes Care, 2018, Vol.41(5), p.1001-1008
    Description: OBJECTIVE Attaining glycemic targets without severe hypoglycemic events (SHEs) is a challenging treatment goal for patients with type 1 diabetes complicated by impaired awareness of hypoglycemia (IAH). The CIT Consortium Protocol 07 (CIT-07) trial showed islet transplantation to be an effective treatment for subjects with IAH and intractable SHEs. We evaluated health-related quality of life (HRQOL), functional health status, and health utility before and after pancreatic islet transplantation in CIT-07 trial participants. RESEARCH DESIGN AND METHODS Four surveys, the Diabetes Distress Scale (DDS), the Hypoglycemic Fear Survey (HFS), the Short Form 36 Health Survey (SF-36), and the EuroQoL 5 Dimensions (EQ-5D), were administered repeatedly before and after islet transplantation. Summary statistics and longitudinal modeling were used to describe changes in survey scores from baseline and to characterize change in relation to a minimally important difference (MID) threshold of half an SD. RESULTS Improvements in condition-specific HRQOL met the MID threshold. Reductions from baseline in the DDS total score and its four DDS subscales (all P ≤ 0.0013) and in the HFS total score and its two subscales (all P 〈 0.0001) were observed across all time points. Improvements were observed after both 1 and 2 years for the EQ-5D visual analog scale (both P 〈 0.0001). CONCLUSIONS In CIT-07, 87.5% of the subjects achieved the primary end point of freedom from SHE along with glycemic control (HbA 1c 〈7% [〈53 mmol/mol]) at 1 year post–initial islet transplantation. The same subjects reported consistent, statistically significant, and clinically meaningful improvements in condition-specific HRQOL as well as self-assessments of overall health.
    Keywords: 0407 ; Clinical Care/Education/Nutrition/Psychosocial Research
    ISSN: 0149-5992
    E-ISSN: 1935-5548
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  • 3
    In: Movement Disorders, June 2015, Vol.30(7), pp.919-927
    Description: UNLABELLED: This study was undertaken to determine the prevalence and correlates of cognitive impairment (CI) and neuropsychiatric symptoms (NPS) in early, untreated patients with Parkinson's disease (PD).BACKGROUND: Both CI and NPS are common in PD and impact disease course and quality of life. However, limited knowledge is available about cognitive abilities and NPS.METHODS: Parkinson's Progression Markers Initiative (PPMI) is a multi-site study of early, untreated PD patients and healthy controls (HCs), the latter with normal cognition. At baseline, participants were assessed with a neuropsychological battery and for symptoms of depression, anxiety, impulse control disorders (ICDs), psychosis, and apathy.RESULTS: Baseline data of 423 PD patients and 196 HCs yielded no between-group differences in demographic characteristics. Twenty-two percent of PD patients met the PD-recommended screening cutoff for CI on the Montral Cognitive Assessment (MoCA), but only 9% met detailed neuropsychological testing criteria for mild cognitive impairment (MCI)-level impairment. The PD patients were more depressed than HCs (P 〈 0.001), with twice as many (14% vs. 7%) meeting criteria for clinically significant depressive symptoms. The PD patients also experienced more anxiety (P 〈 0.001) and apathy (P 〈 0.001) than HCs. Psychosis was uncommon in PD (3%), and no between-group difference was seen in ICD symptoms (P = 0.51).CONCLUSIONS: Approximately 10% of PD patients in the early, untreated disease state met traditional criteria of CI, which is a lower frequency compared with previous studies. Multiple dopaminergic-dependent NPS are also more common in these patients compared with the general population, but others associated with dopamine replacement therapy are not or are rare. Future analyses of this cohort will examine biological predictors and the course of CI and NPS. © 2015 International Parkinson and Movement Disorder Society.
    Keywords: Anxiety ; Apathy ; Cognition ; Depression ; Impulse Control Disorder ; Parkinson'S Disease ; Psychosis
    ISSN: 0885-3185
    E-ISSN: 1531-8257
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  • 4
    In: Respirology, January 2014, Vol.19(1), pp.116-121
    Description: On a population basis, influenza activity is associated with asthma hospitalizations in the United States, and this association can be exploited to more accurately forecast asthma admissions. Our results suggest that improvements in influenza surveillance, prevention and treatment may help predict and decrease hospitalizations of asthma patients.
