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Results for “double robustness”

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At least 91 records · Page 5Linked to original sources
PubMed2005

Meiosis-specific yeast Hop1 protein promotes pairing of double-stranded DNA helices via G/C isochores.

In eukaryotes, genetic exchange between homologs is facilitated by a tripartite proteinaceous structure called the synaptonemal complex (SC). Several lines of evidence indicate that the genes that encode components of SC are essential for meiotic chromosome pairing and recombination. However, the molecular mechanism by which SC proteins promote these processes is obscure. Here, we report that Saccharomyces cerevisiae Hop1 protein, a component of SC, promotes pairing between two double-stranded DNA helices containing a centrally located G/C isochore. Significantly, pairing was rapid and robust, and required four contiguous G/C base pairs. Using a series of truncated DNA double helices we show that 20 bp on either side of 8 bp target G/C sequence is essential for pairing. To our knowledge, Hop1 is the first protein shown to do so from yeast or any other organism. These results indicate that Hop1 protein is likely to play a direct role in meiotic chromosome pairing and recombination.

Base Pairing↗
PubMed1997

Effect of pindolol in hastening response to fluoxetine in the treatment of major depression: a double-blind, placebo-controlled trial.

OBJECTIVE: In two preliminary studies, pindolol produced robust results in hastening clinical response to antidepressant drugs in depressed patients. Validity of those pilot studies was limited by use of an open-label, unblinded study design, and so the authors conducted a double-blind, placebo-controlled trial to assess the effectiveness of pindolol in hastening response to fluoxetine. METHOD: Drug-free outpatients with major depression were concurrently treated with fluoxetine (20 mg/day) and either placebo or pindolol (5.0 mg b.i.d. or 2.5 mg t.i.d.), for 6 weeks, in a randomized, double-blind manner. After 6 weeks, all patients received fluoxetine and placebo and were followed for 3 further weeks in a single-blind manner. RESULTS: Forty-three patients completed at least 1 week of the protocol. Rates of partial remission after 2 weeks of treatment with fluoxetine and either pindolol or placebo were 17% (four of 23 patients) and 20% (four of 20 patients), respectively. At study completion, 65% of the patients (N = 28) demonstrated at least a partial remission, and there was no difference between treatment groups. The pindolol group, but not the placebo group, demonstrated significant reductions in blood pressure and pulse rate. The average time to remission and the rates of attrition, overall response, and side effects were similar in the two groups. CONCLUSIONS: These findings do not support the efficacy of pindolol in hastening clinical response in patients treated with fluoxetine.

Adolescent↗
PubMed2002

A simple algorithm for calculating electrical double layer interactions in asymmetric electrolytes-Poisson-Boltzmann theory.

A simple, general, and numerically robust algorithm is presented for calculating the disjoining pressure and interaction free energy per unit area between two identically charged flat plates due to electrical double layer interactions according to the nonlinear Poisson-Boltzmann theory. The result is applicable to electrolytes with any number of ionic species having any combination of valencies as well as to constant potential, constant charge, or charge regulation boundary conditions on the plates. The algorithm is very simple to implement on commonly available numerical software environments and is therefore particularly suitable for use in data analysis.

Journal Article↗
PubMed2006

Mode transitions in a model reaction-diffusion system driven by domain growth and noise.

Pattern formation in many biological systems takes place during growth of the underlying domain. We study a specific example of a reaction-diffusion (Turing) model in which peak splitting, driven by domain growth, generates a sequence of patterns. We have previously shown that the pattern sequences which are presented when the domain growth rate is sufficiently rapid exhibit a mode-doubling phenomenon. Such pattern sequences afford reliable selection of certain final patterns, thus addressing the robustness problem inherent of the Turing mechanism. At slower domain growth rates this regular mode doubling breaks down in the presence of small perturbations to the dynamics. In this paper we examine the breaking down of the mode doubling sequence and consider the implications of this behaviour in increasing the range of reliably selectable final patterns.

Animals↗
PubMed2005

Induction and mode of action of the viral stress-inducible murine proteins, P56 and P54.

