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

The hidden perils of read mapping as a quality assessment tool in genome sequencing

This article provides a comparative analysis of the various methods of genome sequencing focusing on verification of the assembly quality. The results of a comparative assessment of various de novo assembly tools, as well as sequencing technologies, are presented using a recently completed sequence of the genome of Lactobacillus fermentum 3872. In particular, quality of assemblies is assessed by using CLC Genomics Workbench read mapping and Optical mapping developed by OpGen. Over-extension of contigs without prior knowledge of contig location can lead to misassembled contigs, even when commonly used quality indicators such as read mapping suggest that a contig is well assembled. Precautions must also be undertaken when using long read sequencing technology, which may also lead to misassembled contigs

Cardiogenic Induction of Pluripotent Stem Cells Streamlined Through a Conserved SDF-1/VEGF/BMP2 Integrated Network

BACKGROUND: Pluripotent stem cells produce tissue-specific lineages through programmed acquisition of sequential gene expression patterns that function as a blueprint for organ formation. As embryonic stem cells respond concomitantly to diverse signaling pathways during differentiation, extraction of a pro-cardiogenic network would offer a roadmap to streamline cardiac progenitor output. METHODS AND RESULTS: To resolve gene ontology priorities within precursor transcriptomes, cardiogenic subpopulations were here generated according to either growth factor guidance or stage-specific biomarker sorting. Innate expression profiles were independently delineated through unbiased systems biology mapping, and cross-referenced to filter transcriptional noise unmasking a conserved progenitor motif (55 up- and 233 down-regulated genes). The streamlined pool of 288 genes organized into a core biological network that prioritized the "Cardiovascular Development" function. Recursive in silico deconvolution of the cardiogenic neighborhood and associated canonical signaling pathways identified a combination of integrated axes, CXCR4/SDF-1, Flk-1/VEGF and BMP2r/BMP2, predicted to synchronize cardiac specification. In vitro targeting of the resolved triad in embryoid bodies accelerated expression of Nkx2.5, Mef2C and cardiac-MHC, enhanced beating activity, and augmented cardiogenic yield. CONCLUSIONS: Transcriptome-wide dissection of a conserved progenitor profile thus revealed functional highways that coordinate cardiogenic maturation from a pluripotent ground state. Validating the bioinformatics algorithm established a strategy to rationally modulate cell fate, and optimize stem cell-derived cardiogenesis

Trade-Offs and Constraints in Allosteric Sensing

Sensing extracellular changes initiates signal transduction and is the first stage of cellular decision-making. Yet relatively little is known about why one form of sensing biochemistry has been selected over another. To gain insight into this question, we studied the sensing characteristics of one of the biochemically simplest of sensors: the allosteric transcription factor. Such proteins, common in microbes, directly transduce the detection of a sensed molecule to changes in gene regulation. Using the Monod-Wyman-Changeux model, we determined six sensing characteristics – the dynamic range, the Hill number, the intrinsic noise, the information transfer capacity, the static gain, and the mean response time – as a function of the biochemical parameters of individual sensors and of the number of sensors. We found that specifying one characteristic strongly constrains others. For example, a high dynamic range implies a high Hill number and a high capacity, and vice versa. Perhaps surprisingly, these constraints are so strong that most of the space of characteristics is inaccessible given biophysically plausible ranges of parameter values. Within our approximations, we can calculate the probability distribution of the numbers of input molecules that maximizes information transfer and show that a population of one hundred allosteric transcription factors can in principle distinguish between more than four bands of input concentrations. Our results imply that allosteric sensors are unlikely to have been selected for high performance in one sensing characteristic but for a compromise in the performance of many

Therapeutic aims of drugs offering only progression-free survival are misunderstood by patients, and oncologists may be overly optimistic about likely benefits

