9,477 research outputs found
Glassy Dynamics of Protein Folding
A coarse grained model of a random polypeptide chain, with only discrete
torsional degrees of freedom and Hookean springs connecting pairs of
hydrophobic residues is shown to display stretched exponential relaxation under
Metropolis dynamics at low temperatures with the exponent , in
agreement with the best experimental results. The time dependent correlation
functions for fluctuations about the native state, computed in the Gaussian
approximation for real proteins, have also been found to have the same
functional form. Our results indicate that the energy landscape exhibits
universal features over a very large range of energies and is relatively
independent of the specific dynamics.Comment: RevTeX, 4 pages, multicolumn, including 5 figures; larger
computations performed, error bars improve
Sampling constrained probability distributions using Spherical Augmentation
Statistical models with constrained probability distributions are abundant in
machine learning. Some examples include regression models with norm constraints
(e.g., Lasso), probit, many copula models, and latent Dirichlet allocation
(LDA). Bayesian inference involving probability distributions confined to
constrained domains could be quite challenging for commonly used sampling
algorithms. In this paper, we propose a novel augmentation technique that
handles a wide range of constraints by mapping the constrained domain to a
sphere in the augmented space. By moving freely on the surface of this sphere,
sampling algorithms handle constraints implicitly and generate proposals that
remain within boundaries when mapped back to the original space. Our proposed
method, called {Spherical Augmentation}, provides a mathematically natural and
computationally efficient framework for sampling from constrained probability
distributions. We show the advantages of our method over state-of-the-art
sampling algorithms, such as exact Hamiltonian Monte Carlo, using several
examples including truncated Gaussian distributions, Bayesian Lasso, Bayesian
bridge regression, reconstruction of quantized stationary Gaussian process, and
LDA for topic modeling.Comment: 41 pages, 13 figure
DELVING INTO BEHAVIORAL FINANCE: UNCOVERING THE LINKAGE BETWEEN INVESTMENT PREFERENCE, INVESTORâS PROFILE, PERSONALITY TRAITS, RISK PERCEPTION, AND INVESTMENT GOALS
Investment is a popular economic vehicle where, in the hope of producing more revenue, people invest their capital. Investors are expected to make investment decisions that maximize returns. This study conducted a survey of 96 working adults who made investments in stock, bonds, short-term instruments, mutual funds, and/or foreign currencies. It used explanatory variables such as the profile of investors, the perception of risk, personality characteristics, and investment goals. Investment preference was the outcome variable. Significant results revealed that for medium-term investments, only the conservative and moderate investor profiles had a significant relationship with investor preference. Investment goals showed only partial significance
Cost-effectiveness of alternative methods of surgical repair of inguinal hernia
Objectives: To assess the relative cost-effectiveness of laparoscopic methods of inguinal hernia repair compared with open flat mesh and open non-mesh repair. Methods: Data on the effectiveness of these alternatives came from three systematic reviews comparing: (i) laparoscopic methods with open flat mesh or non-mesh methods; (ii) open flat mesh with open non-mesh repair; and (iii) methods that used synthetic mesh to repair the hernia defect with those that did not. Data on costs were obtained from the authors of economic evaluations previously conducted alongside trials included in the reviews. A Markov model was used to model cost-effectiveness for a five-year period after the initial operation. The outcomes of the model were presented using a balance sheet approach and as cost per hernia recurrence avoided and cost per extra day at usual activities. Results: Open flat mesh was the most cost-effective method of preventing recurrences. Laparoscopic repair provided a shorter period of convalescence and less long-term pain compared with open flat mesh but was more costly. The mean incremental cost per additional day back at usual activities compared with open flat mesh was âŹ38 and âŹ80 for totally extraperitoneal and transabdominal preperitoneal repair, respectively. Conclusions: Laparoscopic repair is not cost-effective compared with open flat mesh repair in terms of cost per recurrence avoided. Decisions about the use of laparoscopic repair depend on whether the benefits (reduced pain and earlier return to usual activities) outweigh the extra costs and intraoperative risks. On the evidence presented here, these extra costs are unlikely to be offset by the short-term benefits of laparoscopic repair.Luke Vale, Adrian Grant, Kirsty McCormack, Neil W. Scott and the EU Hernia Trialists Collaboratio
Confidence interval estimation for the changepoint of treatment stratification in the presence of a qualitative covariate-treatment interaction