Mammalian cells respond to virus infection or other viral stresses, such as double-stranded (ds) RNA and interferons (IFN), by robust and rapid induction of viral stress-inducible proteins. The induction and actions of one such protein, the human P56, have been extensively studied. However, little is known about the distantly related mouse proteins, MuP56 and MuP54. Here, we report that, in mouse cells, they could be induced by IFN, dsRNA or Sendai virus infection. MuP56 and MuP54 inhibited protein synthesis in vitro by binding to the "c", but not the "e", subunit of the translation initiation factor, eIF-3. The N-terminal region of the MuP54 was sufficient for inhibiting translation, but it and the corresponding region of MuP56 bound to two different regions of eIF3c. Thus, members of the human and murine P56 family have similar but non-identical functions.

Animals↗
PubMed2025

Efficiency of DNA repair mechanisms of domestic dog primary fibroblasts isolated from small and large breeds of different ages in response to double stranded breaks (DSB).

Aging is associated with increased genomic instability, a phenomenon largely driven by the accumulation of DNA damage over time, and large species of mammals seem to have more robust DNA repair systems associated with longer lives. Among DNA lesions, double-strand breaks (DSBs) are particularly deleterious and have been implicated in age-related functional decline and disease. In this study, we investigated how age and body mass affect the efficiency of DSB repair (DSBr) in primary fibroblast cells isolated from domestic dogs, a species that exhibits significant intraspecies variation in lifespan and body mass. Primary fibroblast cells were isolated from puppies and senior dogs of both large and small breeds. Cells were treated with 100 µM etoposide to induce DSBs and subsequently analyzed at two post-treatment recovery intervals (2 and 24 h) to correlated with the two pathways associated with DSBr, the fast, non-homologous end joining (NHEJ) and the much slower, homologous recombination (HR). Cells were stained for γ-H2AX foci and images were collected using confocal microscopy. We found that mean fluorescence per cell was higher in older dogs of both size classes in the 2 h recovery, indicating higher amounts of DNA damage but suggesting similar efficiencies through the NHEJ repair mechanism in older dogs despite size class. We also show that mean fluorescence per cell was higher in the older large breed dogs in the 24 h recovery, suggesting that the slower phase associated with HR seems to be deficient in cells from older, larger breeds of dogs. These findings support the broader theory that aging is associated with impaired genomic maintenance and establish domestic dogs as a valuable model for studying the cellular mechanisms of age-related genomic instability.

Animals↗
PubMed1992

Effects of alprazolam on pituitary-adrenal and catecholaminergic responses to metabolic stress in humans.

Concurrent effects of benzodiazepines on stress-induced activation of the three classical "stress" systems: pituitary-adrenal, adrenomedullary, and sympathoneural systems have not been extensively investigated in humans. In the present study, the effects of alprazolam (1.5 mg) on plasma levels of adrenocorticotropin hormone (ACTH), epinephrine, norepinephrine, dihydroxyphenylglycol (DHPG, the intraneuronal metabolite of norepinephrine), and mood states were examined in 10 healthy volunteers undergoing glucoprivic stress. Glucoprivic stress was induced by intravenous administration of the glucose analog, 2-deoxyglucose (2DG), at a dose (50 mg/kg) that impairs cellular glucose metabolism and produces a state comparable to hypoglycemia. Alprazolam and 2DG were administered in a double-blind, placebo-controlled manner. 2DG produced robust elevations in plasma ACTH and epinephrine levels, modest elevations in plasma norepinephrine levels, and decreases in plasma DHPG levels. Alprazolam significantly attenuated the 2DG-induced increases in plasma ACTH and epinephrine, but did not significantly effect plasma norepinephrine and DHPG. These data suggest that benzodiazepines attenuate metabolic stress-induced activation of the pituitary-adrenal and adrenomedullary systems but do not effect 2DG-related effects on peripheral sympathoneural function. The possible mechanisms involved are discussed.

Adrenocorticotropic Hormone↗
PubMed1994

A simultaneous evaluation method of purity and apparent stability constant of Ca-chelating agents and selectivity coefficient of Ca-selective electrodes.

