Knowledge-based flow field zoning

Automation flow field zoning in two dimensions is an important step towards easing the three-dimensional grid generation bottleneck in computational fluid dynamics. A knowledge based approach works well, but certain aspects of flow field zoning make the use of such an approach challenging. A knowledge based flow field zoner, called EZGrid, was implemented and tested on representative two-dimensional aerodynamic configurations. Results are shown which illustrate the way in which EZGrid incorporates the effects of physics, shape description, position, and user bias in a flow field zoning

AI at Ames: Artificial Intelligence research and application at NASA Ames Research Center, Moffett Field, California, February 1985

Charts are given that illustrate function versus domain for artificial intelligence (AI) applications and interests and research area versus project number for AI research. A list is given of project titles with associated project numbers and page numbers. Also, project descriptions, including title, participants, and status are given

Knowledge-based zonal grid generation for computational fluid dynamics

Automation of flow field zoning in two dimensions is an important step towards reducing the difficulty of three-dimensional grid generation in computational fluid dynamics. Using a knowledge-based approach makes sense, but problems arise which are caused by aspects of zoning involving perception, lack of expert consensus, and design processes. These obstacles are overcome by means of a simple shape and configuration language, a tunable zoning archetype, and a method of assembling plans from selected, predefined subplans. A demonstration system for knowledge-based two-dimensional flow field zoning has been successfully implemented and tested on representative aerodynamic configurations. The results show that this approach can produce flow field zonings that are acceptable to experts with differing evaluation criteria

Identifying acne treatment uncertainties via a James Lind Alliance Priority Setting Partnership

Objectives: The Acne Priority Setting Partnership (PSP) was set up to identify and rank treatment uncertainties by bringing together people with acne, and professionals providing care within and beyond the National Health Service (NHS). Setting: The UK with international participation. Participants: Teenagers and adults with acne, parents, partners, nurses, clinicians, pharmacists, private practitioners. Methods: Treatment uncertainties were collected via separate online harvesting surveys, embedded within the PSP website, for patients and professionals. A wide variety of approaches were used to promote the surveys to stakeholder groups with a particular emphasis on teenagers and young adults. Survey submissions were collated using keywords and verified as uncertainties by appraising existing evidence. The 30 most popular themes were ranked via weighted scores from an online vote. At a priority setting workshop, patients and professionals discussed the 18 highest-scoring questions from the vote, and reached consensus on the top 10. Results: In the harvesting survey, 2310 people, including 652 professionals and 1456 patients (58% aged 24 y or younger), made submissions containing at least one research question. After checking for relevance and rephrasing, a total of 6255 questions were collated into themes. Valid votes ranking the 30 most common themes were obtained from 2807 participants. The top 10 uncertainties prioritised at the workshop were largely focused on management strategies, optimum use of common prescription medications and the role of nondrug based interventions. More female than male patients took part in the harvesting surveys and vote. A wider range of uncertainties were provided by patients compared to professionals. Conclusions: Engaging teenagers and young adults in priority setting is achievable using a variety of promotional methods. The top 10 uncertainties reveal an extensive knowledge gap about widely used interventions and the relative merits of drug versus non-drug based treatments in acne management

Real time quaking-induced conversion analysis of cerebrospinal fluid in sporadic Creutzfeldt-Jakob disease

OBJECTIVE: Current cerebrospinal fluid (CSF) tests for sporadic Creutzfeldt-Jakob disease (sCJD) are based on the detection of surrogate markers of neuronal damage such as CSF 14-3-3 which are not specific for sCJD. A number of prion protein conversion assays have been developed, including real-time quaking induced conversion (RT-QuIC). The objective of this study is to investigate whether CSF RT-QuIC analysis could be used as a diagnostic test in sCJD. METHODS: An exploratory study was undertaken which analysed 108 CSF samples from patients with neuropathologically confirmed sCJD or from control patients. Of the 108 CSF samples 56 were from sCJD patients (30 female, 26 male, aged 31–84 years; 62.3 ± 13.5 years) and 52 were from control patients (26 female, 26 male, aged 43–84 years; 67.8 ± 10.4 years). A confirmatory group of 118 patients were subsequently examined which consisted of 67 cases of neuropathologically confirmed sCJD (33 female, 34 male, aged 39–82 years; 67.5 ± 9.0 years) and 51 control cases (26 female, 25 male, aged 36–87 years; 63.5 ± 11.6 years). RESULTS: The exploratory study showed that RT-QuIC analysis had a sensitivity of 91% and a specificity of 98% for the diagnosis of sCJD. These results were confirmed in the confirmatory study which showed that CSF RT-QuIC analysis had a sensitivity and specificity of 87% and 100% respectively. INTERPRETATION: This study shows that CSF RT-QuIC analysis has the potential to be a more specific diagnostic test for sCJD than current CSF tests

Fluorescence strategies for high-throughput quantification of protein interactions

