pH-Induced Folding of the Caspase-Cleaved Par-4 Tumor Suppressor: Evidence of Structure Outside of the Coiled Coil Domain

Prostate apoptosis response-4 (Par-4) is a 38 kDa largely intrinsically disordered tumor suppressor protein that functions in cancer cell apoptosis. Par-4 down-regulation is often observed in cancer while up-regulation is characteristic of neurodegenerative conditions such as Alzheimer’s disease. Cleavage of Par-4 by caspase-3 activates tumor suppression via formation of an approximately 25 kDa fragment (cl-Par-4) that enters the nucleus and inhibits Bcl-2 and NF-ƙB, which function in pro-survival pathways. Here, we have investigated the structure of cl-Par-4 using biophysical techniques including circular dichroism (CD) spectroscopy, dynamic light scattering (DLS), and intrinsic tyrosine fluorescence. The results demonstrate pH-dependent folding of cl-Par-4, with high disorder and aggregation at neutral pH, but a largely folded, non-aggregated conformation at acidic p

Solving the Vlasov equation for one-dimensional models with long range interactions on a GPU

We present a GPU parallel implementation of the numeric integration of the Vlasov equation in one spatial dimension based on a second order time-split algorithm with a local modified cubic-spline interpolation. We apply our approach to three different systems with long-range interactions: the Hamiltonian Mean Field, Ring and the self-gravitating sheet models. Speedups and accuracy for each model and different grid resolutions are presented

Asthma and Risk of Non-Respiratory Tract Infection: A Population-Based Case-Control Study

OBJECTIVES: Asthmatics have increased risks of airway-related infections. Little is known about whether this is true for non-airway-related serious infections such as Escherichia coli bloodstream infection (BSI). We assessed whether asthma is associated with a risk of developing community-acquired E coli BSI. DESIGN: The study was designed as a population-based retrospective case-control study. SETTING: This population-based study was conducted in Olmsted County, Minnesota. PARTICIPANTS: The study included 259 all eligible community-acquired E coli BSI cases in Olmsted County, MN between 1998 and 2007 and 259 birthday-matched, gender-matched and residency-matched controls. PRIMARY AND SECONDARY OUTCOME MEASURES: Only community-acquired E coli BSI cases as the primary outcome was included. Asthma status as an exposure was ascertained by predetermined criteria. An adjusted OR and 95% CI for the association between asthma and risk of community-acquired E coli BSI was calculated using conditional logistic regression. RESULTS: Of 259 eligible cases, 179 (69%) were women and mean age was 61±22 years. Of the 259 cases 37 (14%) and 16 (6%) of 259 controls had a prior history of asthma (adjusted OR 2.74; 95% CI 1.11 to 6.76; p=0.029). The population attributable risk of asthma for community-acquired E coli BSI was 9%. Although not statistically significant, there was a borderline association between having a history of food allergy and increased risk of community-acquired E coli BSI (6% vs 2%; adjusted OR 3.51; 95% CI 0.94 to 13.11; p=0.062). CONCLUSIONS: Based on the findings of the current population-based, case-control investigation, a history of asthma may be associated with risk of community-acquired E coli BSI. The impact of asthma on risk of microbial infections may go beyond airways

Exact Relativistic Two-Body Motion in Lineal Gravity

We consider the N-body problem in (1+1) dimensional lineal gravity. For 2 point masses (N=2) we obtain an exact solution for the relativistic motion. In the equal mass case we obtain an explicit expression for their proper separation as a function of their mutual proper time. Our solution gives the exact Hamiltonian to infinite order in the gravitational coupling constant.Comment: latex, 11 pages, 2 figures, final version to appear in Phys. Rev. Let

Statistical Mechanics of Relativistic One-Dimensional Self-Gravitating Systems

We consider the statistical mechanics of a general relativistic one-dimensional self-gravitating system. The system consists of $N$-particles coupled to lineal gravity and can be considered as a model of $N$ relativistically interacting sheets of uniform mass. The partition function and one-particle distitrubion functions are computed to leading order in $1/c$ where $c$ is the speed of light; as $c\to\infty$ results for the non-relativistic one-dimensional self-gravitating system are recovered. We find that relativistic effects generally cause both position and momentum distribution functions to become more sharply peaked, and that the temperature of a relativistic gas is smaller than its non-relativistic counterpart at the same fixed energy. We consider the large-N limit of our results and compare this to the non-relativistic case.Comment: latex, 60 pages, 22 figure

Using the ecology model to describe the impact of asthma on patterns of health care

