211 research outputs found
Assessment of an Outdoor Recreation and Education Program
Introduce economically disadvantaged urban youth, ages 8-12, to outdoor recreation and education. Foster a belief that outdoor recreation plays an important and positive role in the health and fitness of Americaâs youth
Determinants of low bone turnover in type 2 diabetes-the role of PTH
Determinants of low bone turnover in type 2 diabetes (T2DM) are poorly understood. To investigate the relationship between markers of bone turnover, glycaemic control, disease duration and calciotropic hormones in T2DM we assessed baseline biochemical data from the DiabOS Study, a prospective multicenter observational cohort study. In a cross-sectional study-design data from 110 postmenopausal women and men aged 50-75 years diagnosed with T2DM for at least 3 years and 92 non-diabetic controls were evaluated. Biochemical markers of bone formation (N-terminal propeptide of type I procollagen [PINP]), bone-specific alkaline phosphatase [BAP]) and resorption (C-terminal cross-linking telopeptide of type I collagen [CTX]), measures of calcium homeostasis (intact parathormone [iPTH], 25-Hydroxyvitamin D, calcium, magnesium) and glycaemic control were assessed. After adjustment for age, gender and body mass index (BMI), patients with T2DM had lower serum levels of PINP (p < 0.001), CTX (p < 0.001), iPTH (p = 0.03) and magnesium (p < 0.001) compared to controls. Serum calcium, creatinine, 25-Hydroxyvitamin D and sclerostin did not differ between both groups. In multivariate linear regression analyses only serum iPTH remained an independent determinant of bone turnover markers in T2DM (PINP: p = 0.02; CTX: p < 0.001 and BAP: p < 0.01), whereas glycated haemoglobin (HbA1c), disease duration, age and BMI were not associated with bone turnover. In conclusion low bone turnover in T2DM is associated with low iPTH. The underlying mechanism remains to be elucidated
Suppression of Raf-1 kinase activity and MAP kinase signalling by RKIP
Raf-1 phosphorylates and activates MEK-1, a kinase that activates the extracellular signal regulated kinases (ERK). This kinase cascade controls the proliferation and differentiation of different cell types. Here we describe a Raf-1-interacting protein, isolated using a yeast two-hybrid screen. This protein inhibits the phosphorylation and activation of MEK by Raf-1 and is designated RKIP (Raf kinase inhibitor protein). In vitro, RKIP binds to Raf-1, MEK and ERK, but not to Ras. RKIP co-immunoprecipitates with Raf-1 and MEK from cell lysates and colocalizes with Raf-1 when examined by confocal microscopy. RKIP is not a substrate for Raf-1 or MEK, but competitively disrupts the interaction between these kinases. RKIP overexpression interferes with the activation of MEK and ERK, induction of AP-1-dependent reporter genes and transformation elicited by an oncogenically activated Raf-1 kinase. Downregulation of endogenous RKIP by expression of antisense RNA or antibody microinjection induces the activation of MEK-, ERK- and AP-1-dependent transcription. RKIP represents a new class of protein-kinase-inhibitor protein that regulates the activity of the Raf/MEK/ERK modul
Considerations in the preclinical assessment of the safety of antisense oligonucleotides
The nucleic acid therapeutics field has made tremendous progress in the past decades. Continuous advances in chemistry and design have led to many successful clinical applications, eliciting even more interest from researchers including both academic groups and drug development companies. Many preclinical studies in the field focus on improving the delivery of antisense oligonucleotide drugs (ONDs) and/or assessing their efficacy in target tissues, often neglecting the evaluation of toxicity, at least in early phases of development. A series of consensus recommendations regarding regulatory considerations and expectations have been generated by the Oligonucleotide Safety Working Group and the Japanese Research Working Group for the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use S6 and Related Issues (WGS6) in several white papers. However, safety aspects should also be kept in sight in earlier phases while screening and designing OND to avoid subsequent failure in the development phase. Experts and members of the network "DARTER," a COST Action funded by the Cooperation in Science and Technology of the EU, have utilized their collective experience working with OND, as well as their insights into OND-mediated toxicities, to generate a series of consensus recommendations to assess OND toxicity in early stages of preclinical research. In the past few years, several publications have described predictive assays, which can be used to assess OND-mediated toxicity in vitro or ex vivo to filter out potential toxic candidates before moving to in vivo phases of preclinical development, that is, animal toxicity studies. These assays also have the potential to provide translational insight since they allow a safety evaluation in human in vitro systems. Yet, small preliminary in vivo studies should also be considered to complement this early assessment. In this study, we summarize the state of the art and provide guidelines and recommendations on the different tests available for these early stage preclinical assessments.Functional Genomics of Muscle, Nerve and Brain Disorder
Pancreatic ÎČ-cell imaging in humans: Fiction or option?
