Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 286
Filter
Add more filters

Publication year range
1.
Phys Rev Lett ; 130(6): 062501, 2023 Feb 10.
Article in English | MEDLINE | ID: mdl-36827565

ABSTRACT

The Majorana Demonstrator searched for neutrinoless double-ß decay (0νßß) of ^{76}Ge using modular arrays of high-purity Ge detectors operated in vacuum cryostats in a low-background shield. The arrays operated with up to 40.4 kg of detectors (27.2 kg enriched to ∼88% in ^{76}Ge). From these measurements, the Demonstrator has accumulated 64.5 kg yr of enriched active exposure. With a world-leading energy resolution of 2.52 keV FWHM at the 2039 keV Q_{ßß} (0.12%), we set a half-life limit of 0νßß in ^{76}Ge at T_{1/2}>8.3×10^{25} yr (90% C.L.). This provides a range of upper limits on m_{ßß} of (113-269) meV (90% C.L.), depending on the choice of nuclear matrix elements.

2.
BMC Med Imaging ; 20(1): 8, 2020 01 28.
Article in English | MEDLINE | ID: mdl-31992224

ABSTRACT

BACKGROUND: The accuracy of 2D and 3D strain analyses was evaluated by comparing strain and cardiac function parameters in Fontan repair patients and normal child volunteers. METHODS: We retrospectively enrolled 32 patients with Fontan circulation and 32 child volunteers who had undergone clinical cardiac magnetic resonance (CMR) assessment of the dominant ventricle with a 1.5-Tesla MRI scanner. Global and regional strain (2D and 3D) of the dominant ventricle in both groups was assessed using CMR feature-tracking. Correlations between cardiac function and strain data were assessed using Pearson's correlation coefficient values. The intraclass correlation coefficient (ICC) and coefficient of variation (CoV) were determined to evaluate repeatability and agreement. RESULTS: The 2D GLS showed significant differences between the Fontan repair patients and volunteers (- 16.49 ± 5.00 vs. -19.49 ± 2.03; p = 0.002). The 2D GRS and 2D GCS showed no significant differences between two groups. 2D GRS: 38.96 ± 14.48 vs. 37.46 ± 7.77; 2D GCS: - 17.64 ± 5.00 vs. -16.89 ± 2.96, respectively; p > 0.05). The 3D global radial strain (GRS), global circumferential strain (GCS), and global longitudinal strain (GLS) showed significant differences between the Fontan repair patients and volunteers (3D GRS: 36.35 ± 16.72 vs. 44.96 ± 9.98; 3D GLS: - 8.86 ± 6.84 vs. -13.67 ± 2.44; 3D GCS: - 13.70 ± 7.84 vs. -18.01 ± 1.78; p < 0.05, respectively). The ejection fraction (EF) and 3D GCS were significantly associated (r = - 0.491, p = 0.004). The 3D GCS showed correlations with the indexed end-diastolic volume (EDV) (r = 0.523, p = 0.002) and indexed end-systolic volume (ESV) (r = 0.602, p < 0.001). 3D strain showed good reproducibility, with GCS showing the best inter-observer agreement (ICC = 0.87 and CoV = 5.15), followed by GLS (ICC = 0.84 and CoV = 5.36). CONCLUSIONS: 3D GCS is feasible, highly reproducible, and strongly correlated with conventional cardiac function measures. 3D GCS assessments may be useful for monitoring abnormal myocardial motion in patients with Fontan circulation.


Subject(s)
Heart Diseases/surgery , Heart/diagnostic imaging , Magnetic Resonance Imaging, Cine/methods , Adolescent , Child , Echocardiography, Three-Dimensional , Feasibility Studies , Female , Fontan Procedure , Heart/physiopathology , Heart Diseases/diagnostic imaging , Humans , Male , Retrospective Studies , Stroke Volume
3.
Phys Rev Lett ; 120(13): 132502, 2018 Mar 30.
Article in English | MEDLINE | ID: mdl-29694188