    Keywords: Asthma ; Forecasting ; Health‐Care Utilization ; Influenza ; Resource Allocation
    ISSN: 1323-7799
    E-ISSN: 1440-1843
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  • 5
    Language: English
    In: Infection and immunity, 04 January 2016, Vol.84(3), pp.765-74
    Description: Haemophilus haemolyticus and nontypeable Haemophilus influenzae (NTHi) are closely related upper airway commensal bacteria that are difficult to distinguish phenotypically. NTHi causes upper and lower airway tract infections in individuals with compromised airways, while H. haemolyticus rarely causes such infections. The lipooligosaccharide (LOS) is an outer membrane component of both species and plays a role in NTHi pathogenesis. In this study, comparative analyses of the LOS structures and corresponding biosynthesis genes were performed. Mass spectrometric and immunochemical analyses showed that NTHi LOS contained terminal sialic acid more frequently and to a higher extent than H. haemolyticus LOS did. Genomic analyses of 10 strains demonstrated that H. haemolyticus lacked the sialyltransferase genes lic3A and lic3B (9/10) and siaA (10/10), but all strains contained the sialic acid uptake genes siaP and siaT (10/10). However, isothermal titration calorimetry analyses of SiaP from two H. haemolyticus strains showed a 3.4- to 7.3-fold lower affinity for sialic acid compared to that of NTHi SiaP. Additionally, mass spectrometric and immunochemical analyses showed that the LOS from H. haemolyticus contained phosphorylcholine (ChoP) less frequently than the LOS from NTHi strains. These differences observed in the levels of sialic acid and ChoP incorporation in the LOS structures from H. haemolyticus and NTHi may explain some of the differences in their propensities to cause disease.
    Keywords: Haemophilus -- Metabolism ; Haemophilus Infections -- Microbiology ; Haemophilus Influenzae -- Metabolism ; Lipopolysaccharides -- Chemistry ; N-Acetylneuraminic Acid -- Analysis ; Phosphorylcholine -- Analysis
    ISSN: 00199567
    E-ISSN: 1098-5522
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  • 6
    Language: English
    In: PLoS ONE, 01 January 2018, Vol.13(5), p.e0195797
    Description: INTRODUCTION:Activity-monitoring devices may increase activity, but their effectiveness in sedentary, diseased, and less-motivated populations is unknown. METHODS:Subjects with diabetes or pre-diabetes were given a Fitbit and randomized into three groups: Fitbit only, Fitbit with reminders,...
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 7
    Language: English
    Description: In this thesis, we consider the clustering of time series data; specifically, time series that can be modeled in the state space framework. Of primary focus is the pairwise discrepancy between two state space time series. The state space model can be formulated in terms of two equations: the state equation, based on a latent process, and the observation equation. Because the unobserved state process is often of interest, we develop discrepancy measures based on the estimated version of the state process. We compare these measures to discrepancies based on the observed data. In all, seven novel discrepancies are formulated. First, discrepancies derived from Kullback-Leibler (KL) information and Mahalanobis distance (MD) measures are proposed based on the observed data. Next, KL information and MD discrepancies are formulated based on the composite marginal contributions of the smoothed estimates of the unobserved state process. Furthermore, an MD is created based on the joint contributions of the collection of smoothed estimates of the unobserved state process. The cross trajectory distance, a discrepancy heavily influenced by both observed and smoothed data, is proposed as well as a Euclidean distance based on the smoothed state estimates. The performance of these seven novel discrepancies is compared to the often used Euclidean distance based on the observed data, as well as a KL information discrepancy based on the joint contributions of the collection of smoothed state estimates (Bengtsson and Cavanaugh, 2008). We find that those discrepancy measures based on the smoothed estimates of the unobserved state process outperform those discrepancy measures based on the observed data. The best performance was achieved by the discrepancies founded upon the joint contributions of the collection of unobserved states, followed by the discrepancies derived from the marginal contributions. We observed a non-trivial degradation in clustering performance when estimating the parameters of the state space model. To improve estimation, we propose an iterative estimation and clustering routine based on the notion of finding a series' most similar counterparts, pooling them, and estimating a new set of parameters. Under ideal circumstances, we show that the iterative estimation and clustering algorithm can potentially achieve results that approach those obtained in settings where parameters are known. In practice, the algorithm often improves the performance of the model-based clustering measures. We apply our methods to two examples. The first application pertains to the clustering of time course genetic data. We use data from Cho et al. (1998) where a time course experiment of yeast gene expression was performed in order to study the yeast mitotic cell cycle. We attempt to discover the phase to which 219 genes belong. The second application seeks to answer whether or not influenza and pneumonia mortality can be explained geographically. Data from a collection of cities across the U.S. are acquired from the Morbidity and Mortality Weekly Report (MMWR). We cluster the MMWR data without geographic constraints, and compare the results to clusters defined by MMWR geographic regions. We find that influenza and pneumonia mortality cannot be explained by geography.