Diabetes mellitus is a growing worldwide epidemic disease, currently affecting 1 in 12 adults. Treatment of disease complications typically consumes âŒ10% of healthcare budgets in developed societies. Whilst immuneâmediated destruction of insulinâsecreting pancreatic ÎČ cells is responsible for Type 1 diabetes, both the loss and dysfunction of these cells underly the more prevalent Type 2 diabetes. The establishment of robust drug development programmes aimed at ÎČâcell restoration is still hampered by the absence of means to measure ÎČâcell mass prospectively in vivo, an approach which would provide new opportunities for understanding disease mechanisms and ultimately assigning personalized treatments. In the present review, we describe the progress towards this goal achieved by the Innovative Medicines Initiative in Diabetes, a collaborative publicâprivate consortium supported by the European Commission and by dedicated resources of pharmaceutical companies. We compare several of the available imaging methods and molecular targets and provide suggestions as to the likeliest to lead to tractable approaches. Furthermore, we discuss the simultaneous development of animal models that can be used to measure subtle changes in ÎČâcell mass, a prerequisite for validating the clinical potential of the different imaging tracers
First events from the CNGS neutrino beam detected in the OPERA experiment
The OPERA neutrino detector at the underground Gran Sasso Laboratory (LNGS)
was designed to perform the first detection of neutrino oscillations in
appearance mode, through the study of nu_mu to nu_tau oscillations. The
apparatus consists of a lead/emulsion-film target complemented by electronic
detectors. It is placed in the high-energy, long-baseline CERN to LNGS beam
(CNGS) 730 km away from the neutrino source. In August 2006 a first run with
CNGS neutrinos was successfully conducted. A first sample of neutrino events
was collected, statistically consistent with the integrated beam intensity.
After a brief description of the beam and of the various sub-detectors, we
report on the achievement of this milestone, presenting the first data and some
analysis results.Comment: Submitted to the New Journal of Physic
Los Pirineos en el contexto de las montañas del mundo: rasgos generales y peculiaridades
29 pĂĄginas.Este trabajo introductorio intenta presentar la cordillera de los Pirineos, y
especialmente sus caracterĂsticas naturales dominantes, señalando en particular
aquellas que comparte con otras cordilleras del globo, y aquellas que
son peculiares de esta cadena, o compartidas con pocos sistemas montañosos
similares. Veamos pues, en primer lugar, algunos rasgos generales de la
mayor parte de las cordilleras.Peer reviewe
A prospective randomized study comparing electrochemically deposited hydroxyapatite and plasma-sprayed hydroxyapatite on titanium stems: 55 hips followed for 2 years with RSA and DXA
A novel radioresistant mechanism of galectin-1 mediated by H-Ras-dependent pathways in cervical cancer cells
Galectin-1 is a lectin recognized by galactoside-containing glycoproteins, and is involved in cancer progression and metastasis. The role of galectin-1 in radiosensitivity has not previously been investigated. Therefore, this study tests whether galectin-1 is involved in the radiosensitivity mediated by the H-Ras signaling pathway using cervical carcinoma cell lines. A knockdown of galectin-1 expression in HeLa cells decreased clonogenic survival following irradiation. The clonogenic survival increased in both HeLa and C33A cells with galectin-1 overexpression. The overexpression or knockdown of galectin-1 did not alter radiosensitivity, whereas H-Ras was silenced in both cell lines. Whereas K-Ras was knocked down, galectin-1 restored the radiosensitivity in HeLa cells and C33A cells. The knockdown of galectin-1 increased the high-dose radiation-induced cell death of HeLa cells transfected by constitutively active H-Ras. The knockdown of galectin-1 inhibited the radiation-induced phosphorylation of Raf-1 and ERK in HeLa cells. Overexpression of galectin-1 enhanced the phosphorylation of Raf-1 and ERK in C33A cells following irradiation. Galectin-1 decreased the DNA damage detected using comet assay and Îł-H2AX in both cells following irradiation. These findings suggest that galectin-1 mediates radioresistance through the H-Ras-dependent pathway involved in DNA damage repair
Threshold-Free Population Analysis Identifies Larger DRG Neurons to Respond Stronger to NGF Stimulation
Sensory neurons in dorsal root ganglia (DRG) are highly heterogeneous in terms of cell size, protein expression, and signaling activity. To analyze their heterogeneity, threshold-based methods are commonly used, which often yield highly variable results due to the subjectivity of the individual investigator. In this work, we introduce a threshold-free analysis approach for sparse and highly heterogeneous datasets obtained from cultures of sensory neurons. This approach is based on population estimates and completely free of investigator-set parameters. With a quantitative automated microscope we measured the signaling state of single DRG neurons by immunofluorescently labeling phosphorylated, i.e., activated Erk1/2. The population density of sensory neurons with and without pain-sensitizing nerve growth factor (NGF) treatment was estimated using a kernel density estimator (KDE). By subtraction of both densities and integration of the positive part, a robust estimate for the size of the responsive subpopulations was obtained. To assure sufficiently large datasets, we determined the number of cells required for reliable estimates using a bootstrapping approach. The proposed methods were employed to analyze response kinetics and response amplitude of DRG neurons after NGF stimulation. We thereby determined the portion of NGF responsive cells on a true population basis. The analysis of the dose dependent NGF response unraveled a biphasic behavior, while the study of its time dependence showed a rapid response, which approached a steady state after less than five minutes. Analyzing two parameter correlations, we found that not only the number of responsive small-sized neurons exceeds the number of responsive large-sized neuronsâwhich is commonly reported and could be explained by the excess of small-sized cellsâbut also the probability that small-sized cells respond to NGF is higher. In contrast, medium-sized and large-sized neurons showed a larger response amplitude in their mean Erk1/2 activity
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