MC3: a steady-state model and constraint consistency checker for biochemical networks

BACKGROUND: Stoichiometric models provide a structural framework for analyzing steady-state cellular behavior. Models are developed either through augmentations of existing models or more recently through automatic reconstruction tools. There is currently no standardized practice or method for validating the properties of a model before placing it in the public domain. Considerable effort is often required to understand a model’s inconsistencies before its reuse within new research efforts. RESULTS: We present a review of common issues in stoichiometric models typically uncovered during pathway analysis and constraint-based optimization, and we detail succinct and efficient ways to find them. We present MC(3), Model and Constraint Consistency Checker, a computational tool that can be used for two purposes: (a) identifying potential connectivity and topological issues for a given stoichiometric matrix, S, and (b) flagging issues that arise during constraint-based optimization. The MC(3) tool includes three distinct checking components. The first examines the results of computing the basis for the null space for Sv = 0; the second uses connectivity analysis; and the third utilizes Flux Variability Analysis. MC(3) takes as input a stoichiometric matrix and flux constraints, and generates a report summarizing issues. CONCLUSIONS: We report the results of applying MC(3) to published models for several systems including Escherichia coli, an adipocyte cell, a Chinese Hamster Ovary cell, and Leishmania major. Several issues with no prior documentation are identified. MC(3) provides a standalone MATLAB-based comprehensive tool for model validation, a task currently performed either ad hoc or implemented in part within other computational tools

'We’re just gonna scribble it': The affective and social work of destruction in children’s art-making with different semiotic resources

In this paper I explore children’s destruction of their artwork as it occurs on paper or digitally via the interactive whiteboard (IWB). Social semiotics offers a theoretical lens for understanding children’s acts of destruction as meaningful and how different semiotic resources shape the meaning-making involved in destruction differently. To explore this further, I consider two episodes of art-making: firstly, an episode of child-parent art-making that ended in the five year old child scribbling over a drawing on paper with a black crayon, and secondly, an episode of a five year old child using touch to cover over the drawing she had made on the classroom IWB during free-flow activity time. A comparison between these two episodes is used to explore how digital and paper-based semiotic resources may impact differently on the experience of destruction and the affective and relational work that it can achieve

Do people favour policies that protect future generations? Evidence from a British survey of adults

Long-range temporal choices are built into contemporary policy-making, with policy decisions having consequences that play out across generations. Decisions are made on behalf of the public who are assumed to give much greater weight to their welfare than to the welfare of future generations. The paper investigates this assumption. It briefly discusses evidence from sociological and economic studies before reporting the findings of a British survey of people's intergenerational time preferences based on a representative sample of nearly 10,000 respondents. Questions focused on two sets of policies: (i) health policies to save lives and (ii) environmental policies to protect against floods that would severely damage homes, businesses and other infrastructure. For both sets of policies, participants were offered a choice of three policy options, each bringing greater or lesser benefits to their, their children's and their grandchildren's generations. For both saving lives and protecting against floods, only a minority selected the policy that most benefited their generation; the majority selected policies bringing equal or greater benefits to future generations. Our study raises questions about a core assumption of standard economic evaluation, pointing instead to concern for future generations as a value that many people hold in common

Tramadol versus low dose tramadol-paracetamol for patient controlled analgesia during spinal vertebral surgery

Pain intensity may be high in the postoperative period after spinal vertebral surgery. The aim of the study was to compare the effectiveness and cost of patient controlled analgesia (PCA) with tramadol versus low dose tramadol-paracetamol on postoperative pain. A total of 60 patients were randomly divided into two groups. One group received 1.5 mg/kg tramadol (Group T) while the other group received 0.75 mg/kg tramadol plus 1 g of paracetamol (Group P) intravenously via a PCA device immediately after surgery and the patients were transferred to a recovery room, Tramadol was continuously infused at a rate of 0.5 mL/h in both groups, at a dose of 10mg/mL in Group T and 5mg/mL in Group P. The bolus and infusion programs were adjusted to administer a 1mL bolus dose of tramadol with a lock time of 10 minutes. In Group P, 1 g of paracetamol was injected intravenously every 6 hours. The four-point nausea scale, numeric rating scale for pain assessment, Ramsey sedation scale, blood pressure, heart rate, respiration rate, peripheral oxygen saturation values and side effects were recorded at 0, 15 and 30 minutes, and at 1, 2, 4, 6, 12, 18 and 24 hours. The time to reach an Aldrete score of 9 was also recorded. A cost analysis for both groups was performed. In Group P, the numeric rating scale scores were significantly lower than that in Group T at 0 and 15 minutes. The number of side effects, additional analgesic requirement and the total dose of tramadol were lower in Group P than in Group T. However, the total cost of postoperative analgesics was significantly higher in Group P than in Group T (p < 0.001). We conclude that PCA using tramadol-paracetamol could be used safely for postoperative pain relief after spinal vertebral surgery, although at a higher cost than with tramadol alone. © 2010 Elsevier. All rights reserved

