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991.
Myotonic Dystrophy Type-2 (DM2) is an autosomal dominant disease caused by the expansion of a CCTG tetraplet repeat. It is a multisystemic disorder, affecting skeletal muscles, the heart, the eye, the central nervous system and the endocrine system. Since microRNA (miRNA) expression is disrupted in Myotonic Dystrophy Type-1 and many other myopathies, miRNAs deregulation was studied in skeletal muscle biopsies of 13 DM2 patients and 13 controls. Eleven miRNAs were deregulated: 9 displayed higher levels compared to controls (miR-34a-5p, miR-34b-3p, miR-34c-5p, miR-146b-5p, miR-208a, miR-221-3p and miR-381), while 4 were decreased (miR-125b-5p, miR-193a-3p, miR-193b-3p and miR-378a-3p). To explore the relevance of DM2 miRNA deregulation, the predicted interactions between miRNA and mRNA were investigated. Global gene expression was analyzed in DM2 and controls and bioinformatic analysis identified more than 1,000 miRNA/mRNA interactions. Pathway and function analysis highlighted the involvement of the miRNA-deregulated mRNAs in multiple aspects of DM2 pathophysiology. In conclusion, the observed miRNA dysregulations may contribute to DM2 pathogenetic mechanisms. 相似文献
992.
A Lai FR Simonetti G Zehender A De Luca V Micheli P Meraviglia P Corsi P Bagnarelli P Almi A Zoncada S Paolucci A Gonnelli G Colao D Tacconi M Franzetti M Ciccozzi M Zazzi C Balotta 《PloS one》2012,7(8):e42223
About 40% of the Italian HIV-1 epidemic due to non-B variants is sustained by F1 clade, which circulates at high prevalence in South America and Eastern Europe. Aim of this study was to define clade F1 origin, population dynamics and epidemiological networks through phylogenetic approaches. We analyzed pol sequences of 343 patients carrying F1 subtype stored in the ARCA database from 1998 to 2009. Citizenship of patients was as follows: 72.6% Italians, 9.3% South Americans and 7.3% Rumanians. Heterosexuals, Homo-bisexuals, Intravenous Drug Users accounted for 58.1%, 24.0% and 8.8% of patients, respectively. Phylogenetic analysis indicated that 70% of sequences clustered in 27 transmission networks. Two distinct groups were identified; the first clade, encompassing 56 sequences, included all Rumanian patients. The second group involved the remaining clusters and included 10 South American Homo-bisexuals in 9 distinct clusters. Heterosexual modality of infection was significantly associated with the probability to be detected in transmission networks. Heterosexuals were prevalent either among Italians (67.2%) or Rumanians (50%); by contrast, Homo-bisexuals accounted for 71.4% of South Americans. Among patients with resistant strains the proportion of clustering sequences was 57.1%, involving 14 clusters (51.8%). Resistance in clusters tended to be higher in South Americans (28.6%) compared to Italian (17.7%) and Rumanian patients (14.3%). A striking proportion of epidemiological networks could be identified in heterosexuals carrying F1 subtype residing in Italy. Italian Heterosexual males predominated within epidemiological clusters while foreign patients were mainly Heterosexual Rumanians, both males and females, and South American Homo-bisexuals. Tree topology suggested that F1 variant from South America gave rise to the Italian F1 epidemic through multiple introduction events. The contact tracing also revealed an unexpected burden of resistance in epidemiological clusters underlying the need of public interventions to limit the spread of non-B subtypes and transmitted drug resistance. 相似文献
993.
994.
Amyotrophic lateral sclerosis (ALS) is a progressive and seriously disabling adult-onset neurological disease. Accumulating evidence indicates that various miRNAs, expressed in a spatially and temporally controlled manner in the brain, play a key role in neuronal development. In addition, misregulation of microRNAs contributes to some mental disorders and neurodegeneration diseases. Here, we analyzed the expression profiles of 911 human miRNAs using microarray technology in leukocytes, the most readily available human tissue cells, obtained from 8 patients affected by sporadic amyotrophic lateral sclerosis (sALS) and 12 healthy controls. An independent group of 14 sALS patients and 14 controls was used for validation by TaqMan real-time polymerase chain reaction assay. We identified 8 miRNAs that were significantly up- or downregulated in sALS patients as compared to healthy controls. The significant variations in miRNAs profiles detected in leukocytes have been related to miRNAs predominantly expressed in the nervous system. One of these miRNAs, miR-338-3p, has previously been shown to be de-regulated in ALS brains. This study, for the first time, detected specific microRNAs disease-related changes at an earlier stage of sALS. We suggest that miRNAs profiles found in the peripheral blood leukocytes from sALS patients can be relevant to understand the pathogenesis of sALS and/or used as biomarkers of the disease. 相似文献
995.
