The fidelity of dynamic signaling by noisy biomolecular networks

This is the final version of the article. Available from Public Library of Science via the DOI in this record.Cells live in changing, dynamic environments. To understand cellular decision-making, we must therefore understand how fluctuating inputs are processed by noisy biomolecular networks. Here we present a general methodology for analyzing the fidelity with which different statistics of a fluctuating input are represented, or encoded, in the output of a signaling system over time. We identify two orthogonal sources of error that corrupt perfect representation of the signal: dynamical error, which occurs when the network responds on average to other features of the input trajectory as well as to the signal of interest, and mechanistic error, which occurs because biochemical reactions comprising the signaling mechanism are stochastic. Trade-offs between these two errors can determine the system's fidelity. By developing mathematical approaches to derive dynamics conditional on input trajectories we can show, for example, that increased biochemical noise (mechanistic error) can improve fidelity and that both negative and positive feedback degrade fidelity, for standard models of genetic autoregulation. For a group of cells, the fidelity of the collective output exceeds that of an individual cell and negative feedback then typically becomes beneficial. We can also predict the dynamic signal for which a given system has highest fidelity and, conversely, how to modify the network design to maximize fidelity for a given dynamic signal. Our approach is general, has applications to both systems and synthetic biology, and will help underpin studies of cellular behavior in natural, dynamic environments.We acknowledge support from a Medical Research Council and Engineering and Physical Sciences Council funded Fellowship in Biomedical Informatics (CGB) and a Scottish Universities Life Sciences Alliance chair in Systems Biology (PSS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

A High-Resolution Study of the HI Content of Local Group Dwarf Irregular Galaxy WLM

Dwarf irregular galaxies are unique laboratories for studying the interaction between stars and the interstellar medium in low mass environments. We present the highest spatial resolution observations to date of the neutral hydrogen content of the Local Group dwarf irregular galaxy WLM. We find that WLM's neutral hydrogen distribution is typical for a galaxy of its type and size and derive an HI mass of 6.3e7 Msun for WLM. In addition, we derive an HI extent for WLM of 30 arcmin, which is much less than the 45 arcmin extent found by Huchtmeier, Seiradakis, and Materne (1981). We show that the broken ring of high column density neutral hydrogen surrounding the center of WLM is likely the result of star formation propagating out from the center of the galaxy. The young stars and Ha emission in this galaxy are mostly correlated with the high column density neutral hydrogen. The gap in the central ring is the result of star formation in that region using up, blowing out, or ionizing all of the neutral hydrogen. Like many late-type galaxies, WLM's velocity field is asymmetric with the approaching (northern) side appearing to be warped and a steeper velocity gradient for the approaching side than for the receding side in the inner region of the galaxy. We derive a dynamical mass for WLM of 2.16e9 Msun.Comment: 38 pages, 15 figures, 5 tables, accepted by AJ, high resolution version at http://www.astro.wisc.edu/~kepley/kepley_wlm.p

On the criticality of inferred models

Advanced inference techniques allow one to reconstruct the pattern of interaction from high dimensional data sets. We focus here on the statistical properties of inferred models and argue that inference procedures are likely to yield models which are close to a phase transition. On one side, we show that the reparameterization invariant metrics in the space of probability distributions of these models (the Fisher Information) is directly related to the model's susceptibility. As a result, distinguishable models tend to accumulate close to critical points, where the susceptibility diverges in infinite systems. On the other, this region is the one where the estimate of inferred parameters is most stable. In order to illustrate these points, we discuss inference of interacting point processes with application to financial data and show that sensible choices of observation time-scales naturally yield models which are close to criticality.Comment: 6 pages, 2 figures, version to appear in JSTA

PRIVATE SAVINGS IN TRANSITION ECONOMIES: ARE THERE TERMS OF TRADE SHOCKS?

The paper examines the impact of terms of trade shocks on private savings in the transition economies after accounting for the effect of other determinants. Economic agents in the transition economies are subject to tight credit constraints which are more pronounced during bad state of nature. Thus, adverse shocks to commodity prices in the world market can force them to reduce savings by a larger amount than they would otherwise have. Empirical analysis using a dynamic panel model and data from twenty one transition economies confirm that most of the determinants of savings identified in the literature also apply to the transition economies. Favorable movements in both the permanent and transitory components of the terms of trade have a significant positive impact on private savings with transitory movements having a larger impact than the permanent component. This reflects the lack of access to foreign borrowing that many of the transition economies have faced during the last decade. Although the impact of terms of trade shocks are found to be asymmetric, the magnitude of the impact appears to be small. The results are robust for alternative estimators, determinants, and country groupings.http://deepblue.lib.umich.edu/bitstream/2027.42/39958/3/wp572.pd

Weighted needle pinprick sensory thresholds: a simple test of sensory function in diabetic peripheral neuropathy

A simple device is described, consisting of 12 weighted 23 gauge disposable needles (0.2 to 5.2 g), for testing sensation in busy diabetic clinics. The pinprick sensory threshold (PPT) is the lightest weighted needle which consistently elicits a sharp sensation. The subjects were 48 healthy controls (hospital staff), 44 diabetic patients without neuropathic symptoms, and 35 diabetic patients with chronic painful neuropathy. In the controls, the mean PPT from the right hand and foot obtained on two test occasions a week apart did not differ significantly. In diabetic patients without symptomatic neuropathy, the mean PPT in the right hand and right foot were significantly higher than in the controls. The diabetic patients with painful neuropathy had clearly increased mean PPT in the right hand and foot compared with controls. Marstock thermal limen in diabetic patients with painful neuropathy correlated significantly with PPT determinations. PPT and thermal thresholds probably give comparable information on small fibre dysfunction in diabetic patients with symptomatic neuropathy. Compared with thermal threshold determinations however, the weighted needle apparatus is inexpensive, simple, and rapid to use

