308 research outputs found
On the Use of Surrogate Functions for Mixed Variable Optimization of Simulated Systems
This research considers the efficient numerical solution of linearly constrained mixed variable programming (MVP) problems, in which the objective function is a black-box stochastic simulation, function evaluations may be computationally expensive, and derivative information is typically not available. MVP problems are those with a mixture of continuous, integer, and categorical variables, the latter of which may take on values only from a predefined list and may even be non-numeric. Mixed Variable Generalized Pattern Search with Ranking and Selection (MGPS-RS) is the only existing, provably convergent algorithm that can be applied to this class of problems. Present in this algorithm is an optional framework for constructing and managing less expensive surrogate functions as a means to reduce the number of true function evaluations that are required to find approximate solutions. In this research, the NOMADm software package, an implementation of pattern search for deterministic MVP problems, is modified to incorporate a sequential selection with memory (SSM) ranking and selection procedure for handling stochastic problems. In doing so, the underlying algorithm is modified to make the application of surrogates more efficient. A second class of surrogates based on the Nadaraya-Watson kernel regression estimator is also added to the software. Preliminary computational testing of the modified software is performed to characterize the relative efficiency of selected surrogate functions for mixed variable optimization in simulated systems
Translation initiation from conserved non-AUG codons provides additional layers of regulation and coding capacity
Neurospora crassa cpc-1 and Saccharomyces cerevisiae GCN4 are homologs specifying transcription activators that drive the transcriptional response to amino acid limitation. The cpc-1 mRNA contains two upstream open reading frames (uORFs) in its >700-nucleotide (nt) 5' leader, and its expression is controlled at the level of translation in response to amino acid starvation. We used N. crassa cell extracts and obtained data indicating that cpc-1 uORF1 and uORF2 are functionally analogous to GCN4 uORF1 and uORF4, respectively, in controlling translation. We also found that the 5' region upstream of the main coding sequence of the cpc-1 mRNA extends for more than 700 nucleotides without any in-frame stop codon. For 100 cpc-1 homologs from Pezizomycotina and from selected Basidiomycota, 5' conserved extensions of the CPC1 reading frame are also observed. Multiple non-AUG near-cognate codons (NCCs) in the CPC1 reading frame upstream of uORF2, some deeply conserved, could potentially initiate translation. At least four NCCs initiated translation in vitro. In vivo data were consistent with initiation at NCCs to produce N-terminally extended N. crassa CPC1 isoforms. The pivotal role played by CPC1, combined with its translational regulation by uORFs and NCC utilization, underscores the emerging significance of noncanonical initiation events in controlling gene expression. IMPORTANCE There is a deepening and widening appreciation of the diverse roles of translation in controlling gene expression. A central fungal transcription factor, the best-studied example of which is Saccharomyces cerevisiae GCN4, is crucial for the response to amino acid limitation. Two upstream open reading frames (uORFs) in the GCN4 mRNA are critical for controlling GCN4 synthesis. We observed that two uORFs in the corresponding Neurospora crassa cpc-1 mRNA appear functionally analogous to the GCN4 uORFs. We also discovered that, surprisingly, unlike GCN4, the CPC1 coding sequence extends far upstream from the presumed AUG start codon with no other in-frame AUG codons. Similar extensions were seen in homologs from many filamentous fungi. We observed that multiple non-AUG near-cognate codons (NCCs) in this extended reading frame, some conserved, initiated translation to produce longer forms of CPC1, underscoring the significance of noncanonical initiation in controlling gene expression
Mobility Edge in Aperiodic Kronig-Penney Potentials with Correlated Disorder: Perturbative Approach
It is shown that a non-periodic Kronig-Penney model exhibits mobility edges
if the positions of the scatterers are correlated at long distances. An
analytical expression for the energy-dependent localization length is derived
for weak disorder in terms of the real-space correlators defining the
structural disorder in these systems. We also present an algorithm to construct
a non-periodic but correlated sequence exhibiting desired mobility edges. This
result could be used to construct window filters in electronic, acoustic, or