Power estimation for non-standardized multisite studies

AbstractA concern for researchers planning multisite studies is that scanner and T1-weighted sequence-related biases on regional volumes could overshadow true effects, especially for studies with a heterogeneous set of scanners and sequences. Current approaches attempt to harmonize data by standardizing hardware, pulse sequences, and protocols, or by calibrating across sites using phantom-based corrections to ensure the same raw image intensities. We propose to avoid harmonization and phantom-based correction entirely. We hypothesized that the bias of estimated regional volumes is scaled between sites due to the contrast and gradient distortion differences between scanners and sequences. Given this assumption, we provide a new statistical framework and derive a power equation to define inclusion criteria for a set of sites based on the variability of their scaling factors. We estimated the scaling factors of 20 scanners with heterogeneous hardware and sequence parameters by scanning a single set of 12 subjects at sites across the United States and Europe. Regional volumes and their scaling factors were estimated for each site using Freesurfer's segmentation algorithm and ordinary least squares, respectively. The scaling factors were validated by comparing the theoretical and simulated power curves, performing a leave-one-out calibration of regional volumes, and evaluating the absolute agreement of all regional volumes between sites before and after calibration. Using our derived power equation, we were able to define the conditions under which harmonization is not necessary to achieve 80% power. This approach can inform choice of processing pipelines and outcome metrics for multisite studies based on scaling factor variability across sites, enabling collaboration between clinical and research institutions

Polymorphisms of the XRCC1, XRCC3 and XPD genes and risk of colorectal adenoma and carcinoma, in a Norwegian cohort: a case control study

BACKGROUND: Genetic polymorphisms in DNA repair genes may influence individual variation in DNA repair capacity, which may be associated with risk of developing cancer. For colorectal cancer the importance of mutations in mismatch repair genes has been extensively documented. Less is known about other DNA repair pathways in colorectal carcinogenesis. In this study we have focused on the XRCC1, XRCC3 and XPD genes, involved in base excision repair, homologous recombinational repair and nucleotide excision repair, respectively. METHODS: We used a case-control study design (157 carcinomas, 983 adenomas and 399 controls) to test the association between five polymorphisms in these DNA repair genes (XRCC1 Arg(194)Trp, Arg(280)His, Arg(399)Gln, XRCC3 Thr(241)Met and XPD Lys(751)Gln), and risk of colorectal adenomas and carcinomas in a Norwegian cohort. Odds ratio (OR) and 95% confidence interval (95% CI) were estimated by binary logistic regression model adjusting for age, gender, cigarette smoking and alcohol consumption. RESULTS: The XRCC1 280His allele was associated with an increased risk of adenomas (OR 2.30, 95% CI 1.19–4.46). The XRCC1 399Gln allele was associated with a reduction of risk of high-risk adenomas (OR 0.62, 95% CI 0.41–0.96). Carriers of the variant XPD 751Gln allele had an increased risk of low-risk adenomas (OR 1.40, 95% CI 1.03–1.89), while no association was found with risk of carcinomas. CONCLUSION: Our results suggest an increased risk for advanced colorectal neoplasia in individuals with the XRCC1 Arg(280)His polymorphism and a reduced risk associated with the XRCC1 Arg(399)Gln polymorphism. Interestingly, individuals with the XPD Lys(751)Gln polymorphism had an increased risk of low-risk adenomas. This may suggest a role in regression of adenomas

Environmental Barcoding Reveals Massive Dinoflagellate Diversity in Marine Environments