ABSTRACT

The Majorana Collaboration is operating an array of high purity Ge detectors to search for neutrinoless double-ß decay in ^{76}Ge. The Majorana Demonstrator comprises 44.1 kg of Ge detectors (29.7 kg enriched in ^{76}Ge) split between two modules contained in a low background shield at the Sanford Underground Research Facility in Lead, South Dakota. Here we present results from data taken during construction, commissioning, and the start of full operations. We achieve unprecedented energy resolution of 2.5 keV FWHM at Q_{ßß} and a very low background with no observed candidate events in 9.95 kg yr of enriched Ge exposure, resulting in a lower limit on the half-life of 1.9×10^{25} yr (90% C.L.). This result constrains the effective Majorana neutrino mass to below 240-520 meV, depending on the matrix elements used. In our experimental configuration with the lowest background, the background is 4.0_{-2.5}^{+3.1} counts/(FWHM t yr).

4.
Ecol Appl ; 27(8): 2369-2381, 2017 12.
Article in English | MEDLINE | ID: mdl-28851094

ABSTRACT

Management guidelines for many fire-prone ecosystems highlight the importance of maintaining a variable mosaic of fire histories for biodiversity conservation. Managers are encouraged to aim for fire mosaics that are temporally and spatially dynamic, include all successional states of vegetation, and also include variation in the underlying "invisible mosaic" of past fire frequencies, severities, and fire return intervals. However, establishing and maintaining variable mosaics in contemporary landscapes is subject to many challenges, one of which is deciding how the fire mosaic should be managed following the occurrence of large, unplanned wildfires. A key consideration for this decision is the extent to which the effects of previous fire history on vegetation and habitats persist after major wildfires, but this topic has rarely been investigated empirically. In this study, we tested to what extent a large wildfire interacted with previous fire history to affect the structure of forest, woodland, and heath vegetation in Booderee National Park in southeastern Australia. In 2003, a summer wildfire burned 49.5% of the park, increasing the extent of recently burned vegetation (<10 yr post-fire) to more than 72% of the park area. We tracked the recovery of vegetation structure for nine years following the wildfire and found that the strength and persistence of fire effects differed substantially between vegetation types. Vegetation structure was modified by wildfire in forest, woodland, and heath vegetation, but among-site variability in vegetation structure was reduced only by severe fire in woodland vegetation. There also were persistent legacy effects of the previous fire regime on some attributes of vegetation structure including forest ground and understorey cover, and woodland midstorey and overstorey cover. For example, woodland midstorey cover was greater on sites with higher fire frequency, irrespective of the severity of the 2003 wildfire. Our results show that even after a large, severe wildfire, underlying fire histories can contribute substantially to variation in vegetation structure. This highlights the importance of ensuring that efforts to reinstate variation in vegetation fire age after large wildfires do not inadvertently reduce variation in vegetation structure generated by the underlying invisible mosaic.


Subject(s)
Biodiversity , Conservation of Natural Resources , Forests , Wildfires , Australian Capital Territory , Ecosystem , New South Wales
6.
Neuroophthalmology ; 40(1): 1-7, 2016 Feb.
Article in English | MEDLINE | ID: mdl-27928375

ABSTRACT

The authors report the screening process and recruitment figures for the VISION (Visual Impairment in Stroke; Intervention Or Not) trial. This is a prospective, randomised, single-blinded, three-arm controlled trial in 14 UK acute hospital stroke units. Stroke teams identified stroke survivors suspected as having homonymous hemianopia. Interventions included Fresnel prisms versus visual search training versus standard care (information only). Primary outcome was change in visual field assessment from baseline to 26 weeks. Secondary measures included change in quality-of-life questionnaires. Recruitment opened in May 2011. A total of 1171 patients were screened by the local principal investigators. Of 1171 patients, 178 (15.2%) were eligible for recruitment: 87 patients (7.4%) provided consent and were recruited; 91 patients (7.8%) did not provide consent, and 993 of 1171 patients (84.8%) failed to meet the eligibility criteria. Almost half were excluded due to complete/partial recovery of hemianopia (43.6%; n = 511). The most common ineligibility reason was recovery of hemianopia. When designing future trials in this area, changes in eligibility criteria/outcome selection to allow more patients to be recruited should be considered, e.g., less stringent levels of visual acuity/refractive error. Alternative outcomes measurable in the home environment, rather than requiring hospital attendance for follow-up, could facilitate increased recruitment.

