Exact distributed kinetic Monte Carlo simulations for on-lattice chemical kinetics: lessons learnt from medium- and large-scale benchmarks

Kinetic Monte-Carlo (KMC) simulations have been instrumental in multiscale catalysis studies, enabling the elucidation of the complex dynamics of heterogeneous catalysts and the prediction of macroscopic performance metrics, such as activity and selectivity. However, the accessible length- and time-scales have been a limiting factor in such simulations. For instance, handling lattices containing millions of sites with “traditional” sequential KMC implementations is prohibitive owing to large memory requirements and long simulation times. We have recently established an approach for exact, distributed, lattice-based simulations of catalytic kinetics which couples the Time-Warp algorithm with the Graph-Theoretical KMC framework, enabling the handling of complex adsorbate lateral interactions and reaction events within large lattices. In this work, we develop a lattice-based variant of the Brusselator system, a prototype chemical oscillator pioneered by Prigogine and Lefever in the late 60’s, to benchmark and demonstrate our approach. This system can form spiral wave patterns, which would be computationally intractable with sequential KMC, while our distributed KMC approach can simulate such patterns 16 and 36 times faster with 625 and 1600 processors, respectively. The medium- and large-scale benchmarks thus conducted, demonstrate the robustness of the approach, and reveal computational bottlenecks that could be targeted in further development efforts

The Feasibility and Impact of Delivering a Mind-Body Intervention in a Virtual World

Introduction: Mind-body medical approaches may ameliorate chronic disease. Stress reduction is particularly helpful, but face-to-face delivery systems cannot reach all those who might benefit. An online, 3-dimensional virtual world may be able to support the rich interpersonal interactions required of this approach. In this pilot study, we explore the feasibility of translating a face-to-face stress reduction program into an online virtual setting and estimate the effect size of the intervention. Methods and Findings: Domain experts in virtual world technology joined with mind body practitioners to translate an existing 8 week relaxation response-based resiliency program into an 8-week virtual world-based program in Second Life™ (SL). Twenty-four healthy volunteers with at least one month's experience in SL completed the program. Each subject filled out the Perceived Stress Scale (PSS) and the Symptom Checklist 90- Revised (SCL-90-R) before and after taking part. Participants took part in one of 3 groups of about 10 subjects. The participants found the program to be helpful and enjoyable. Many reported that the virtual environment was an excellent substitute for the preferred face-to-face approach. On quantitative measures, there was a general trend toward decreased perceived stress, (15.7 to 15.0), symptoms of depression, (57.6 to 57.0) and anxiety (56.8 to 54.8). There was a significant decrease of 2.8 points on the SCL-90-R Global Severity Index (p<0.05). Conclusions: This pilot project showed that it is feasible to deliver a typical mind-body medical intervention through a virtual environment and that it is well received. Moreover, the small reduction in psychological distress suggests further research is warranted. Based on the data collected for this project, a randomized trial with less than 50 subjects would be appropriately powered if perceived stress is the primary outcome

Formation of regulatory modules by local sequence duplication

Turnover of regulatory sequence and function is an important part of molecular evolution. But what are the modes of sequence evolution leading to rapid formation and loss of regulatory sites? Here, we show that a large fraction of neighboring transcription factor binding sites in the fly genome have formed from a common sequence origin by local duplications. This mode of evolution is found to produce regulatory information: duplications can seed new sites in the neighborhood of existing sites. Duplicate seeds evolve subsequently by point mutations, often towards binding a different factor than their ancestral neighbor sites. These results are based on a statistical analysis of 346 cis-regulatory modules in the Drosophila melanogaster genome, and a comparison set of intergenic regulatory sequence in Saccharomyces cerevisiae. In fly regulatory modules, pairs of binding sites show significantly enhanced sequence similarity up to distances of about 50 bp. We analyze these data in terms of an evolutionary model with two distinct modes of site formation: (i) evolution from independent sequence origin and (ii) divergent evolution following duplication of a common ancestor sequence. Our results suggest that pervasive formation of binding sites by local sequence duplications distinguishes the complex regulatory architecture of higher eukaryotes from the simpler architecture of unicellular organisms

