A conditional probability analysis of cystic fibrosis transmembrane conductance regulator gating indicates that ATP has multiple effects during the gating cycle

ATP-binding cassette (ABC) transporters bind and hydrolyze ATP. In the cystic fibrosis transmembrane conductance regulator Cl− channel, this interaction with ATP generates a gating cycle between a closed (C) and two open (O1 and O2) conformations. To understand better how ATP controls channel activity, we examined gating transitions from the C to the O1 and O2 states and from these open states to the C conformation. We made three main observations. First, we found that the channel can open into either the O1 or O2 state, that the frequency of transitions to both states was increased by ATP concentration, and that ATP increased the relative proportion of openings into O1 vs. O2. These results indicate that ATP can interact with the closed state to open the channel in at least two ways, which may involve binding to nucleotide-binding domains (NBDs) NBD1 and NBD2. Second, ATP prolonged the burst duration and altered the way in which the channel closed. These data suggest that ATP also interacts with the open channel. Third, the channel showed runs of specific types of open–closed transitions. This finding suggests a mechanism with more than one cycle of gating transitions. These data suggest models to explain how ATP influences conformational transitions in cystic fibrosis transmembrane conductance regulator and perhaps other ABC transporters.

The Contribution of the Activation Entropy to the Gas-Phase Stability of Modified Nucleic Acid Duplexes

Tricyclo-DNA (tcDNA) is a sugar-modified analogue of DNA currently tested for the treatment of Duchenne muscular dystrophy in an antisense approach. Tandem mass spectrometry plays a key role in modern medical diagnostics and has become a widespread technique for the structure elucidation and quantification of antisense oligonucleotides. Herein, mechanistic aspects of the fragmentation of tcDNA are discussed, which lay the basis for reliable sequencing and quantification of the antisense oligonucleotide. Excellent selectivity of tcDNA for complementary RNA is demonstrated in direct competition experiments. Moreover, the kinetic stability and fragmentation pattern of matched and mismatched tcDNA heteroduplexes were investigated and compared with non-modified DNA and RNA duplexes. Although the separation of the constituting strands is the entropy-favored fragmentation pathway of all nucleic acid duplexes, it was found to be only a minor pathway of tcDNA duplexes. The modified hybrid duplexes preferentially undergo neutral base loss and backbone cleavage. This difference is due to the low activation entropy for the strand dissociation of modified duplexes that arises from the conformational constraint of the tc-sugar-moiety. The low activation entropy results in a relatively high free activation enthalpy for the dissociation comparable to the free activation enthalpy of the alternative reaction pathway, the release of a nucleobase. The gas-phase behavior of tcDNA duplexes illustrates the impact of the activation entropy on the fragmentation kinetics and suggests that tandem mass spectrometric experiments are not suited to determine the relative stability of different types of nucleic acid duplexes.

Heavy tails, importance sampling and cross-entropy

We consider the problem of estimating P(Yi + (...) + Y-n > x) by importance sampling when the Yi are i.i.d. and heavy-tailed. The idea is to exploit the cross-entropy method as a toot for choosing good parameters in the importance sampling distribution; in doing so, we use the asymptotic description that given P(Y-1 + (...) + Y-n > x), n - 1 of the Yi have distribution F and one the conditional distribution of Y given Y > x. We show in some specific parametric examples (Pareto and Weibull) how this leads to precise answers which, as demonstrated numerically, are close to being variance minimal within the parametric class under consideration. Related problems for M/G/l and GI/G/l queues are also discussed.

Conditional performance evaluation and the relevance of money flows for Australian international equity funds

This paper assesses the importance of fund flows in the performance evaluation of Australian international equity funds. Two concepts of fund flows are considered in the context of a conditional asset pricing model. The first measure is net fund flow relative to fund size and the second is net fund flow relative to sector flows. We find that incorporating a fund flow measure relative to the sector flow results in a reduction of measured perverse market timing. The results indicate that, at the individual fund level, cash flows are relevant in assessing management outcomes.

Effect of conditional release from hospitalization on mortality risk

Objectives: This study considered the protective value provided by conditional release. It assessed the contribution of conditional release to mortality risk among patients with mental disorders severe enough to require psychiatric hospitalization during a mental health treatment span of 13.5 years in Victoria, Australia. Methods: Death records were obtained from the Australian National Death Index for a sample of 24,973 Victorian Psychiatric Case Register patients with a history of psychiatric hospitalizations: 8,879 had experienced at least one conditional release during community care intervals and 16,094 had not. Risk of death was assessed with standardized mortality ratios of the general population of Victoria. Relative risk of death among patients with and without past experience of conditional release was computed with risk and odds ratios. The contribution of conditional release to mortality, taking into account use of community care services, age, gender, inpatient experience, and diagnosis, as well as other controls, was assessed with logistic regression. Results: Patients who had been hospitalized showed higher mortality risk than the general population. Sixteen percent ( 4,034) died. Patients exposed to conditional release, however, had a 14 percent reduction in probability of noninjury-related death and a 24 percent reduction per day on orders in the probability of death from injury compared with those not offered such oversight throughout their mental health treatment, all other factors taken into account. Conclusions: Conditional release can offer protective oversight for those considered dangerous to self or others and appears to reduce mortality risk among those with disorders severe enough to require psychiatric hospitalization.