To determine the purity (q) of Ca-chelating agents (such as EGTA and BAPTA) and their apparent stability constants to Ca2+ (K') using Ca(2+)-selective electrodes precisely, we have developed a new method using the double-log optimization. Free Ca2+ concentration was plotted against the ratio of the concentrations of Ca(2+)-bound to Ca(2+)-free chelator on double logarithmic co-ordinates in which a linear relationship with a slope of -1 must hold for the metal-chelator reaction with a stoichiometry of 1 to 1. Not only the q and K' values but also the selectivity coefficient of the electrode could be simultaneously estimated on the double-log plot through an optimizing method. Error analyses using a Monte Carlo simulation showed that the double-log plot is statistically more reliable and robust than the Scatchard plot and that the optimizing method is more objective and reliable than previous methods involving extrapolation and truncation procedures.

Calcium↗
PubMed2004

Selectivity control in the separation of aromatic amino acid enantiomers with sulphated beta-cyclodextrin.

Control of selectivity in the enantiomeric separation of three aromatic amino acids (phenylalanine, tyrosine and tryptophan) is demonstrated by electrokinetic capillary chromatography utilising temperature variations coupled with the use of sulphated-beta-cyclodextrin (s-beta-CD) as a pseudostationary phase. The concentration of s-beta-CD and temperature were used as experimental variables to control the observed selectivity. A double-coated capillary was used and proved very robust with reproducibility of migration times being <2.0% R.S.D. between runs and <2.6% on using a new capillary. The system was modelled successfully using an artificial neural network (ANN) comprising one input layer, two hidden layers and one output layer. The model accurately described the observed separations with a correlation coefficient of 0.999 being observed between predicted and observed migration times. Selectivity optimisation was achieved using the normalised resolution product and minimum resolution criteria, with both providing optima at different experimental conditions. The selectivity changes observed also allowed the estimation of electrolyte temperatures within the capillary at high operating currents (>100 microA). Using a 50 microm i.d. capillary and an electrolyte comprising 20 mM phosphate and 15 mM s-beta-CD, a temperature of 52 degrees C was calculated within the capillary at an applied voltage of +30 kV.

Amino Acids, Aromatic↗
PubMed2004

Divergent anticodon recognition in contrasting glutamyl-tRNA synthetases.

The pathogenic bacterium Helicobacter pylori utilizes two essential glutamyl-tRNA synthetases (GluRS1 and GluRS2). These two enzymes are closely related in evolution and yet they aminoacylate contrasting tRNAs. GluRS1 is a canonical discriminating GluRS (D-GluRS) that biosynthesizes Glu-tRNA(Glu) and cannot make Glu-tRNA(Gln). In contrast, GluRS2 is non-canonical as it is only essential for the production of misacylated Glu-tRNA(Gln). The co-existence and evident divergence of these two enzymes was capitalized upon to directly examine how GluRS2 acquired tRNA(Gln) specificity. One key feature that distinguishes tRNA(Glu) from tRNA(Gln) is the third position in the anticodon of each tRNA (C36 versus G36, respectively). By comparing sequence alignments of different GluRSs, including GluRS1s and GluRS2s, to the crystal structure of the Thermus thermophilus D-GluRS:tRNA(Glu) complex, a divergent pattern of conservation in enzymes that aminoacylate tRNA(Glu)versus those specific for tRNA(Gln) emerged and was experimentally validated. In particular, when an arginine conserved in discriminating GluRSs and GluRS1s was inserted into Hp GluRS2 (Glu334Arg GluRS2), the catalytic efficiency of the mutant enzyme (k(cat)/K(Mapp)) was reduced by approximately one order of magnitude towards tRNA(Gln). However, this mutation did not introduce activity towards tRNA(Glu). In contrast, disruption of a glycine that is conserved in all GluRS2s but not in other GluRSs (Gly417Thr GluRS2) generated a mutant GluRS2 with weak activity towards tRNA(Glu1). Synergy between these two mutations was observed in the double mutant (Glu334Arg/Gly417Thr GluRS2), which specifically and more robustly aminoacylates tRNA(Glu1) instead of tRNA(Gln). As GluRS1 and GluRS2 are related by an apparent gene duplication event, these results demonstrate that we can experimentally map critical evolutionary events in the emergence of new tRNA specificities.