7.
Oecologia ; 179(1): 237-48, 2015 Sep.
Article in English | MEDLINE | ID: mdl-25935217

ABSTRACT

Altered disturbance regimes are a major driver of biodiversity loss worldwide. Maintaining or re-creating natural disturbance regimes is therefore the focus of many conservation programmes. A key challenge, however, is to understand how co-occurring disturbances interact to affect biodiversity. We experimentally tested for the interactive effects of prescribed fire and large macropod herbivores on the web-building spider assemblage of a eucalypt forest understorey and investigated the role of vegetation in mediating these effects using path analysis. Fire had strong negative effects on the density of web-building spiders, which were partly mediated by effects on vegetation structure, while negative effects of large herbivores on web density were not related to changes in vegetation. Fire amplified the effects of large herbivores on spiders, both via vegetation-mediated pathways and by increasing herbivore activity. The importance of vegetation-mediated pathways and fire-herbivore interactions differed for web density and richness and also differed between web types. Our results demonstrate that for some groups of web-building spiders, the effects of co-occurring disturbance drivers may be mostly additive, whereas for other groups, interactions between drivers can amplify disturbance effects. In our study system, the use of prescribed fire in the presence of high densities of herbivores could lead to reduced densities and altered composition of web-building spiders, with potential cascading effects through the arthropod food web. Our study highlights the importance of considering both the independent and interactive effects of disturbances, as well as the mechanisms driving their effects, in the management of disturbance regimes.


Subject(s)
Conservation of Natural Resources/methods , Ecosystem , Environmental Monitoring/methods , Fires , Herbivory/physiology , Spiders/growth & development , Animals , Australia , Biodiversity , Eucalyptus/growth & development , Food Chain
8.
J Environ Qual ; 44(4): 1210-5, 2015 Jul.
Article in English | MEDLINE | ID: mdl-26437102

ABSTRACT

Carbon dioxide off-setting policy in the agricultural sector is focused on manipulating the terrestrial carbon cycle by reafforestation and increasing the retention of carbon within agricultural soils. We quantified the amount of carbon stored in the living and dead biomass and the surface soils of a previously grazed woodland ecosystem. We demonstrate that modification of coarse woody debris management could potentially store 8 to 15 t C ha. This large carbon pool raises the prospect that appropriate management of temperate woodlands to retain coarse woody debris and increase its volume into the future could achieve increased landscape carbon storage.

9.
J Occup Rehabil ; 25(3): 577-88, 2015 Sep.
Article in English | MEDLINE | ID: mdl-25595331

ABSTRACT

PURPOSE: Back pain is a common problem and has significant societal impact. Sickness certification is commonly issued to patients consulting their general practitioner with low back pain. The aim of this study was to investigate the association of certification for low back pain with clinical outcomes and cost consequences. METHODS: A prospective cohort study using linked questionnaire and medical record data from 806 low back pain patients in 8 UK general practices: comparison of 116 (14.4%) who received a sickness certificate versus 690 who did not receive certification. The primary clinical measure was the Roland and Morris Disability Questionnaire (RMDQ). Data on back pain consultation and work absenteeism were used to calculate healthcare and societal costs. RESULTS: Participants issued a sickness certificate had higher back-related disability at baseline consultation and 6-month follow-up [mean difference 3.1 (95% CI 1.8, 4.4) on the RMDQ], indicating worse health status. After fully adjusting for baseline differences, most changes in clinical outcomes at 6 months were not significantly different between study groups. Productivity losses were significantly higher for the certification group, with most absence occurring after the expected end of certification; mean difference in costs due to absenteeism over 6 months was £1,956 (95% CI £941, £3040). CONCLUSIONS: There was no clear evidence of a difference in clinical outcomes between individuals issued a sickness certificate and those not issued a certification for their back pain. With little overall contrast in clinical outcomes, policy makers and care providers may wish to draw on the likely difference in societal costs alongside issues in ethical and moral care in their consideration of patient care for low back pain.