PURPOSE: The use of novel and often expensive drugs offering limited survival benefit in advanced disease is controversial. Treatment recommendations are influenced by patient characteristics and trial data showing overall response rates (ORR), progression-free survival (PFS) and overall survival (OS). PFS is frequently the primary outcome in licencing studies. PATIENTS AND METHODS: As part of a longitudinal study Assessing the 'VALue' to patients of PROgression Free Survival (AVALPROFS), oncologists completed checklists at baseline following consultations with patients. Questions probed perceived clinical benefits of the drugs to populations in general. Patients completed study-specific interview schedules at baseline, 6 weeks into treatment, and at withdrawal due to toxicity or progression. Patients also completed tumour- and treatment-specific quality of life questionnaires monthly for their time in the study. Only baseline results are reported here. RESULTS: Thirty-two UK oncologists discussed management options with 90 patients with heterogeneous advanced cancers. Oncologists' estimates of medical benefit in general from treatment varied between 10 and 80 %. They expected 46/90 (51 %) of their patients to derive some clinical benefit from the prescribed treatment but were either unsure or expected none for 44/90 (49 %). Predictions of life expectancy were variable but 62 % (56/90) of patients were expected to survive longer with treatment. A majority of patients 51/90 (57 %) had 'no idea' or were 'unclear' what PFS meant and 45/90 (50 %) thought extension of life was the primary therapeutic aim of treatment. CONCLUSION: Discussions between doctors and patients with metastatic disease about future management plans and likely therapeutic gains are challenging. Factors influencing decisions about putative benefits of novel drugs are often applied inconsistently can be overly optimistic and may even contradict published data

A chemical survey of exoplanets with ARIEL

Thousands of exoplanets have now been discovered with a huge range of masses, sizes and orbits: from rocky Earth-like planets to large gas giants grazing the surface of their host star. However, the essential nature of these exoplanets remains largely mysterious: there is no known, discernible pattern linking the presence, size, or orbital parameters of a planet to the nature of its parent star. We have little idea whether the chemistry of a planet is linked to its formation environment, or whether the type of host star drives the physics and chemistry of the planet’s birth, and evolution. ARIEL was conceived to observe a large number (~1000) of transiting planets for statistical understanding, including gas giants, Neptunes, super-Earths and Earth-size planets around a range of host star types using transit spectroscopy in the 1.25–7.8 μm spectral range and multiple narrow-band photometry in the optical. ARIEL will focus on warm and hot planets to take advantage of their well-mixed atmospheres which should show minimal condensation and sequestration of high-Z materials compared to their colder Solar System siblings. Said warm and hot atmospheres are expected to be more representative of the planetary bulk composition. Observations of these warm/hot exoplanets, and in particular of their elemental composition (especially C, O, N, S, Si), will allow the understanding of the early stages of planetary and atmospheric formation during the nebular phase and the following few million years. ARIEL will thus provide a representative picture of the chemical nature of the exoplanets and relate this directly to the type and chemical environment of the host star. ARIEL is designed as a dedicated survey mission for combined-light spectroscopy, capable of observing a large and well-defined planet sample within its 4-year mission lifetime. Transit, eclipse and phase-curve spectroscopy methods, whereby the signal from the star and planet are differentiated using knowledge of the planetary ephemerides, allow us to measure atmospheric signals from the planet at levels of 10–100 part per million (ppm) relative to the star and, given the bright nature of targets, also allows more sophisticated techniques, such as eclipse mapping, to give a deeper insight into the nature of the atmosphere. These types of observations require a stable payload and satellite platform with broad, instantaneous wavelength coverage to detect many molecular species, probe the thermal structure, identify clouds and monitor the stellar activity. The wavelength range proposed covers all the expected major atmospheric gases from e.g. H2O, CO2, CH4 NH3, HCN, H2S through to the more exotic metallic compounds, such as TiO, VO, and condensed species. Simulations of ARIEL performance in conducting exoplanet surveys have been performed – using conservative estimates of mission performance and a full model of all significant noise sources in the measurement – using a list of potential ARIEL targets that incorporates the latest available exoplanet statistics. The conclusion at the end of the Phase A study, is that ARIEL – in line with the stated mission objectives – will be able to observe about 1000 exoplanets depending on the details of the adopted survey strategy, thus confirming the feasibility of the main science objectives.Peer reviewedFinal Published versio

Measurement of the branching fraction and CP content for the decay B(0) -> D(*+)D(*-)