Amino Acid Sequence↗
PubMed1998

Adaptive significance of circadian programs in cyanobacteria.

Prokaryotic cyanobacteria express robust circadian (daily) rhythms, even when growing with doubling times that are considerably faster than once every 24 h. This biological clock orchestrates cellular events to occur in an optimal temporal program. Competition experiments demonstrate that fitness is enhanced when the circadian period resonates with the period of the environmental cycle.

Adaptation, Physiological↗
PubMed2006

Heteronuclear isotropic mixing separated local field NMR spectroscopy.

This paper presents a theoretical, numerical, and experimental study of a new class of separated local field (SLF) techniques. These techniques are based on the heteronuclear isotropic mixing leading to spin exchange via the local field (HIMSELF). It is shown that highly efficient and robust SLF experiments can be designed based on double channel windowless homonuclear decoupling sequences. Compared to rotating frame techniques based on Hartmann-Hahn cross polarization, the new approach is less susceptible to the frequency offset and chemical shift interaction and can be applied in the structural studies of macromolecules that are uniformly labeled with isotopes such as (13)C and (15)N. Furthermore, isotropic mixing sequences allow for transfer of any magnetization component of one nucleus to the corresponding component of its dipolar coupled partner. The performance of HIMSELF is studied by analysis of the average Hamiltonian and numerical simulation and is experimentally demonstrated on a single crystalline sample of a dipeptide and a liquid crystalline sample exhibiting motionally averaged dipolar couplings.

Carbon Isotopes↗
PubMedDate not supplied

The use of double anonymity in peer review: a decision whose time has come?

The process of peer review for submissions to scientific journals is a well-established and widely used procedure. However, there may still be room for improvement in the procedural aspects of peer review. Advantages and disadvantages of the current system, against the introduction of systems using either no anonymity, or double anonymity, are assessed. Recommendations to improve the robustness and fairness of the peer review process are proffered for the reader's consideration.

Journal Article↗
PubMed2006

Efficacy and safety of pregabalin in the treatment of generalized anxiety disorder: a 6-week, multicenter, randomized, double-blind, placebo-controlled comparison of pregabalin and venlafaxine.

OBJECTIVE: Pregabalin has demonstrated robust, rapid efficacy in reducing symptoms of generalized anxiety disorder (GAD) in 4 placebo-controlled clinical trials. The current study compared the efficacy and safety of pregabalin and venlafaxine in patients diagnosed with moderate to severe GAD. METHOD: The study was conducted from December 21, 1999, to July 31, 2001. Outpatients (N = 421) in primary care or psychiatry settings meeting DSM-IV criteria for GAD were randomly assigned to 6 weeks of double-blind treatment with pregabalin 400 or 600 mg/day, venlafaxine 75 mg/day, or placebo. The primary analysis was change in Hamilton Rating Scale for Anxiety (HAM-A) total score from baseline to last-observation-carried-forward (LOCF) endpoint. Secondary analyses included the change in HAM-A psychic (emotional) and somatic (physical) factor scores, significant improvement at week 1, and week 1 improvement sustained at every visit through endpoint. RESULTS: Pregabalin at both dosages (400 mg/day, p = .008; 600 mg/day, p = .03) and venlafaxine (p = .03) produced significantly-greater improvement in HAM-A total score at LOCF endpoint than did placebo. Only the pregabalin 400-mg/day treatment group experienced significant improvement in all a priori primary and secondary efficacy measures. Pregabalin in both dosage treatment groups (400 mg/day, p < .01; 600 mg/day, p < .001) significantly improved HAM-A total score at week 1, with significant improvement through LOCF endpoint. Statistically significant improvement began at week 2 for venlafaxine. Discontinuation rates due to associated adverse events were greatest in the venlafaxine treatment group: venlafaxine, 20.4%; pregabalin 400 mg/day, 6.2%; pregabalin 600 mg/day, 13.6%; placebo, 9.9%. CONCLUSION: Pregabalin was safe, well tolerated, and rapidly efficacious across the physical-somatic as well as the emotional symptoms of GAD in the majority of patients studied in primary care and psychiatric settings.

Adult↗
PubMed2001

A supramolecular system for quantifying aromatic stacking interactions.