photonic non-periodic structures.Comment: RevTex, 4 pages including 2 Postscript figure
The solvation and dissociation of 4-benzylaniline hydrochloride in chlorobenzene
A reaction scheme is proposed to account for the liberation of 4-benzylaniline from 4-benzylaniline hydrochloride, using chlorobenzene as a solvent at a temperature of 373 K. Two operational regimes are explored: âclosedâ reaction conditions correspond to the retention of evolved hydrogen chloride gas within the reaction medium, whereas an âopenâ system permits gaseous hydrogen chloride to be released from the reaction medium. The solution phase chemistry is analyzed by 1H NMR spectroscopy. Complete liberation of solvated 4-benzylaniline from solid 4-benzylaniline hydrochloride is possible under âopenâ conditions, with the entropically favored conversion of solvated hydrogen chloride to the gaseous phase thought to be the thermodynamic driver that effectively controls a series of interconnecting equilibria. A kinetic model is proposed to account for the observations of the open system
Rickettsia parkeri in Amblyomma americanum Ticks, Tennessee and Georgia, USA
To determine the geographic distribution of the newly recognized human pathogen Rickettsia parkeri, we looked for this organism in ticks from Tennessee and Georgia, USA. Using PCR and sequence analysis, we identified R. parkeri in 2 Amblyomma americanum ticks. This rickettsiosis may be underdiagnosed in the eastern United States
Clinical and Research Considerations for Patients with Hypertensive Acute Heart Failure
Management approaches for patients in the emergency department (ED) who present with acute heart failure (AHF) have largely focused on intravenous diuretics. Yet, the primary pathophysiologic derangement underlying AHF in many patients is not solely volume overload. Patients with hypertensive AHF (H-AHF) represent a clinical phenotype with distinct pathophysiologic mechanisms that result in elevated ventricular filling pressures. To optimize treatment response and minimize adverse events in this subgroup, we propose that clinical management be tailored to a conceptual model of disease based on these mechanisms. This consensus statement reviews the relevant pathophysiology, clinical characteristics, approach to therapy, and considerations for clinical trials in ED patients with H-AHF
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Morphology and ploidy level determination of Pteris vittata callus during induction and regeneration
Effect of nesiritide in patients with acute decompensated heart failure
Background Nesiritide is approved in the United States for early relief of dyspnea in patients with acute heart failure. Previous meta-analyses have raised questions regarding renal toxicity and the mortality associated with this agent. Methods We randomly assigned 7141 patients who were hospitalized with acute heart failure to receive either nesiritide or placebo for 24 to 168 hours in addition to standard care. Coprimary end points were the change in dyspnea at 6 and 24 hours, as measured on a 7-point Likert scale, and the composite end point of rehospitalization for heart failure or death within 30 days. Results Patients randomly assigned to nesiritide, as compared with those assigned to placebo, more frequently reported markedly or moderately improved dyspnea at 6 hours (44.5% vs. 42.1%, P = 0.03) and 24 hours (68.2% vs. 66.1%, P = 0.007), but the prespecified level for significance (Pâ€0.005 for both assessments or Pâ€0.0025 for either) was not met. The rate of rehospitalization for heart failure or death from any cause within 30 days was 9.4% in the nesiritide group versus 10.1% in the placebo group (absolute difference, â0.7 percentage points; 95% confidence interval [CI], â2.1 to 0.7; P = 0.31). There were no significant differences in rates of death from any cause at 30 days (3.6% with nesiritide vs. 4.0% with placebo; absolute difference, â0.4 percentage points; 95% CI, â1.3 to 0.5) or rates of worsening renal function, defined by more than a 25% decrease in the estimated glomerular filtration rate (31.4% vs. 29.5%; odds ratio, 1.09; 95% CI, 0.98 to 1.21; P = 0.11). Conclusions Nesiritide was not associated with an increase or a decrease in the rate of death and rehospitalization and had a small, nonsignificant effect on dyspnea when used in combination with other therapies. It was not associated with a worsening of renal function, but it was associated with an increase in rates of hypotension. On the basis of these results, nesiritide cannot be recommended for routine use in the broad population of patients with acute heart failure. (Funded by Scios; ClinicalTrials.gov number, NCT00475852.
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