Subject(s)
Low Back Pain/diagnosis , Physicians, Primary Care , Work Capacity Evaluation , Adult , Female , Humans , Male , Primary Health Care , Prospective Studies , Sick Leave/statistics & numerical data , United Kingdom/epidemiology
10.
Br J Cancer ; 110(12): 2837-46, 2014 Jun 10.
Article in English | MEDLINE | ID: mdl-24867697

ABSTRACT

BACKGROUND: The purpose of this study was to determine the accuracy of sentinel lymph node (SLN) biopsy with technetium 99 (99mTc) and/or blue dye-enhanced lymphoscintigraphy in vulval cancer. METHODS: Sensitive searches of databases were performed upto October 2013. Studies with at least 75% of women with FIGO stage IB or II vulval cancer evaluating SLN biopsy with 99mTc, blue dye or both with reference standard of inguinofemoral lymphadenectomy (IFL) or clinical follow-up were included. Meta-analyses were performed using Meta-Disc version 1.4. RESULTS: Of the 2950 references, 29 studies (1779 women) were included; most of them evaluated 99mTc combined with blue dye. Of these, 24 studies reported results for SLN followed by IFL, and 5 reported clinical follow-up only for SLN negatives. Pooling of all studies was inappropriate because of heterogeneity. Mean SLN detection rates were 94.0% for 99mTc, 68.7% for blue dye and 97.7% for both. SLN biopsy had pooled sensitivity of 95% (95% CI 92-98%) with negative predictive value (NPV) of 97.9% in studies using 99mTc/blue dye, ultrastaging and immunohistochemistry with IFL as reference. Pooled sensitivity for SLN with clinical follow-up for SLN-negatives was 91% (85-95%) with NPV 95.6%. Patients undergoing SLN biopsy experienced less morbidity than those undergoing IFL. CONCLUSIONS: Sentinel lymph node biopsy using 99mTC, blue dye and ultrastaging with immunohistochemistry is highly accurate when restricted to carefully selected patients, within a rigorous protocol, with close follow-up and where sufficient numbers for learning curve optimisation exist. Patients must make an informed choice between the slightly higher groin recurrence rates of SLN biopsy vs the greater morbidity of IFL.


Subject(s)
Lymph Nodes/pathology , Sentinel Lymph Node Biopsy , Vulvar Neoplasms/pathology , Coloring Agents , Early Detection of Cancer , Female , Humans , Immunohistochemistry , Lymph Nodes/diagnostic imaging , Lymph Nodes/surgery , Lymphatic Metastasis , Lymphoscintigraphy , Neoplasm Recurrence, Local , Radiopharmaceuticals , Staining and Labeling , Technetium , Vulvar Neoplasms/diagnostic imaging
11.
Conserv Biol ; 28(6): 1594-603, 2014 Dec.
Article in English | MEDLINE | ID: mdl-25048948

ABSTRACT

Biodiversity surrogates and indicators are commonly used in conservation management. The focal species approach (FSA) is one method for identifying biodiversity surrogates, and it is underpinned by the hypothesis that management aimed at a particular focal species will confer protection on co-occurring species. This concept has been the subject of much debate, in part because the validity of the FSA has not been subject to detailed empirical assessment of the extent to which a given focal species actually co-occurs with other species in an assemblage. To address this knowledge gap, we used large-scale, long-term data sets of temperate woodland birds to select focal species associated with threatening processes such as habitat isolation and loss of key vegetation attributes. We quantified co-occurrence patterns among focal species, species in the wider bird assemblage, and species of conservation concern. Some, but not all, focal species were associated with high levels of species richness. One of our selected focal species was negatively associated with the occurrence of other species (i.e., it was an antisurrogate)-a previously undescribed property of nominated focal species. Furthermore, combinations of focal species were not associated with substantially elevated levels of bird species richness, relative to levels associated with individual species. Our results suggest that although there is some merit to the underpinning concept of the FSA, there is also a need to ensure that actions are sufficiently flexible because management tightly focused on a given focal species may not benefit some other species, including species of conservation concern, such of which might not occur in species-rich assemblages.