    Keywords: Clustering ; Kullback-Leibler ; Mahalanobis Distance ; State Space ; Time Series ; Biostatistics
    Source: University of Iowa Libraries
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  • 8
    Language: English
    In: PloS one, 2017, Vol.12(8), pp.e0182605
    Description: Society needs information about how vegetation communities in coastal regions will be impacted by hydrologic changes associated with climate change, particularly sea level rise. Due to anthropogenic influences which have significantly decreased natural coastal vegetation communities, it is important for us to understand how remaining natural communities will respond to sea level rise. The Cape Canaveral Barrier Island complex (CCBIC) on the east central coast of Florida is within one of the most biologically diverse estuarine systems in North America and has the largest number of threatened and endangered species on federal property in the contiguous United States. The high level of biodiversity is susceptible to sea level rise. Our objective was to model how vegetation communities along a gradient ranging from hydric to upland xeric on CCBIC will respond to three sea level rise scenarios (0.2 m, 0.4 m, and 1.2 m). We used a probabilistic model of the current relationship between elevation and vegetation community to determine the impact sea level rise would have on these communities. Our model correctly predicted the current proportions of vegetation communities on CCBIC based on elevation. Under all sea level rise scenarios the model predicted decreases in mesic and xeric communities, with the greatest losses occurring in the most xeric communities. Increases in total area of salt marsh were predicted with a 0.2 and 0.4 m rise in sea level. With a 1.2 m rise in sea level approximately half of CCBIC's land area was predicted to transition to open water. On the remaining land, the proportions of most of the vegetation communities were predicted to remain similar to that of current proportions, but there was a decrease in proportion of the most xeric community (oak scrub) and an increase in the most hydric community (salt marsh). Our approach provides a first approximation of the impacts of sea level rise on terrestrial vegetation communities, including important xeric upland communities, as a foundation for management decisions and future modeling.
    Keywords: Global Warming ; Plants ; Wetlands
    E-ISSN: 1932-6203
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  • 9
    Language: English
    In: Movement Disorders, 2015, Vol.30(7), p.919(9)
    Description: To purchase or authenticate to the full-text of this article, please visit this link: http://onlinelibrary.wiley.com/doi/10.1002/mds.26170/abstract Byline: Daniel Weintraub, Tanya Simuni, Chelsea Caspell-Garcia, Christopher Coffey, Shirley Lasch, Andrew Siderowf, Dag Aarsland, Paolo Barone, David Burn, Lama M. Chahine, Jamie Eberling, Alberto J. Espay, Eric D. Foster, James B. Leverenz, Irene Litvan, Irene Richard, Matthew D. Troyer, Keith A. Hawkins, Keywords: anxiety; apathy; cognition; depression; impulse control disorder; Parkinson's disease; psychosis Abstract This study was undertaken to determine the prevalence and correlates of cognitive impairment (CI) and neuropsychiatric symptoms (NPS) in early, untreated patients with Parkinson's disease (PD). Background Both CI and NPS are common in PD and impact disease course and quality of life. However, limited knowledge is available about cognitive abilities and NPS. Methods Parkinson's Progression Markers Initiative (PPMI) is a multi-site study of early, untreated PD patients and healthy controls (HCs), the latter with normal cognition. At baseline, participants were assessed with a neuropsychological battery and for symptoms of depression, anxiety, impulse control disorders (ICDs), psychosis, and apathy. Results Baseline data of 423 PD patients and 196 HCs yielded no between-group differences in demographic characteristics. Twenty-two percent of PD patients met the PD-recommended screening cutoff for CI on the Montral Cognitive Assessment (MoCA), but only 9% met detailed neuropsychological testing criteria for mild cognitive impairment (MCI)-level impairment. The PD patients were more depressed than HCs (P〈0.001), with twice as many (14% vs. 7%) meeting criteria for clinically significant depressive symptoms. The PD patients also experienced more anxiety (P〈0.001) and apathy (P〈0.001) than HCs. Psychosis was uncommon in PD (3%), and no between-group difference was seen in ICD symptoms (P=0.51). Conclusions Approximately 10% of PD patients in the early, untreated disease state met traditional criteria of CI, which is a lower frequency compared with previous studies. Multiple dopaminergic-dependent NPS are