This is the pre-print version of the Article. The official published version can be accessed from the links below. Copyright @ 2002 APS.We report a measurement of the branching fraction of the decay B0→D*+D*- and of the CP-odd component of its final state using the BABAR detector. With data corresponding to an integrated luminosity of 20.4  fb-1 collected at the Υ(4S) resonance during 1999–2000, we have reconstructed 38 candidate signal events in the mode B0→D*+D*- with an estimated background of 6.2±0.5 events. From these events, we determine the branching fraction to be B(B0→D*+D*-)=[8.3±1.6(stat)±1.2(syst)]×10-4. The measured CP-odd fraction of the final state is 0.22±0.18(stat)±0.03(syst).This work is supported by DOE and NSF (USA), NSERC (Canada), IHEP (China), CEA and CNRS-IN2P3 (France), BMBF (Germany), INFN (Italy), NFR (Norway), MIST (Russia), and PPARC (United Kingdom). Individuals have received support from the A.P. Sloan Foundation, Research Corporation, and Alexander von Humboldt Foundation

Search for rare quark-annihilation decays, B --> Ds(*) Phi

We report on searches for B- --> Ds- Phi and B- --> Ds*- Phi. In the context of the Standard Model, these decays are expected to be highly suppressed since they proceed through annihilation of the b and u-bar quarks in the B- meson. Our results are based on 234 million Upsilon(4S) --> B Bbar decays collected with the BABAR detector at SLAC. We find no evidence for these decays, and we set Bayesian 90% confidence level upper limits on the branching fractions BF(B- --> Ds- Phi) Ds*- Phi)<1.2x10^(-5). These results are consistent with Standard Model expectations.Comment: 8 pages, 3 postscript figues, submitted to Phys. Rev. D (Rapid Communications

Measurement of D-s(+) and D-s(*+) production in B meson decays and from continuum e(+)e(-) annihilation at √s=10.6 GeV

This is the pre-print version of the Article. The official published version can be accessed from the links below. Copyright @ 2002 APSNew measurements of Ds+ and Ds*+ meson production rates from B decays and from qq̅ continuum events near the Υ(4S) resonance are presented. Using 20.8 fb-1 of data on the Υ(4S) resonance and 2.6 fb-1 off-resonance, we find the inclusive branching fractions B(B⃗Ds+X)=(10.93±0.19±0.58±2.73)% and B(B⃗Ds*+X)=(7.9±0.8±0.7±2.0)%, where the first error is statistical, the second is systematic, and the third is due to the Ds+→φπ+ branching fraction uncertainty. The production cross sections σ(e+e-→Ds+X)×B(Ds+→φπ+)=7.55±0.20±0.34pb and σ(e+e-→Ds*±X)×B(Ds+→φπ+)=5.8±0.7±0.5pb are measured at center-of-mass energies about 40 MeV below the Υ(4S) mass. The branching fractions ΣB(B⃗Ds(*)+D(*))=(5.07±0.14±0.30±1.27)% and ΣB(B⃗Ds*+D(*))=(4.1±0.2±0.4±1.0)% are determined from the Ds(*)+ momentum spectra. The mass difference m(Ds+)-m(D+)=98.4±0.1±0.3MeV/c2 is also measured.This work was supported by DOE and NSF (USA), NSERC (Canada), IHEP (China), CEA and CNRS-IN2P3 (France), BMBF (Germany), INFN (Italy), NFR (Norway), MIST (Russia), and PPARC (United Kingdom). Individuals have received support from the Swiss NSF, A. P. Sloan Foundation, Research Corporation, and Alexander von Humboldt Foundation

Measurement of CP-violation asymmetries in D0 to Ks pi+ pi-

We report a measurement of time-integrated CP-violation asymmetries in the resonant substructure of the three-body decay D0 to Ks pi+ pi- using CDF II data corresponding to 6.0 invfb of integrated luminosity from Tevatron ppbar collisions at sqrt(s) = 1.96 TeV. The charm mesons used in this analysis come from D*+(2010) to D0 pi+ and D*-(2010) to D0bar pi-, where the production flavor of the charm meson is determined by the charge of the accompanying pion. We apply a Dalitz-amplitude analysis for the description of the dynamic decay structure and use two complementary approaches, namely a full Dalitz-plot fit employing the isobar model for the contributing resonances and a model-independent bin-by-bin comparison of the D0 and D0bar Dalitz plots. We find no CP-violation effects and measure an asymmetry of ACP = (-0.05 +- 0.57 (stat) +- 0.54 (syst))% for the overall integrated CP-violation asymmetry, consistent with the standard model prediction.Comment: 15 page