Subject(s)
Animal Distribution , Biodiversity , Birds/physiology , Conservation of Natural Resources/methods , Forests , Animals , New South Wales
12.
BJOG ; 121(4): 464-76, 2014 Mar.
Article in English | MEDLINE | ID: mdl-24299112

ABSTRACT

OBJECTIVE: To undertake a cost-effectiveness analysis that compares positron emission tomography - computed tomography (PET-CT) imaging plus standard practice with standard practice alone in the diagnosis of recurrent or persistent cervical cancer during routine surveillance and follow-up of women who have previously been diagnosed and treated. DESIGN: Model-based economic evaluation using data from a systematic review, supplemented with data from other sources, and taking a UK National Health Service (NHS) perspective. SETTING: Secondary Care in England. POPULATION: Women at least 3 months after the completion of treatment, with either recurrent or persistent cervical cancer. METHODS: A state transition (Markov) model was developed using TreeAge Pro 2011. The structure of the model was informed by the reviews of the trials and clinical input. In the model, two diagnostic strategies were examined. A one-way sensitivity analysis, probabilistic sensitivity analysis, and a value of information analysis were also carried out. MAIN OUTCOME MEASURES: Cost-effectiveness based on incremental cost per quality-adjusted life year (QALY). RESULTS: Adding PET-CT to the current treatment strategy of clinical examination and scanning [magnetic resonance imaging (MRI) and/or CT scan] during the routine surveillance and follow-up of women with recurrent or persistent cervical cancer is significantly more costly, with only a minimal increase in effectiveness. The incremental cost-effectiveness ratio (ICER) for the strategy of PET-CT as an adjunct to the standard treatment strategy that included clinical examination, MRI, and/or CT scan, compared with the usual treatment alone, was over £1 million per QALY. CONCLUSION: The results of the current analysis suggest that use of PET-CT in the diagnosis of recurrent or persistent cervical cancer is not cost-effective. Current guidelines recommending imaging using PET-CT as a diagnostic or surveillance tool need to be reconsidered in light of these results. This study did not specifically investigate the use of PET-CT in women with symptoms and radiological suspicion of recurrence where exenteration was considered. More research in that specific area is required.


Subject(s)
Neoplasm Recurrence, Local/diagnosis , Positron-Emission Tomography/economics , Tomography, X-Ray Computed/economics , Uterine Cervical Neoplasms/diagnosis , Chemoradiotherapy, Adjuvant , Cost-Benefit Analysis , Decision Support Techniques , Female , Humans , Hysterectomy , Magnetic Resonance Imaging/economics , Markov Chains , Models, Economic , Neoplasm Recurrence, Local/economics , Neoplasm Recurrence, Local/mortality , Quality-Adjusted Life Years , State Medicine/economics , Survival Rate , United Kingdom , Uterine Cervical Neoplasms/economics , Uterine Cervical Neoplasms/mortality , Uterine Cervical Neoplasms/therapy
13.
BJOG ; 121(4): 398-407, 2014 Mar.
Article in English | MEDLINE | ID: mdl-24299154

