2,243 publications from this institution
Background:In humans, glucocorticoids (GCs) regulate a broad spectrum of physiologic functions and exert both genomic and non-genomic actions through their ubiquitously expressed glucocorticoid receptor (hGR).The rapid non-genomic actions of GCs are likely to be mediated by membrane hGRs that transduce the glucocorticoid signal via activation of kinases.S-palmitoylation plays an important role in plasma membrane (PM) localization and occurs through a highly conserved 9 amino acid motif in the ligand-binding domain (LBD) of steroid receptors.A highly homologous sequence is present in the LBD of the hGRα protein, suggesting that the hGR might also undergo S-palmitoylation.Objective and hypotheses: To determine the role of S-palmitoylation of hGR in mediating rapid glucocorticoid signaling following translocation and binding to the PM.Methods: In vitro studies were performed to determine the specific residues within the 9 amino acid motif of the LBD of hGRα that are crucial for rapid glucocorticoid signaling.Specifically, we determined whether mutation of the amino acids at position -2, 0 and +5/6, relative to cysteine in the 9 amino acid motif, significantly reduces localization of the receptor to the PM, Spalmitoylation, association with caveolin-1, and MAPK and PI3K activation.Results: Both the wild-type and the mutant receptors hGRαY663A, hGRαC665A and hGRáLL670/671AA showed similar distribution to the PM.Addition of 2-bromopalmitate, an S-palmitoylation inhibitor, did not prevent PM localization of the receptor or colocalization with caveolin-1.Compared with the wild-type hGR, all hGR mutant receptors resulted in decreased activation of MAPK signaling from 60 min onwards.A similar reduction in wildtype GR-induced MAPK signaling at 60 min was observed after treatment with 2-bromopalmitate.Conclusions: S-palmitoylation facilitates sustained activation of the MAPK pathway.Further studies are required to confirm that the hGR protein mediates this effect through the 9 amino acid motif in the LBD.
A rehabilitation plan is presented for a two-story industrial steel structure in Iran. The building was found to have unsatisfactory performance: The first-floor two-way composite slab was prone to uncontrollable vibrations during normal operation (forklift vehicles), and the lateral load resisting system did not comply with current seismic code provisions. Notably, a recent vibration rehabilitation attempt applied to an almost identical structure had added columns and struts of nearly 120 tons of steel with little improvement. To resolve this twofold problem while respecting the minimum disruption requirement for a facility that operates nearly 24/7 and the height/width clearance restrictions due to existing industrial machinery and vehicle traffic, a combined rehabilitation scheme was proposed that involved: (1) keeping the extra columns of the failed rehabilitation scheme, (2) stiffening the joists, (3) adopting toggle-brace dampers in the main girders, and (4) strengthening the existing lateral X-braces and their connections.
The most prominent scenario on the origins of life is that life began with RNA. This is a rather convenient hypothesis that has been based on an acceleration of complexity in the evolutionary time trajectory, including life. The negentropy introduced with life, and the progressively increasing complexity and specialized molecular mechanisms began with the genetic molecules of life and, in fact, with the least complicated one, which is the RNA. However, there are no solid explanations on key questions, such as the process through which the RNA was formed, and why those four bases and not five or two. Even if by an unbelievable turn of events and abundant evolutionary time, RNA was formed out of pure chance, the questions remain of where are the other molecules that should also have been made by chance and the process through which the RNA self-replicated. Herein, a novel approach identifying steroids as the first molecules to have started life is being suggested. The hypothesis presented herein describes early steroid-like clusters, organized in the three-dimensional space, which might have led to the formation of RNA. Molecular dynamic (MD) simulations support the initial formation of cyclohexanes that, through their physicochemical properties and a chemical cascade in the prehistoric earth could lead to the first early version of an RNA molecule. All in all, the herein proposed path for the creation of RNA, is a good Newtonian approximation that is compatible with human senses and observations. It is obvious that quantum mechanics, physics, and chemistry orchestrated at subatomic level the creation of the first molecules that gave rise to the first living cell and eventually life as we know it.
Predictive relationships are offered for the response of on‐ground 2D rigid blocks undergoing rocking. Among others, this is pertinent to (1) modern or classical antiquity structures that utilize rocking as a seismic protection mechanism and (2) freestanding contents (e.g., cabinets, bookcases, and museum artifacts) located on the ground or lower floors of stiff buildings. Blocks of varying dimensions were subjected to a full range assessment of seismic response under increasing intensity levels of ordinary (no‐pulse and no‐long‐duration) ground motions, parameterized by peak ground acceleration or velocity. Both response and intensity were normalized, allowing the fitting of general‐purpose parametric expressions to determine the mean and dispersion of response for an arbitrary block of interest. These can be utilized in the same way as conventional strength‐ratio/ductility/period relationships of yielding oscillators, to enable the rapid assessment or design of simple rocking systems.