also more common in these patients compared with the general population, but others associated with dopamine replacement therapy are not or are rare. Future analyses of this cohort will examine biological predictors and the course of CI and NPS. [c] 2015 International Parkinson and Movement Disorder Society Article Note: Funding agencies: The study is funded by the Michael J. Fox Foundation (MJFF). The MJFF designed the study and is overseeing its conduct at the study sites but is not involved in data analysis. The Foundation reviewed and approved this manuscript for submission. Details regarding MJFF's Parkinson Progression Marker Initiative (PPMI) have been previously published (Marek K, Jennings D, Lasch S, Siderowf A, Tanner C, Simuni T, et al. The Parkinson Progression Marker Initiative (PPMI). Prog Neurobiol 2011; 95:629-35). Relevant conflicts of interest/financial disclosures: Nothing to report. Full financial disclosures and author roles may be found in the online version of this article. Parkinson's Progression Markers Initiative authors are listed in the Appendix. Supporting information: Additional Supporting Information may be found in the online version of this article Additional Supporting Information may be found in the online version of this article at the publisher's web-site. CAPTION(S): Supplementary Information
    Keywords: Somatotropin ; Batteries ; Cognition ; Depression (Mood Disorder) ; Prevalence Studies (Epidemiology)
    ISSN: 0885-3185
    Source: Cengage Learning, Inc.
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  • 10
    In: Movement Disorders, December 2015, Vol.30(14), pp.1885-1892
    Description: To purchase or authenticate to the full-text of this article, please visit this link: http://onlinelibrary.wiley.com/doi/10.1002/mds.26325/abstract Byline: Norbert Schuff, I-Wei Wu, Shannon Buckley, Eric D. Foster, Christopher S. Coffey, Darren R. Gitelman, Susan Mendick, John Seibyl, Tanya Simuni, Yu Zhang, Joseph Jankovic, Christine Hunter, Caroline M. Tanner, Linda Rees, Stewart Factor, Daniela Berg, Isabel Wurster, Katharina Gauss, Fabienne Sprenger, Klaus Seppi, Werner Poewe, Brit Mollenhauer, Susanne Knake, Zoltan Mari, Arita McCoy, Madelaine Ranola, Kenneth Marek Keywords: neuroimaging; substantia nigra; dopamine; fractional anisotropy ABSTRACT Background This study reports the baseline characteristics of diffusion tensor imaging data in Parkinson's disease (PD) patients and healthy control subjects from the Parkinson's Progression Markers Initiative. The main goals were to replicate previous findings of abnormal diffusion imaging values from the substantia nigra. in a large multicenter cohort and determine whether nigral diffusion alterations are associated with dopamine deficits. Methods Two hundred twenty subjects (PD=153; control=67) from 10 imaging sites were included. All subjects had a full neurological exam, a (.sub.123I)ioflupane dopamine transporter (DAT) single-photon emission computer tomography scan, and diffusion tensor imaging. Fractional anisotropy as well as radial and axial diffusivity was computed within multiple regions across the substantia nigra. Results A repeated-measures analysis of variance found a marginally nonsignificant interaction between regional fractional anisotropy of the substantia nigra and disease status (P=0.08), conflicting with an earlier study. However, a linear mixed model that included control regions in addition to the nigral regions revealed a significant interaction between regions and disease status (P=0.002), implying a characteristic distribution of reduced fractional anisotropy across the substantia nigra in PD. Reduced fractional anisotropy in PD was also associated with diminished DAT binding ratios. Both axial and radial diffusivity were also abnormal in PD. Conclusions Although routine nigral measurements of fractional anisotropy are clinically not helpful, the findings in this study suggest that more-sophisticated diffusion imaging protocols should be used when exploring the clinical utility of this imaging modality. [c] 2015 International Parkinson and Movement Disorder Society Article Note: Relevant conflicts of interest/financial disclosures: Nothing to report. Full financial disclosures and author roles may be found in the online version of this article. Supporting information: Additional Supporting Information may be found in the online version of this article Additional Supporting Information may be found in the online version of this article at the publisher's web-site. CAPTION(S): Supplementary Information Supplementary Information
    Keywords: Neuroimaging ; Substantia Nigra ; Dopamine ; Fractional Anisotropy
    ISSN: 0885-3185
    E-ISSN: 1531-8257
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