The goal in stratified medicine is to administer the \textquotedblbest\textquotedbl treatment to a patient. Not all patients might benefit from the same treatment; the choice of best treatment can depend on certain patient characteristics. In this article, it is assumed that a time-to-event outcome is considered as a patient-relevant outcome and a qualitative interaction between a continuous covariate and treatment exists, ie,~that patients with different values of one specific covariate should be treated differently. We suggest and investigate different methods for confidence interval estimation for the covariate value, where the treatment recommendation should be changed based on data collected in a randomized clinical trial. An adaptation of Fieller's theorem, the delta method, and different bootstrap approaches (normal, percentile-based, wild bootstrap) are investigated and compared in a simulation study. Extensions to multivariable problems are presented and evaluated. We observed appropriate confidence interval coverage following Fieller's theorem irrespective of sample size but at the cost of very wide or even infinite confidence intervals. The delta method and the wild bootstrap approach provided the smallest intervals but inadequate coverage for small to moderate event numbers, also depending on the location of the true changepoint. For the percentile-based bootstrap, wide intervals were observed, and it was slightly conservative regarding coverage, whereas the normal bootstrap did not provide acceptable results for many scenarios. The described methods were also applied to data from a randomized clinical trial comparing two treatments for patients with symptomatic, severe carotid artery stenosis, considering patient's age as predictive marker
The incidence and risk factors for new onset atrial fibrillation in the PROSPER study
Aims Atrial fibrillation/flutter (AF) is the most common arrhythmia in older people. It associates with reduced exercise capacity, increased risk of stroke, and mortality. We aimed to determine retrospectively whether pravastatin reduces the incidence of AF and whether any electrocardiographic measures or clinical conditions might be risk factors for its development. Methods and results The PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) was a randomized, double-blind controlled trial that recruited 5804 individuals aged 70-82 years with a history of, or risk factors for, vascular disease. A total of 2891 were allocated to pravastatin and 2913 to placebo; mean follow-up was 3.2 years. Electrocardiograms (ECGs), which were recorded at baseline, annually thereafter, and at run-out, were processed by computer and reviewed manually. In all, 264 of 2912 (9.1%) of the placebo group and 283 of 2888 (9.8%) of the pravastatin-treated group developed AF [hazard ratio 1.08 (0.92,1.28), P = 0.35)]. Multivariate analysis showed that PR and QTc intervals, age, left ventricular hypertrophy, and ST-T abnormalities were related to development of AF after adjustment for many variables including alcohol consumption, which itself was univariately predictive of developing AF. Previous myocardial infarction on the ECG was not a risk factor. A history of vascular disease was strongly linked with developing AF but not diabetes and hypertension. Conclusion Pravastatin does not reduce the incidence of AF in older people at risk of vascular disease, at least in the short-medium term. Risk factors for AF include older age, prolongation of PR or QTc intervals, left ventricular hypertrophy, and ST-T abnormalities on the EC
DeltaStream: A 36 channel low noise, large dynamic range silicon detector readout ASIC optimised for large detector capacitance
Simple models of protein folding and of non--conventional drug design
While all the information required for the folding of a protein is contained
in its amino acid sequence, one has not yet learned how to extract this
information to predict the three--dimensional, biologically active, native
conformation of a protein whose sequence is known. Using insight obtained from
simple model simulations of the folding of proteins, in particular of the fact
that this phenomenon is essentially controlled by conserved (native) contacts
among (few) strongly interacting ("hot"), as a rule hydrophobic, amino acids,
which also stabilize local elementary structures (LES, hidden, incipient
secondary structures like --helices and --sheets) formed early
in the folding process and leading to the postcritical folding nucleus (i.e.,
the minimum set of native contacts which bring the system pass beyond the
highest free--energy barrier found in the whole folding process) it is possible
to work out a succesful strategy for reading the native structure of designed
proteins from the knowledge of only their amino acid sequence and of the
contact energies among the amino acids. Because LES have undergone millions of
years of evolution to selectively dock to their complementary structures, small
peptides made out of the same amino acids as the LES are expected to
selectively attach to the newly expressed (unfolded) protein and inhibit its
folding, or to the native (fluctuating) native conformation and denaturate it.
These peptides, or their mimetic molecules, can thus be used as effective
non--conventional drugs to those already existing (and directed at neutralizing
the active site of enzymes), displaying the advantage of not suffering from the
uprise of resistance
Role of Secondary Motifs in Fast Folding Polymers: A Dynamical Variational Principle
A fascinating and open question challenging biochemistry, physics and even
geometry is the presence of highly regular motifs such as alpha-helices in the
folded state of biopolymers and proteins. Stimulating explanations ranging from
chemical propensity to simple geometrical reasoning have been invoked to
rationalize the existence of such secondary structures. We formulate a
dynamical variational principle for selection in conformation space based on
the requirement that the backbone of the native state of biologically viable
polymers be rapidly accessible from the denatured state. The variational
principle is shown to result in the emergence of helical order in compact
structures.Comment: 4 pages, RevTex, 4 eps figure
Hypervitaminosis A is prevalent in children with CKD and contributes to hypercalcemia.
Vitamin A accumulates in renal failure, but the prevalence of hypervitaminosis A in children with predialysis chronic kidney disease (CKD) is not known. Hypervitaminosis A has been associated with hypercalcemia. In this study we compared dietary vitamin A intake with serum retinoid levels and their associations with hypercalcemia
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