The type I glucocorticoid receptor antagonist spironolactone was administered to healthy volunteers to determine the effect of type I receptor blockade on adrenocorticotropic hormone (ACTH) and Cortisol secretion in humans. On separate days and in a double-blind, randomized fashion, placebo and each of four increasing doses of spironolactone were administered orally to subjects. Doses were selected to be within the clinically used range and, following drug administration, baseline and ovine-corticotropin releasing hormone (oCRH)-stimulated ACTH and Cortisol plasma levels were measured. In contrast to the clear effects of type II glucocorticoid receptor blockade on human pituitary adrenal function, no relationship between spironolactone dose or plasma levels and either basal or oCRH-stimulated pituitary-adrenal function was noted at doses comparable to those which induce type I receptor blockade and cardiovascular therapeutic effects in the kidney. These data suggest that, at physiologically relevant doses, type I glucocorticoid receptor blockade does not affect HPA axis function.
Abstract Context Safety concerns have been raised regarding premature mortality, diabetes, neoplasia, and cerebrovascular disease in association with GH therapy. Objective To assess incidence of key safety outcomes. Design Prospective, multinational, observational study (1999 to 2015). Setting A total of 22,311 GH-treated children from 827 investigative sites in 30 countries. Patients Children with growth disorders. Interventions GH treatment. Main outcome measures Standardized mortality ratio (SMR) and standardized incidence ratio (SIR) with 95% CIs for mortality, diabetes, and primary cancer using general population registries. Results Predominant short stature diagnoses were GH deficiency (63%), idiopathic short stature (13%), and Turner syndrome (8%), with mean ± SD follow-up of 4.2 ± 3.2 years (∼92,000 person-years [PY]). Forty-two deaths occurred in patients with follow-up, with an SMR (95% CI) of 0.61 (0.44, 0.82); the SMR was elevated for patients with cancer-related organic GH deficiency [5.87 (3.21, 9.85)]. Based on 18 cases, type 2 diabetes mellitus (T2DM) risk was elevated [SIR: 3.77 (2.24, 5.96)], but 72% had risk factors. In patients without cancer history, 14 primary cancers were observed [SIR: 0.71 (0.39, 1.20)]. Second neoplasms occurred in 31 of 622 cancer survivors [5.0%; 10.7 (7.5, 15.2) cases/1000 PY] and intracranial tumor recurrences in 67 of 823 tumor survivors [8.1%; 16.9 (13.3, 21.5) cases/1000 PY]. All three hemorrhagic stroke cases had risk factors. Conclusions GeNeSIS (Genetics and Neuroendocrinology of Short Stature International Study) data support the favorable safety profile of pediatric GH treatment. Overall risk of death or primary cancer was not elevated in GH-treated children, and no hemorrhagic strokes occurred in patients without risk factors. T2DM incidence was elevated compared with the general population, but most cases had diabetes risk factors.
The dependence of mankind on the urban built environment is an integral part of culture that is so firmly embedded in our daily life that we are mostly unaware of its existence, as long as functionality is provided. The aging of our structures and the action of natural hazards, such as earthquakes, threaten the functionality of our urban environment and extraordinary expenditures are required to just maintain the status quo. Throughout the world, buildings are reaching the end of their useful life and develop new pathologies that increase their seismic risk, an effect that we aim to capture. In the paper, first, a methodology for structural performance assessment with consideration of capacity degradation over time is presented, utilizing IN2 analysis and an extension of the PEER probabilistic framework to rapidly achieve accurate estimates of limit-state exceedance probabilities of deteriorated structures. In the second part the methodology is applied to an example of a three-storey asymmetric reinforced concrete building. At this stage of the study only an influence of corrosion on longitudinal and transverse reinforcement of the structural elements is considered in the estimation of the seismic risk. The N2 method is used for seismic performance assessment of the structure. It is shown that the capacity in terms of the maximum base shear, as well as in terms of the maximum ground acceleration corresponding to limit states in the nonlinear range, is reduced over time, since the corrosion affects the capacity of both the beams and columns. Consequently, the expected frequency of violating life-safety or near-collapse limit states over the time interval increases in comparison to the typical case where the strength deterioration is neglected.
[3H](4-Fluorobutyl)propyl[2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[2,3-d]pyrimidin-4-yl]amine ([3H]LWH-154), a novel potent radiolabelled analog of the nonpeptide corticotropin-releasing hormone type 1 receptor (CRHR1) selective antagonist, butylethyl[2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[2,3-d]pyrimidin-4-yl]amine (antalarmin), was prepared for the development of positron emission tomography radiotracers for CRHR1 and evaluation as a nonpeptide radioligand for use in pharmacological studies. The precursor (4-fluorobutyl)prop-2-enyl[2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[2,3-d]pyrimidin-4-yl]amine (6) for tritiation was prepared in two steps from 3 in 76% total yield. Catalytic reduction of unsaturated fluoride 6 using tritium gas and palladium as catalyst gave [3H]LWH-154. After HPLC purification, [3H]LWH-154 of high radiochemical purity was obtained with a specific activity of 69 Ci/mmol. Copyright © 2000 John Wiley & Sons, Ltd.