The stressed synapse: the impact of stress and glucocorticoids on glutamate transmission 总被引:1,自引:0,他引:1
Mounting evidence suggests that acute and chronic stress, especially the stress-induced release of glucocorticoids, induces changes in glutamate neurotransmission in the prefrontal cortex and the hippocampus, thereby influencing some aspects of cognitive processing. In addition, dysfunction of glutamatergic neurotransmission is increasingly considered to be a core feature of stress-related mental illnesses. Recent studies have shed light on the mechanisms by which stress and glucocorticoids affect glutamate transmission, including effects on glutamate release, glutamate receptors and glutamate clearance and metabolism. This new understanding provides insights into normal brain functioning, as well as the pathophysiology and potential new treatments of stress-related neuropsychiatric disorders. 相似文献
996.
Ruggeri M Bonetto C Lasalvia A De Girolamo G Fioritti A Rucci P Santonastaso P Neri G Pileggi F Ghigi D Miceli M Scarone S Cocchi A Torresani S Faravelli C Zimmermann C Meneghelli A Cremonese C Scocco P Leuci E Mazzi F Gennarelli M Brambilla P Bissoli S Bertani ME Tosato S De Santi K Poli S Cristofalo D Tansella M;THE GET UP GROUP 《Trials》2012,13(1):73-16
ABSTRACT: BACKGROUND: Multi-element interventions for first-episode psychosis (FEP) are promising, but have mostly been conducted in non-epidemiologically representative samples, thereby raising the risk of underestimating the complexities involved in treating FEP in 'real-world' services. METHODS/DESIGN: The Psychosis early Intervention and Assessment of Needs and Outcome (PIANO) trial is part of a larger research program (Genetics, Endophenotypes and Treatment: Understanding early Psychosis - GET UP) which aims to compare, at 9?months, the effectiveness of a multi-component psychosocial intervention versus treatment as usual (TAU) in a large epidemiologically based cohort of patients with FEP and their family members recruited from all public community mental health centers (CMHCs) located in two entire regions of Italy (Veneto and Emilia Romagna), and in the cities of Florence, Milan and Bolzano. The GET UP PIANO trial has a pragmatic cluster randomized controlled design. The randomized units (clusters) are the CMHCs, and the units of observation are the centers' patients and their family members. Patients in the experimental group will receive TAU plus: 1) cognitive behavioral therapy sessions, 2) psycho-educational sessions for family members, and 3) case management. Patient enrolment will take place over a 1-year period. Several psychopathological, psychological, functioning, and service use variables will be assessed at baseline and follow-up. The primary outcomes are: 1) change from baseline to follow-up in positive and negative symptoms' severity and subjective appraisal; 2) relapse occurrences between baseline and follow-up, that is, episodes resulting in admission and/or any case-note records of re-emergence of positive psychotic symptoms. The expected number of recruited patients is about 400, and that of relatives about 300. Owing to the implementation of the intervention at the CMHC level, the blinding of patients, clinicians, and raters is not possible, but every effort will be made to preserve the independency of the raters. We expect that this study will generate evidence on the best treatments for FEP, and will identify barriers that may hinder its feasibility in 'real-world' clinical settings, patient/family conditions that may render this intervention ineffective or inappropriate, and clinical, psychological, environmental, and service organization predictors of treatment effectiveness, compliance, and service satisfaction. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT01436331. 相似文献
997.
998.