Patient recruitment to a randomized clinical trial of behavioral therapy for chronic heart failure

BACKGROUND: Patient recruitment is one of the most difficult aspects of clinical trials, especially for research involving elderly subjects. In this paper, we describe our experience with patient recruitment for the behavioral intervention randomized trial, "The relaxation response intervention for chronic heart failure (RRCHF)." Particularly, we identify factors that, according to patient reports, motivated study participation. METHODS: The RRCHF was a three-armed, randomized controlled trial designed to evaluate the efficacy and cost of a 15-week relaxation response intervention on veterans with chronic heart failure. Patients from the Veterans Affairs (VA) Boston Healthcare System in the United States were recruited in the clinic and by telephone. Patients' reasons for rejecting the study participation were recorded during the screening. A qualitative sub-study in the trial consisted of telephone interviews of participating patients about their experiences in the study. The qualitative study included the first 57 patients who completed the intervention and/or the first follow-up outcome measures. Factors that distinguished patients who consented from those who refused study participation were identified using a t-test or a chi-square test. The reason for study participation was abstracted from the qualitative interview. RESULTS: We successfully consented 134 patients, slightly more than our target number, in 27 months. Ninety-five of the consented patients enrolled in the study. The enrollment rate among the patients approached was 18% through clinic and 6% through telephone recruitment. The most commonly cited reason for declining study participation given by patients recruited in the clinic was 'Lives Too Far Away'; for patients recruited by telephone it was 'Not Interested in the Study'. One factor that significantly distinguished patients who consented from patients who declined was the distance between their residence and the study site (t-test: p < .001). The most frequently reported reason for study participation was some benefit to the patient him/herself. Other reasons included helping others, being grateful to the VA, positive comments by trusted professionals, certain characteristics of the recruiter, and monetary compensation. CONCLUSIONS: The enrollment rate was low primarily because of travel considerations, but we were able to identify and highlight valuable information for planning recruitment for future similar studies

Therapeutic effect of hyperbaric oxygen in psoriasis vulgaris: two case reports and a review of the literature

<p>Abstract</p> <p>Introduction</p> <p>Psoriasis is an inflammatory and immunological cutaneous disease. The high morbidity in patients with psoriasis results from severe clinical manifestations and/or adverse effects of treatment. The Undersea and Hyperbaric Medical Society and Federal Medicare and Medicaid Services have approved the use of hyperbaric oxygen (HBO₂) for more than 15 indications, including wound healing, infections and late effects of radiation, which are largely unresponsive to conventional treatments. Accumulated data show that HBO₂ has anti-inflammatory effects and other positive influences on the immune system, making it a rational treatment in the management of psoriasis plaques and arthritis.</p> <p>Case presentation</p> <p>We present the cases of two patients with long histories of psoriasis vulgarus who exhibited marked improvement with use of HBO_2. The first patient was 40 years old and had pustular psoriasis and psoriatic arthritis. He was treated with six sessions of HBO₂ (at 2.8 atmospheres of pressure for 60 minutes), which successfully controlled his symptoms. At the 18-month post-treatment follow up, the patient exhibited complete remission of psoriasis and marked improvement in psoriatic arthritis without medication. The second patient was 55 years old with extensive psoriatic lesions, and exhibited marked improvement within 15 sessions of HBO₂. No adverse effects of HBO₂ were identified.</p> <p>Conclusions</p> <p>HBO₂ may possess potential therapeutic efficacy in the management of psoriasis. We outline the pathogenesis of psoriasis and the selective anti-inflammatory and immunosuppressive effects of HBO₂. We hope that this will provide a basis for elucidating the mechanisms of action and consequently pave the way for further controlled studies.</p

Data collection, handling and fitting strategies to optimize accuracy and precision of oxygen uptake kinetics estimation from breath-by-breath measurements.