Conditional osmotic stress in yeast:a system to study transport through aquaglyceroporins and osmostress signaling

The accumulation and transport of solutes are hallmarks of osmoadaptation. In this study we have employed the inability of the Saccharomyces cerevisiae gpd1Δ gpd2Δ mutant both to produce glycerol and to adapt to high osmolarity to study solute transport through aquaglyceroporins and the control of osmostress-induced signaling. High levels of different polyols, including glycerol, inhibited growth of the gpd1Δ gpd2Δ mutant. This growth inhibition was suppressed by expression of the hyperactive allele Fps1-AΔ of the osmogated yeast aquaglyceroporin, Fps1. The degree of suppression correlated with the relative rate of transport of the different polyols tested. Transport studies in secretory vesicles confirmed that Fps1-Δ1 transports polyols at increased rates compared with wild type Fps1. Importantly, wild type Fps1 and Fps1-Δ1 showed similarly low permeability for water. The growth defect on polyols in the gpd1Δ gpd2Δ mutant was also suppressed by expression of a heterologous aquaglyceroporin, rat AQP9. We surmised that this suppression was due to polyol influx, causing the cells to passively adapt to the stress. Indeed, when aquaglyceroporin-expressing gpd1Δ gpd2Δ mutants were treated with glycerol, xylitol, or sorbitol, the osmosensing HOG pathway was activated, and the period of activation correlated with the apparent rate of polyol uptake. This observation supports the notion that deactivation of the HOG pathway is closely coupled to osmotic adaptation. Taken together, our "conditional" osmotic stress system facilitates studies on aquaglyceroporin function and reveals features of the osmosensing and signaling system. © 2005 by The American Society for Biochemistry and Molecular Biology, Inc.

Design concept evaluation based on rough number and information entropy theory

Concept evaluation at the early phase of product development plays a crucial role in new product development. It determines the direction of the subsequent design activities. However, the evaluation information at this stage mainly comes from experts' judgments, which is subjective and imprecise. How to manage the subjectivity to reduce the evaluation bias is a big challenge in design concept evaluation. This paper proposes a comprehensive evaluation method which combines information entropy theory and rough number. Rough number is first presented to aggregate individual judgments and priorities and to manipulate the vagueness under a group decision-making environment. A rough number based information entropy method is proposed to determine the relative weights of evaluation criteria. The composite performance values based on rough number are then calculated to rank the candidate design concepts. The results from a practical case study on the concept evaluation of an industrial robot design show that the integrated evaluation model can effectively strengthen the objectivity across the decision-making processes.

Entropy feature extraction of EEG signals for automatic person identification

The use of human brain electroencephalography (EEG) signals for automatic person identi cation has been investigated for a decade. It has been found that the performance of an EEG-based person identication system highly depends on what feature to be extracted from multi-channel EEG signals. Linear methods such as Power Spectral Density and Autoregressive Model have been used to extract EEG features. However these methods assumed that EEG signals are stationary. In fact, EEG signals are complex, non-linear, non-stationary, and random in nature. In addition, other factors such as brain condition or human characteristics may have impacts on the performance, however these factors have not been investigated and evaluated in previous studies. It has been found in the literature that entropy is used to measure the randomness of non-linear time series data. Entropy is also used to measure the level of chaos of braincomputer interface systems. Therefore, this thesis proposes to study the role of entropy in non-linear analysis of EEG signals to discover new features for EEG-based person identi- cation. Five dierent entropy methods including Shannon Entropy, Approximate Entropy, Sample Entropy, Spectral Entropy, and Conditional Entropy have been proposed to extract entropy features that are used to evaluate the performance of EEG-based person identication systems and the impacts of epilepsy, alcohol, age and gender characteristics on these systems. Experiments were performed on the Australian EEG and Alcoholism datasets. Experimental results have shown that, in most cases, the proposed entropy features yield very fast person identication, yet with compatible accuracy because the feature dimension is low. In real life security operation, timely response is critical. The experimental results have also shown that epilepsy, alcohol, age and gender characteristics have impacts on the EEG-based person identication systems.

The conditional performance of euro bond funds: evidence from Portugal during the debt crisis

This paper evaluates the performance of a survivorship bias-free data set of Portuguese funds investing in Euro-denominated bonds by using conditional models that consider the public information available to investors when the returns are generated. We find that bond funds underperform the market significantly and by an economically relevant magnitude. This underperformance cannot be explained by the expenses they charge. Our findings support the use of conditional performance evaluation models, since we find strong evidence of both time-varying risk and performance, dependent on the slope of the term structure and the inverse relative wealth variables. We also show that survivorship bias has a significant impact on performance estimates. Furthermore, during the European debt crisis, bond fund managers performed significantly better than in non-crisis periods and were able to achieve neutral performance. This improved performance throughout the crisis seems to be related to changes in funds’ investment styles.