Rowena F. Stern is with University of British Columbia, Ales Horak is with University of British Columbia, Rose L. Andrew is with University of British Columbia, Mary-Alice Coffroth is with State University of New York at Buffalo, Robert A. Andersen is with the Bigelow Laboratory for Ocean Sciences, Frithjof C. Küpper is with the Scottish Marine Institute, Ian Jameson is with CSIRO Marine and Atmospheric Research, Mona Hoppenrath is with the German Center for Marine Biodiversity Research, Benoît Véron is with University of Caen Lower Normandy and the National Institute for Environmental Studies, Fumai Kasai is with the National Institute for Environmental Studies, Jerry Brand is with UT Austin, Erick R. James is with University of British Columbia, Patrick J. Keeling is with University of British Columbia.Background -- Dinoflagellates are an ecologically important group of protists with important functions as primary producers, coral symbionts and in toxic red tides. Although widely studied, the natural diversity of dinoflagellates is not well known. DNA barcoding has been utilized successfully for many protist groups. We used this approach to systematically sample known “species”, as a reference to measure the natural diversity in three marine environments. Methodology/Principal Findings -- In this study, we assembled a large cytochrome c oxidase 1 (COI) barcode database from 8 public algal culture collections plus 3 private collections worldwide resulting in 336 individual barcodes linked to specific cultures. We demonstrate that COI can identify to the species level in 15 dinoflagellate genera, generally in agreement with existing species names. Exceptions were found in species belonging to genera that were generally already known to be taxonomically challenging, such as Alexandrium or Symbiodinium. Using this barcode database as a baseline for cultured dinoflagellate diversity, we investigated the natural diversity in three diverse marine environments (Northeast Pacific, Northwest Atlantic, and Caribbean), including an evaluation of single-cell barcoding to identify uncultivated groups. From all three environments, the great majority of barcodes were not represented by any known cultured dinoflagellate, and we also observed an explosion in the diversity of genera that previously contained a modest number of known species, belonging to Kareniaceae. In total, 91.5% of non-identical environmental barcodes represent distinct species, but only 51 out of 603 unique environmental barcodes could be linked to cultured species using a conservative cut-off based on distances between cultured species. Conclusions/Significance -- COI barcoding was successful in identifying species from 70% of cultured genera. When applied to environmental samples, it revealed a massive amount of natural diversity in dinoflagellates. This highlights the extent to which we underestimate microbial diversity in the environment.This project was funded by Genome Canada and the Canadian Barcode of Life Network. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Biological Sciences, School o

Household quarantine of second degree contacts is an effective non-pharmaceutical intervention to prevent tertiary cases in the current SARS-CoV pandemic

Background!#!Given the characteristics of SARS-CoV2 with regard to transmission before the onset of symptoms and varying manifestation indices according to age, isolation and quarantine have limited efficacy in the current pandemic. Household quarantine in second degree contacts (Hh-Q2°) outside the case household has so far only been addressed by modellers. In the literature there is no publication based on field data.!##!Methods!#!In a retrospective cohort study on real field data from a county health department (CHD), all PCR-confirmed cases and related contact persons put into quarantine were analysed. Hh-Q2° was used in our CHD from the onset of the pandemic.!##!Results!#!From 9 March to 8 December 2020, 353 PCR-confirmed cases were registered in the CHD Ploen, Northern Germany: 225 (63.7%) primary, 107 (30.3%) secondary and 21 (5.9%) tertiary cases. The 107 secondary cases resulted out of 470 (22.8%) close or 1°contacts and 21 tertiary cases out of 179 (11.7%) indirect or 2°contacts put into quarantine. The efficacy of Hh-Q2° was 51.5% (11.7%/22.8%) of that of quarantine in 1°contacts; 16.4% of all converted cases in quarantined persons were ascertained by Hh-Q2°. One in ten 1°contacts in households with tertiary cases remained asymptomatic.!##!Conclusion!#!The impact of Hh-Q2° in preventing further spread of SARS-CoV2 was considerable. With half the conversion rate in 2°contacts compared to 1°contacts, the efficacy of Hh-Q2° is substantial. Hh-Q2° should definitely be used routinely to control the spread of SARS-CoV2 more efficiently and national authorities should include it in their guidelines