Phase 2 pulmonary oxygen uptake kinetics (ϕ2 τVO2P) reflect muscle oxygen consumption dynamics and are sensitive to changes in state of training or health. This study identified an unbiased method for data collection, handling and fitting to optimize VO2P kinetics estimation. A validated computational model of VO2P kinetics and a Monte Carlo approach simulated 2 x 10(5) moderate intensity transitions using a distribution of metabolic and circulatory parameters spanning normal health. Effects of averaging (interpolation, binning, stacking or separate fitting of up to 10 transitions) and fitting procedures (bi-exponential fitting, or ϕ2 isolation by time removal, statistical or derivative methods followed by mono-exponential fitting) on accuracy and precision of ϕ2 τVO2P estimation were assessed. The optimal strategy to maximize accuracy and precision of τVO2P estimation was 1-s interpolation of 4 bouts, ensemble averaged, with the first 20 s of exercise data removed. Contradictory to previous advice, we found optimal fitting procedures removed no more than 20 s of ϕ1 data. Averaging method was less critical: interpolation, bin averaging and stacking gave similar results, each with greater accuracy compared to analyzing repeated bouts separately. The optimal procedure resulted in ϕ2 τVO2P estimates for transitions from an unloaded or loaded baseline that averaged 1.97±2.08 and 1.04±2.30 s from true, but were within 2 s of true in only 47-62% of simulations. Optimized 95% confidence intervals for τVO2P ranged from 4.08-4.51 s, suggesting a minimally important difference of ~5 s to determine significant changes in τVO2P during interventional and comparative studies

Linking microarray reporters with protein functions

<p>Abstract</p> <p>Background</p> <p>The analysis of microarray experiments requires accurate and up-to-date functional annotation of the microarray reporters to optimize the interpretation of the biological processes involved. Pathway visualization tools are used to connect gene expression data with existing biological pathways by using specific database identifiers that link reporters with elements in the pathways.</p> <p>Results</p> <p>This paper proposes a novel method that aims to improve microarray reporter annotation by BLASTing the original reporter sequences against a species-specific EMBL subset, that was derived from and crosslinked back to the highly curated UniProt database. The resulting alignments were filtered using high quality alignment criteria and further compared with the outcome of a more traditional approach, where reporter sequences were BLASTed against EnsEMBL followed by locating the corresponding protein (UniProt) entry for the high quality hits. Combining the results of both methods resulted in successful annotation of > 58% of all reporter sequences with UniProt IDs on two commercial array platforms, increasing the amount of Incyte reporters that could be coupled to Gene Ontology terms from 32.7% to 58.3% and to a local GenMAPP pathway from 9.6% to 16.7%. For Agilent, 35.3% of the total reporters are now linked towards GO nodes and 7.1% on local pathways.</p> <p>Conclusion</p> <p>Our methods increased the annotation quality of microarray reporter sequences and allowed us to visualize more reporters using pathway visualization tools. Even in cases where the original reporter annotation showed the correct description the new identifiers often allowed improved pathway and Gene Ontology linking. These methods are freely available at http://www.bigcat.unimaas.nl/public/publications/Gaj_Annotation/.</p

Treatment of gastrointestinal stromal tumours in paediatric and young adult patients with sunitinib: a multicentre case series