A supramolecular complex for investigating the thermodynamic properties of intermolecular aromatic stacking interactions has been developed. The conformation of the complex is locked in a single well-defined conformation by an array of H-bonding interactions that force two aromatic rings on one end of the complex into a stacked geometry. Chemical double-mutant cycles have been used to measure an anthracene-aniline interaction (+0.6 +/- 0.8 kJ mol(-1)) and a pentafluorophenyl-aniline interaction (-0.4 +/- 0.9 kJ mol(-1)) in this system. Although the interactions are very weak, the pentafluorophenyl interaction is attractive, whereas the anthracene interaction is repulsive: this is consistent with the dominance of pi-electron electrostatic interactions. The nitropyrrole subunits used to control the conformation of these complexes lead to problems of aggregation and multiple conformational equilibria. The implications for the thermodynamic analysis are examined in detail, and the double-mutant-cycle approach is found to be remarkably robust with respect to such effects, since systematic errors in individual experiments are removed in a pair-wise fashion when the cycle is constructed.

Journal Article↗
PubMed2006

ITP in dynamically double-coated fused-silica capillaries.

Bidirectional ITP in fused-silica capillaries double-coated with Polybrene and poly-(vinylsulfonate) is a robust approach for analysis of low-molecular-mass compounds. EOF towards the cathode is strong (mobility >4.0 x 10(-8) m(2)/Vs) within the entire pH range investigated (2.40-8.08), dependent on ionic strength and buffer used and, at constant ionic strength, higher at alkaline pH. Electrokinetic separations and transport in such coated capillaries can be described with a dynamic computer model which permits the combined simulation of electrophoresis and electroosmosis in which the EOF is predicted either with a constant (i.e. pH- and ionic strength-independent) or a pH- and ionic strength-dependent electroosmotic mobility. Detector profiles predicted by computer simulation agree qualitatively well with bidirectional isotachopherograms that are monitored with a setup comprising two axial contactless conductivity detectors and a UV absorbance detector. The varying EOF predicted with a pH- and ionic strength-dependent electroosmotic mobility can be regarded as being realistic.

Acids↗
PubMed2006

Diagnosis and treatment of chronic inflammatory demyelinating polyneuropathy.

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an immune-mediated acquired polyneuropathy that may lead to disability. CIDP is characterized by an autoimmune attack against peripheral nervous system myelin, by cellular and humoral mechanisms. Early diagnosis and treatment may yield better functional recovery, probably by minimizing secondary axonal loss from a primary demyelinating insult. Intravenous immunoglobulin and plasmapheresis are considered standard-of-care therapy in CIDP, based on randomized, double-blinded, placebo-controlled evidence. Corticosteroids, despite less robust evidence, are also considered standard therapy for CIDP. Other nonstandard therapies may work in refractory patients. These include azathioprine, cyclophosphamide, cyclosporine A, etanercept, interferon-alpha 2a, mycophenolate mofetil, and tacrolimus. Emerging therapies include interferon-beta 1a, rituximab, and high-dose cyclophosphamide without stem-cell rescue. Because most patients will require prolonged therapy, long-term side effects are important considerations.

Journal Article↗
PubMed1999

Problems and challenges in the design of irritable bowel syndrome clinical trials: experience from published trials.

The last two decades have seen many studies that are of inadequate design and power. This report focuses on what we have learned from the 25 randomized, controlled studies that included at least 30 patients during the period 1976-1998. The most important finding has been that the median placebo response was 47% (range, 0-84%), which is approximately three times the size of the difference between placebo and drug response, median 16% (range, -17-64%). This tells us the importance of reassurance and the powerful nonspecific therapeutic effects of entering patients into clinical trials in irritable bowel syndrome (IBS). Patients should be stratified according to the dominant symptoms that are relevant to the drug's intended effect. A randomized, double-blind, controlled, parallel group study appears the most robust design. Minimizing the placebo response reduces the numbers needed to detect a significant difference. The optimum length of trial is probably >3 months, because the placebo effect takes approximately 12 weeks to start to recede. Dose titration should maximize the chance of detecting a benefit.

Clinical Trials as Topic↗