ABSTRACT

BACKGROUND: Positron emission tomography-computed tomography (PET-CT) is recommended to triage women for exenterative surgery and surveillance after treatment for advanced cervical cancer. OBJECTIVE: To evaluate diagnostic accuracy of additional whole body PET-CT compared with CT/magnetic resonance imaging (MRI) alone in women with suspected recurrent/persistent cervical cancer and in asymptomatic women as surveillance. DESIGN: Systematic reviews. Subjective elicitation to supplement diagnostic information. SEARCH STRATEGY/SELECTION CRITERIA/DATA COLLECTION AND ANALYSIS: Searches of electronic databases were performed to June 2013. Studies in women with suspected recurrent/persistent cervical cancer and in asymptomatic women undergoing follow up with sufficient numeric data were included. We calculated sensitivity, specificity and corresponding 95% confidence intervals. Meta-analyses employed a bivariate model that included a random-effects term for between-study variations (CT studies) and univariate random effects meta-analyses (PET-CT studies) for sensitivity and specificity separately. SUBJECTIVE ELICITATION: Prevalence of recurrence and the accuracy of imaging elicited using the allocation of points technique. Coherence of elicited subjective probabilities with estimates in the literature examined. RESULTS: We identified 15 relevant studies; none directly compared additional PET-CT with MRI or CT separately. Most CT and MRI studies used older protocols and the majority did not distinguish between asymptomatic and symptomatic women. Meta-analysis of nine PET-CT studies in mostly symptomatic women showed sensitivity of 94.8 (95% CI 91.2-96.9), and specificity of 86.9% (95% CI 82.2-90.5). The summary estimate of the sensitivity of CT for detection of recurrence was 89.64% (95% CI 81.59-94.41) and specificity was 76% (95% CI 43.68-92.82). Meta-analysis for MRI test accuracy studies was not possible because of clinical heterogeneity. The sensitivity and specificity of MRI in pelvic recurrence varied between 82 and 100% and between 78 and 100%, respectively. Formal statistical comparisons of the accuracy of index tests were not possible. Subjective elicitation provided estimates comparable to the literature. Subjective estimates of the increase in accuracy from the addition of PET-CT were less than elicited increases required to justify the use in PET-CT for surveillance. CONCLUSION: Evidence to support additional PET-CT is scarce, of average quality and does not distinguish between application for surveillance and diagnosis. Guidelines recommending PET-CT in recurrent cervical cancer need to be reconsidered in the light of the existing evidence base.


Subject(s)
Neoplasm Recurrence, Local/diagnostic imaging , Positron-Emission Tomography/methods , Tomography, X-Ray Computed/methods , Uterine Cervical Neoplasms/diagnostic imaging , Female , Humans , Magnetic Resonance Imaging , Models, Statistical , Sensitivity and Specificity
14.
ScientificWorldJournal ; 2014: 805856, 2014.
Article in English | MEDLINE | ID: mdl-25136688

ABSTRACT

The growth of the internet and networked systems has exposed software to an increased amount of security threats. One of the responses from software developers to these threats is the introduction of security activities in the software development lifecycle. This paper describes an approach to reduce the need for costly human expertise to perform risk analysis in software, which is common in secure development methodologies, by automating threat modeling. Reducing the dependency on security experts aims at reducing the cost of secure development by allowing non-security-aware developers to apply secure development with little to no additional cost, making secure development more accessible. To automate threat modeling two data structures are introduced, identification trees and mitigation trees, to identify threats in software designs and advise mitigation techniques, while taking into account specification requirements and cost concerns. These are the components of our model for automated threat modeling, AutSEC. We validated AutSEC by implementing it in a tool based on data flow diagrams, from the Microsoft security development methodology, and applying it to VOMS, a grid middleware component, to evaluate our model's performance.


Subject(s)
Computer Security , Models, Theoretical , Risk Assessment , Software Design
15.
Br J Cancer ; 109(10): 2533-47, 2013 Nov 12.
Article in English | MEDLINE | ID: mdl-24129233

ABSTRACT

BACKGROUND: This study examines the cost-effectiveness of sentinel lymph node biopsy, a potentially less morbid procedure, compared with inguinofemoral lymphadenectomy (IFL) among women with stage I and stage II vulval squamous cell carcinoma. METHODS: A model-based economic evaluation was undertaken based on clinical evidence from a systematic review of published sources. A decision tree model was developed with the structure being informed by clinical input, taking the perspective of the health-care provider. RESULTS: For overall survival for 2 years, IFL was found to be the most cost-effective option and dominated all other strategies, being the least costly and most effective. For morbidity-free related outcomes for 2 years, sentinel lymph node (SLN) biopsy with 99mTc and blue dye and haematoxylin & eosin (H&E) histopathology, with ultrastaging and immunohistochemistry reserved for those that test negative following H&E is likely to be the most effective approach. CONCLUSION: SLN biopsy using 99mTc and blue dye with ultrastaging may be considered the most cost-effective strategy based on the outcome of survival free of morbidity for 2 years. The findings here also indicate that using blue dye and H&E for the identification of the SLN and the identification of metastasis, respectively, are not sensitive enough to be used on their own.