Background: Gastrointestinal stromal tumours (GIST) are rarely encountered mesenchymal tumours of the gastrointestinal tract (1.5 people per 100,000/year) that are even more rarely seen in paediatric patients (1-2% of all cases). The standard treatment for advanced adult GIST is imatinib with sunitinib as a second-line option. Although the efficacy and tolerability of sunitinib in adults with GIST has been established, little is known of the profile of sunitinib in paediatric/young adult patients with GIST given the rarity of this disease. Methods: Paediatric/young adult patients aged up to 21 years with diagnosis of GIST who were treated with sunitinib were identified from retrospective records from three centres in Europe and the US. Most patients commenced sunitinib in a 6-week cycle, however, dosing could be reduced, delayed, changed to (or initiated with) a continuous schedule. Objective response (Response Evaluation Criteria In Solid Tumours [RECIST]) and adverse events were recorded. Results: We identified 9 paediatric/young adult patients (aged 11-21 years) with GIST who were treated with sunitinib de novo (n = 1) or following failure of imatinib (n = 8). Progressive disease was previously documented for all patients including 7 patients during imatinib therapy. Baseline patient and tumour profile characteristics showed a distinct profile (notably all were wild-type KIT/PDGFR) compared to that established for adults. Sunitinib treatment was associated with a best response of stable disease for 7 patients, with disease stabilisation lasting from 1 month to > 73 months and a median progression free survival time of 15 months. There was some evidence of better disease control for sunitinib when compared to prior imatinib. Most adverse events with sunitinib were manageable and all were consistent with the known profile of the agent. Conclusion: The ability to draw firm conclusions from this case series is limited by the small number of patients and the use of retrospective data which is largely reflective of the rarity of this condition. However, our findings provide initial evidence of clinical benefit and a generally manageable toxicity profile for sunitinib when administered to paediatric/young adult patients with GIST, most of whom had documented progressive disease during prior imatinib treatment

Search for CP violation in D+→ϕπ+ and D+s→K0Sπ+ decays

A search for CP violation in D + → ϕπ + decays is performed using data collected in 2011 by the LHCb experiment corresponding to an integrated luminosity of 1.0 fb−1 at a centre of mass energy of 7 TeV. The CP -violating asymmetry is measured to be (−0.04 ± 0.14 ± 0.14)% for candidates with K − K + mass within 20 MeV/c 2 of the ϕ meson mass. A search for a CP -violating asymmetry that varies across the ϕ mass region of the D + → K − K + π + Dalitz plot is also performed, and no evidence for CP violation is found. In addition, the CP asymmetry in the D+s→K0Sπ+ decay is measured to be (0.61 ± 0.83 ± 0.14)%

Study of Bc+B_c^+ decays to the K+K−π+K^+K^-\pi^+ final state and evidence for the decay Bc+→χc0π+B_c^+\to\chi_{c0}\pi^+

A study of $B_c^+\to K^+K^-\pi^+$ decays is performed for the first time using data corresponding to an integrated luminosity of 3.0 $\mathrm{fb}^{-1}$ collected by the LHCb experiment in $pp$ collisions at centre-of-mass energies of $7$ and $8$ TeV. Evidence for the decay $B_c^+\to\chi_{c0}(\to K^+K^-)\pi^+$ is reported with a significance of 4.0 standard deviations, resulting in the measurement of $\frac{\sigma(B_c^+)}{\sigma(B^+)}\times\mathcal{B}(B_c^+\to\chi_{c0}\pi^+)$ to be $(9.8^{+3.4}_{-3.0}(\mathrm{stat})\pm 0.8(\mathrm{syst}))\times 10^{-6}$. Here $\mathcal{B}$ denotes a branching fraction while $\sigma(B_c^+)$ and $\sigma(B^+)$ are the production cross-sections for $B_c^+$ and $B^+$ mesons. An indication of $\bar b c$ weak annihilation is found for the region $m(K^-\pi^+)<1.834\mathrm{\,Ge\kern -0.1em V\!/}c^2$, with a significance of 2.4 standard deviations.Comment: All figures and tables, along with any supplementary material and additional information, are available at https://lhcbproject.web.cern.ch/lhcbproject/Publications/LHCbProjectPublic/LHCb-PAPER-2016-022.html, link to supplemental material inserted in the reference