BACKGROUND: Asthma changes both the volume and patterns of healthcare of affected people. Most studies of asthma health care utilization have been done in selected insured populations or in a single site such as the emergency department. Asthma is an ambulatory sensitive care condition making it important to understand the relationship between care in all sites across the health service spectrum. Asthma is also more common in people with fewer economic resources making it important to include people across all types of insurance and no insurance categories. The ecology of medical care model may provide a useful framework to describe the use of health services in people with asthma compared to those without asthma and identify subgroups with apparent gaps in care. METHODS: This is a case-control study using the 1999 U.S. Medical Expenditure Panel Survey. Cases are school-aged children (6 to 17 years) and young adults (18 to 44 years) with self-reported asthma. Controls are from the same age groups who have no self-reported asthma. Descriptive analyses and risk ratios are placed within the ecology of medical care model and used to describe and compare the healthcare contact of cases and controls across multiple settings. RESULTS: In 1999, the presence of asthma significantly increased the likelihood of an ambulatory care visit by 20 to 30% and more than doubled the likelihood of making one or more visits to the emergency department (ED). Yet, 18.8% of children and 14.5% of adults with asthma (over a million Americans) had no ambulatory care visits for asthma. About one in 20 to 35 people with asthma (5.2% of children and 3.6% of adults) were seen in the ED or hospital but had no prior or follow-up ambulatory care visits. These Americans were more likely to be uninsured, have no usual source of care and live in metropolitan areas. CONCLUSION: The ecology model confirmed that having asthma changes the likelihood and pattern of care for Americans. More importantly, the ecology model identified a subgroup with asthma who sought only emergent or hospital services

Determining the date of diagnosis – is it a simple matter? The impact of different approaches to dating diagnosis on estimates of delayed care for ovarian cancer in UK primary care

Background Studies of cancer incidence and early management will increasingly draw on routine electronic patient records. However, data may be incomplete or inaccurate. We developed a generalisable strategy for investigating presenting symptoms and delays in diagnosis using ovarian cancer as an example. Methods The General Practice Research Database was used to investigate the time between first report of symptom and diagnosis of 344 women diagnosed with ovarian cancer between 01/06/2002 and 31/05/2008. Effects of possible inaccuracies in dating of diagnosis on the frequencies and timing of the most commonly reported symptoms were investigated using four increasingly inclusive definitions of first diagnosis/suspicion: 1. "Definite diagnosis" 2. "Ambiguous diagnosis" 3. "First treatment or complication suggesting pre-existing diagnosis", 4 "First relevant test or referral". Results The most commonly coded symptoms before a definite diagnosis of ovarian cancer, were abdominal pain (41%), urogenital problems(25%), abdominal distension (24%), constipation/change in bowel habits (23%) with 70% of cases reporting at least one of these. The median time between first reporting each of these symptoms and diagnosis was 13, 21, 9.5 and 8.5 weeks respectively. 19% had a code for definitions 2 or 3 prior to definite diagnosis and 73% a code for 4. However, the proportion with symptoms and the delays were similar for all four definitions except 4, where the median delay was 8, 8, 3, 10 and 0 weeks respectively. Conclusion Symptoms recorded in the General Practice Research Database are similar to those reported in the literature, although their frequency is lower than in studies based on self-report. Generalisable strategies for exploring the impact of recording practice on date of diagnosis in electronic patient records are recommended, and studies which date diagnoses in GP records need to present sensitivity analyses based on investigation, referral and diagnosis data. Free text information may be essential in obtaining accurate estimates of incidence, and for accurate dating of diagnoses

A dynamical classification of the range of pair interactions

We formalize a classification of pair interactions based on the convergence properties of the {\it forces} acting on particles as a function of system size. We do so by considering the behavior of the probability distribution function (PDF) P(F) of the force field F in a particle distribution in the limit that the size of the system is taken to infinity at constant particle density, i.e., in the "usual" thermodynamic limit. For a pair interaction potential V(r) with V(r) \rightarrow \infty) \sim 1/r^a defining a {\it bounded} pair force, we show that P(F) converges continuously to a well-defined and rapidly decreasing PDF if and only if the {\it pair force} is absolutely integrable, i.e., for a > d-1, where d is the spatial dimension. We refer to this case as {\it dynamically short-range}, because the dominant contribution to the force on a typical particle in this limit arises from particles in a finite neighborhood around it. For the {\it dynamically long-range} case, i.e., a \leq d-1, on the other hand, the dominant contribution to the force comes from the mean field due to the bulk, which becomes undefined in this limit. We discuss also how, for a \leq d-1 (and notably, for the case of gravity, a=d-2) P(F) may, in some cases, be defined in a weaker sense. This involves a regularization of the force summation which is generalization of the procedure employed to define gravitational forces in an infinite static homogeneous universe. We explain that the relevant classification in this context is, however, that which divides pair forces with a > d-2 (or a < d-2), for which the PDF of the {\it difference in forces} is defined (or not defined) in the infinite system limit, without any regularization. In the former case dynamics can, as for the (marginal) case of gravity, be defined consistently in an infinite uniform system.Comment: 12 pages, 1 figure; significantly shortened and focussed, additional references, version to appear in J. Stat. Phy