Subject(s)
Carcinoma, Squamous Cell/pathology , Lymph Node Excision/economics , Sentinel Lymph Node Biopsy/economics , Vulvar Neoplasms/pathology , Carcinoma, Squamous Cell/mortality , Cost-Benefit Analysis , Female , Health Care Costs , Humans , Inguinal Canal , Lymph Nodes/pathology , Lymphatic Metastasis , Vulvar Neoplasms/mortality
16.
Biotechnol Bioeng ; 110(3): 792-802, 2013 Mar.
Article in English | MEDLINE | ID: mdl-23055276

ABSTRACT

Dynamic flux balance analysis (DFBA) provides a platform for detailed design, control and optimization of biochemical process technologies. It is a promising modeling framework that combines genome-scale metabolic network analysis with dynamic simulation of the extracellular environment. Dynamic flux balance analysis assumes that the intracellular species concentrations are in equilibrium with the extracellular environment. The resulting underdetermined stoichiometric model is solved under the assumption of a biochemical objective such as growth rate maximization. The model of the metabolism is coupled with the dynamic mass balance equations of the extracellular environment via expressions for the rates of substrate uptake and product excretion, which imposes additional constraints on the linear program (LP) defined by growth rate maximization of the metabolism. The linear program is embedded into the dynamic model of the bioreactor, and together with the additional constraints this provides an accurate model of the substrate consumption, product secretion, and biomass production during operation. A DFBA model consists of a system of ordinary differential equations for which the evaluation of the right-hand side requires not only function evaluations, but also the solution of one or more linear programs. The numerical tool presented here accurately and efficiently simulates large-scale dynamic flux balance models. The main advantages that this approach has over existing implementation are that the integration scheme has a variable step size, that the linear program only has to be solved when qualitative changes in the optimal flux distribution of the metabolic network occur, and that it can reliably simulate behavior near the boundary of the domain where the model is defined. This is illustrated through large-scale examples taken from the literature.


Subject(s)
Biotechnology/methods , Computer Simulation , Metabolic Networks and Pathways , Systems Biology/methods , Biomass , Bioreactors
17.
Proc Natl Acad Sci U S A ; 107(34): 15016-21, 2010 Aug 24.
Article in English | MEDLINE | ID: mdl-20696921

ABSTRACT

Plants produce a variety of proteinase inhibitors (PIs) that have a major function in defense against insect herbivores. In turn, insects have developed strategies to minimize the effect of dietary PIs on digestion. We have discovered that Helicoverpa larvae that survive consumption of a multidomain serine PI from Nicotiana alata (NaPI) contain high levels of a chymotrypsin that is not inhibited by NaPI. Here we describe the isolation of this NaPI-resistant chymotrypsin and an NaPI-susceptible chymotrypsin from Helicoverpa larvae, together with their corresponding cDNAs. We investigated the mechanism of resistance by mutating selected positions of the NaPI-susceptible chymotrypsin using the corresponding amino acids of the NaPI-resistant chymotrypsin. Four critical residues that conferred resistance to NaPI were identified. Molecular modeling revealed that a Phe-->Leu substitution at position 37 in the chymotrypsin results in the loss of important binding contacts with NaPI. Identification of the molecular mechanisms that contribute to PI resistance in insect digestive proteases will enable us to develop better inhibitors for the control of lepidopteran species that are major agricultural pests worldwide.


Subject(s)
Chymotrypsin/antagonists & inhibitors , Chymotrypsin/genetics , Insect Proteins/antagonists & inhibitors , Insect Proteins/genetics , Moths/drug effects , Moths/enzymology , Plant Proteins/metabolism , Protease Inhibitors/metabolism , Protease Inhibitors/pharmacology , Solanum tuberosum/metabolism , Amino Acid Sequence , Animals , Arginine/chemistry , Binding Sites/genetics , Chymotrypsin/chemistry , Insect Proteins/chemistry , Larva/drug effects , Larva/enzymology , Larva/genetics , Models, Molecular , Molecular Sequence Data , Moths/genetics , Moths/pathogenicity , Plant Proteins/pharmacology , Recombinant Proteins/antagonists & inhibitors , Recombinant Proteins/chemistry , Recombinant Proteins/genetics , Sequence Homology, Amino Acid
18.
J Cardiovasc Transl Res ; 16(1): 77-85, 2023 02.
Article in English | MEDLINE | ID: mdl-35759180