Epidemiology and economic burden of herpes zoster and post-herpetic neuralgia in Italy: A retrospective, population-based study

<p>Abstract</p> <p>Background</p> <p>Data on the epidemiology and cost of herpes zoster (HZ) and post-herpetic neuralgia (PHN) in Italy are limited. This retrospective, population-based study was designed to determine the incidence of HZ and the proportion developing PHN in Italy and the associated medical resource utilisation and costs. It focused primarily on immunocompetent patients aged ≥50 years who would be eligible for preventive vaccination.</p> <p>Method</p> <p>Data were extracted from a primary-care database and national hospital-discharge records covering four major regions in Italy for 2003-2005. Cases of HZ and PHN (1 and 3 months' duration; PHN1 and PHN3) were identified by ICD9-CM codes and, additionally for PHN, prescription of neuropathic pain medication.</p> <p>Results</p> <p>Over 3 years, 5675 incident cases of HZ were documented in adults, of which 3620 occurred in immunocompetent patients aged ≥50 years (incidence of 6.31 per 1000 person-years [95% CI: 6.01-6.62]). Of the immunocompetent patients aged ≥50 years with HZ, 9.4% (95% CI: 8.2-10.7) and 7.2% (95% CI: 6.2-8.2) developed PHN1 and PHN3, respectively. Increasing age, female sex, and being immunologically compromised conferred increased risk for both HZ and PHN. Overall, about 1.3% of HZ and almost 2% of PHN cases required inpatient care, with 16.9% of all HZ-related hospitalisations due specifically to PHN. In patients aged ≥50 years, mean stay was 7.8 ± 5.4 days for HZ and 10.2 ± 8.6 days for PHN, and direct costs associated with inpatient care were more than 20 times outpatient costs per HZ case (mean ± SD: €2592 ± €1313 vs. €122.68 ± €97.51) and over 5 times more per episode of PHN (mean ± SD: €2806 ± €2641 vs. €446.10 ± €442.97). Total annual costs were €41.2 million, of which €28.2 million were direct costs and €13.0 million indirect costs.</p> <p>Conclusions</p> <p>This study, the largest to date on the epidemiology and economic impact of HZ and PHN in Italy, confirms the considerable disease and economic burden posed by HZ. As HZ and PHN disproportionately affect the elderly, without intervention this problem is likely to grow as the proportion of elderly in the Italian population continues to increase.</p

Host-specific pit-forming epizoans on Silurian crinoids

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75404/1/j.1502-3931.1978.tb01229.x.pd

Stochastic Simulation of Biomolecular Networks in Dynamic Environments

This is the final version of the article. Available from Public Library of Science via the DOI in this record.Simulation of biomolecular networks is now indispensable for studying biological systems, from small reaction networks to large ensembles of cells. Here we present a novel approach for stochastic simulation of networks embedded in the dynamic environment of the cell and its surroundings. We thus sample trajectories of the stochastic process described by the chemical master equation with time-varying propensities. A comparative analysis shows that existing approaches can either fail dramatically, or else can impose impractical computational burdens due to numerical integration of reaction propensities, especially when cell ensembles are studied. Here we introduce the Extrande method which, given a simulated time course of dynamic network inputs, provides a conditionally exact and several orders-of-magnitude faster simulation solution. The new approach makes it feasible to demonstrate-using decision-making by a large population of quorum sensing bacteria-that robustness to fluctuations from upstream signaling places strong constraints on the design of networks determining cell fate. Our approach has the potential to significantly advance both understanding of molecular systems biology and design of synthetic circuits.MV acknowledges support under an MRC Biomedical Informatics Fellowship. PT acknowledges support by the Royal Commission for the Exhibition of 1851. RG acknowledges support from the Leverhulme Trust (RPG-2013-171). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Impact of herpes zoster and post-herpetic neuralgia on patients’ quality of life: a patient-reported outcomes survey

Background: The impact of herpes zoster (HZ) and post-herpetic neuralgia (PHN) on patients’ quality of life (QoL) is currently poorly documented. Subjects and methods: Telephone interviews in Germany identified patients ≥50 years old with painful HZ diagnosed during the previous 5 years. Bespoke questions evaluated previous HZ episodes. Results: Of 11,009 respondents, 280 met the screening criteria, and 32 (11%) developed PHN. PHN was associated with significantly worse outcomes than HZ (all P < 0.05). Mean pain scores associated with PHN and HZ, respectively, were 7.1 and 6.2 (average) and 8.2 and 7.0 (worst). Many patients with PHN (91%) and HZ (73%) experienced problems with daily activities, including work, studies, housework, family and leisure activities. Mean pain interference scores in patients with PHN versus HZ were highest for sleep (6.5 versus 4.9), normal work (6.1 versus 4.4) and mood (5.9 versus 4.4). Most employed interviewees with PHN (70%) and HZ (64%) stopped work during the disease. Pain and QoL outcomes were not significantly different between all patients versus those diagnosed during the previous 12 months or between patients aged 50–59 years versus ≥60 years. Conclusions: HZ causes substantial pain, which seriously interferes with many aspects of daily life, particularly in patients with PHN