David M. Katz Joanne E. Berger-Sweeney James H. Eubanks Monica J. Justice Jeffrey L. Neul Lucas Pozzo-Miller Mary E. Blue Diana Christian Jacqueline N. Crawley Maurizio Giustetto Jacky Guy C. James Howell Miriam Kron Sacha B. Nelson Rodney C. Samaco Laura R. Schaevitz Coryse St. Hillaire-Clarke Juan L. Young Huda Y. Zoghbi Laura A. Mamounas 《Disease models & mechanisms》2012,5(6):733-745
In September of 2011, the National Institute of Neurological Disorders and Stroke (NINDS), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the International Rett Syndrome Foundation (IRSF) and the Rett Syndrome Research Trust (RSRT) convened a workshop involving a broad cross-section of basic scientists, clinicians and representatives from the National Institutes of Health (NIH), the US Food and Drug Administration (FDA), the pharmaceutical industry and private foundations to assess the state of the art in animal studies of Rett syndrome (RTT). The aim of the workshop was to identify crucial knowledge gaps and to suggest scientific priorities and best practices for the use of animal models in preclinical evaluation of potential new RTT therapeutics. This review summarizes outcomes from the workshop and extensive follow-up discussions among participants, and includes: (1) a comprehensive summary of the physiological and behavioral phenotypes of RTT mouse models to date, and areas in which further phenotypic analyses are required to enhance the utility of these models for translational studies; (2) discussion of the impact of genetic differences among mouse models, and methodological differences among laboratories, on the expression and analysis, respectively, of phenotypic traits; and (3) definitions of the standards that the community of RTT researchers can implement for rigorous preclinical study design and transparent reporting to ensure that decisions to initiate costly clinical trials are grounded in reliable preclinical data. 相似文献
999.
Vallin E Gallagher J Granger L Martin E Belougne J Maurizio J Duverger Y Scaglione S Borrel C Cortier E Abouzid K Carre-Pierrat M Gieseler K Ségalat L Kuwabara PE Ewbank JJ 《PloS one》2012,7(2):e30482
Methods that use homologous recombination to engineer the genome of C. elegans commonly use strains carrying specific insertions of the heterologous transposon Mos1. A large collection of known Mos1 insertion alleles would therefore be of general interest to the C. elegans research community. We describe here the optimization of a semi-automated methodology for the construction of a substantial collection of Mos1 insertion mutant strains. At peak production, more than 5,000 strains were generated per month. These strains were then subject to molecular analysis, and more than 13,300 Mos1 insertions characterized. In addition to targeting directly more than 4,700 genes, these alleles represent the potential starting point for the engineered deletion of essentially all C. elegans genes and the modification of more than 40% of them. This collection of mutants, generated under the auspices of the European NEMAGENETAG consortium, is publicly available and represents an important research resource. 相似文献
1000.
M Remelli D Valensin L Toso E Gralka R Guerrini E Marzola H Kozłowski 《Metallomics : integrated biometal science》2012,4(8):794-806
Among the common features shared by neurodegenerative diseases there is the central role played by specific proteins or peptides which accumulate in neurons as insoluble plaques or tangles, containing abnormal amounts of redox-active metal ions, like copper and iron. In the case of transmissible spongiform encephalopathies (TSE), the involved protein is known as "prion protein" (PrP(C)) since "prions" (proteinaceous and infectious) are the agents which make TSE transmissible. It is widely accepted that PrP(C), in its wild-type form, can bind up to six Cu(II) ions, four of them in the so-called "octarepeat domain" and the others in the "fifth (non-octarepeat) binding-site". The latter domain contains two His residues, acting as anchoring sites for Cu(II) ions, and other potential binding residues, such as Lys and Met. While it is widely accepted that Lys residues do not take part in complex-formation, the role of methionines is still debated. In order to shed light on this issue, some peptides have been synthesized, either directly mimicking the sequence of the second half of the fifth binding site of human-PrP(C) (apo-form) or analogues where Met residues have been substituted by n-leucine. In addition, a series of short peptides, containing both His and Met residues in different relative positions, have been investigated, for the sake of comparison. Spectroscopic results, including NMR spectra of systems containing Ni(II) as a probe for the paramagnetic Cu(II) ion, agree on the exclusion of any direct interaction between the sulphur atom of Met residues and the Cu(II) ion already bound to His-imidazole side-chains. However, thermodynamic data show that Met-109 somewhat contributes to stability of complex species and this can be attributed to different electronic and steric effects. 相似文献