ABSTRACT

Myocardial fibrosis confers an almost threefold mortality risk in heart disease. There are no prognostic therapies and novel therapeutic targets are needed. Many thousands of unannotated small open reading frames (smORFs) have been identified across the genome with potential to produce micropeptides (< 100 amino acids). We sought to investigate the role of smORFs in myocardial fibroblast activation.Analysis of human cardiac atrial fibroblasts (HCFs) stimulated with profibrotic TGFß1 using RNA sequencing (RNA-Seq) and ribosome profiling (Ribo-Seq) identified long intergenic non-coding RNA LINC01013 as TGFß1 responsive and containing an actively translated smORF. Knockdown of LINC01013 using siRNA reduced expression of profibrotic markers at baseline and blunted their response to TGFß1. In contrast, overexpression of a codon-optimised smORF invoked a profibrotic response comparable to that seen with TGFß1 treatment, whilst FLAG-tagged peptide associated with the mitochondria.Together, these data support a novel LINC01013 smORF micropeptide-mediated mechanism of fibroblast activation. TGFß1 stimulation of atrial fibroblasts induces expression of LINC01013, whose knockdown reduces fibroblast activation. Overexpression of a smORF contained within LINC01013 localises to mitochondria and activates fibroblasts.


Subject(s)
Atrial Fibrillation , RNA, Long Noncoding , Humans , Proteomics , RNA, Long Noncoding/genetics , Fibroblasts , Micropeptides
19.
Nature ; 442(7100): 287-90, 2006 Jul 20.
Article in English | MEDLINE | ID: mdl-16855587

ABSTRACT

The determination of melt distribution in the crust and the nature of the crust-mantle boundary (the 'Moho') is fundamental to the understanding of crustal accretion processes at oceanic spreading centres. Upper-crustal magma chambers have been imaged beneath fast- and intermediate-spreading centres but it has been difficult to image structures beneath these magma sills. Using three-dimensional seismic reflection images, here we report the presence of Moho reflections beneath a crustal magma chamber at the 9 degrees 03' N overlapping spreading centre, East Pacific Rise. Our observations highlight the formation of the Moho at zero-aged crust. Over a distance of less than 7 km along the ridge crest, a rapid increase in two-way travel time of seismic waves between the magma chamber and Moho reflections is observed, which we suggest is due to a melt anomaly in the lower crust. The amplitude versus offset variation of reflections from the magma chamber shows a coincident region of higher melt fraction overlying this anomalous region, supporting the conclusion of additional melt at depth.

20.
Int J Legal Med ; 125(5): 617-28, 2011 Sep.
Article in English | MEDLINE | ID: mdl-20461525

ABSTRACT

Injuries caused by gunshots can produce what bloodstain pattern analysts know as "backspatter." Observations about the presence or absence of backspatter on an individual may be used in court as evidence of guilt or innocence. The discharge of three firearms (.22 caliber revolver, .38 caliber revolver, and .308 caliber rifle) and the resulting impact of bullets on a blood source were recorded using high-speed digital video imaging. Blood droplets, firearm muzzle gases, and ballistic shock waves were visualized using standard reflected light and shadowgraphy imaging techniques. A significant interaction between air currents, muzzle gases, and particulate material emanating from the firearms upon discharge with backspattered blood was observed. Blood droplets, initially spattered back toward the firearm and the shooter, were observed to change direction under the influence of firearm-induced air currents and were blown forward toward and beyond their original source location. Implications for experts testifying in court and for bloodstain pattern instructors are discussed.


Subject(s)
Blood Stains , Firearms , Forensic Ballistics/legislation & jurisprudence , Gases , Homicide/legislation & jurisprudence , Wounds, Gunshot/pathology , Air Movements , Humans , Lighting/instrumentation , Lighting/legislation & jurisprudence , Shadowing Technique, Histology/instrumentation , Video Recording/instrumentation
SELECTION OF CITATIONS
SEARCH DETAIL