Advances in high-throughput characterization of protein networks in vivo have resulted in large databases of unexplored protein interactions that occur during normal cell function. Their further characterization requires quantitative experimental strategies that are easy to implement in laboratories without specialized equipment. We have overcome many of the previous limitations to thermodynamic quantification of protein interactions, by developing a series of in-solution fluorescence-based strategies. These methods have high sensitivity, a broad dynamic range, and can be performed in a high-throughput manner. In three case studies we demonstrate how fluorescence (de)quenching and fluorescence resonance energy transfer can be used to quantitatively probe various high-affinity protein–DNA and protein–protein interactions. We applied these methods to describe the preference of linker histone H1 for nucleosomes over DNA, the ionic dependence of the DNA repair enzyme PARP1 in DNA binding, and the interaction between the histone chaperone Nap1 and the histone H2A–H2B heterodimer

Bayesian approach to determining penetrance of pathogenic SDH variants.

BACKGROUND: Until recently, determining penetrance required large observational cohort studies. Data from the Exome Aggregate Consortium (ExAC) allows a Bayesian approach to calculate penetrance, in that population frequencies of pathogenic germline variants should be inversely proportional to their penetrance for disease. We tested this hypothesis using data from two cohorts for succinate dehydrogenase subunits A, B and C (SDHA-C) genetic variants associated with hereditary pheochromocytoma/paraganglioma (PC/PGL). METHODS: Two cohorts were 575 unrelated Australian subjects and 1240 unrelated UK subjects, respectively, with PC/PGL in whom genetic testing had been performed. Penetrance of pathogenic SDHA-C variants was calculated by comparing allelic frequencies in cases versus controls from ExAC (removing those variants contributed by The Cancer Genome Atlas). RESULTS: Pathogenic SDHA-C variants were identified in 106 subjects (18.4%) in cohort 1 and 317 subjects (25.6%) in cohort 2. Of 94 different pathogenic variants from both cohorts (seven in SDHA, 75 in SDHB and 12 in SDHC), 13 are reported in ExAC (two in SDHA, nine in SDHB and two in SDHC) accounting for 21% of subjects with SDHA-C variants. Combining data from both cohorts, estimated lifetime disease penetrance was 22.0% (95% CI 15.2% to 30.9%) for SDHB variants, 8.3% (95% CI 3.5% to 18.5%) for SDHC variants and 1.7% (95% CI 0.8% to 3.8%) for SDHA variants. CONCLUSION: Pathogenic variants in SDHB are more penetrant than those in SDHC and SDHA. Our findings have important implications for counselling and surveillance of subjects carrying these pathogenic variants

Temperature correction of spectra to improve solute concentration monitoring by in situ ultraviolet and mid-infrared spectrometries towards isothermal local model performance

Changes in temperature can significantly affect spectroscopic-based methods for in situ monitoring of processes. As varying temperature is inherent to many processes, associated temperature effects on spectra are unavoidable, which can hinder solute concentration determination. Ultraviolet (UV) and mid-infrared (IR) data were acquired for l-ascorbic acid (LAA) in MeCN/H2O (80:20 w/w) at different concentrations and temperatures. For both techniques, global partial least squares (PLS) models for prediction of LAA concentration constructed without preprocessing of the spectra required a high number of latent variables to account for the effects of temperature on the spectra (root mean square error of cross validation (RMSECV) of 0.18 and 0.16 g/100 g solvent, for UV and IR datasets, respectively). The PLS models constructed on the first derivative spectra required fewer latent variables, yielding variable results in accuracy (RMSECV of 0.23 and 0.06 g/100 g solvent, respectively). Corresponding isothermal local models constructed indicated improved model performance that required fewer latent variables in the absence of temperature effects (RMSECV of 0.01 and 0.04 g/100 g solvent, respectively). Temperature correction of the spectral data via loading space standardization (LSS) enabled the construction of global models using the same number of latent variables as the corresponding local model, which exhibited comparable model performance (RMSECV of 0.06 and 0.04 g/100 g solvent, respectively). The additional chemometric effort required for LSS is justified if prediction of solute concentration is required for in situ monitoring and control of cooling crystallization with an accuracy and precision approaching that attainable using an isothermal local model. However, the model performance with minimal preprocessing may be sufficient, for example, in the early phase development of a cooling crystallization process, where high accuracy is not always required. UV and IR spectrometries were used to determine solubility diagrams for LAA in MeCN/H2O (80:20 w/w), which were found to be accurate compared to those obtained using the traditional techniques of transmittance and gravimetric measurement. For both UV and IR spectrometries, solubility values obtained from models with LSS temperature correction were in better agreement with those determined gravimetrically. In this first example of the application of LSS to UV spectra, significant improvement in the predicted solute concentration is achieved with the additional chemometric effort. There is no extra experimental burden associated with the use of LSS if a structured approach is employed to acquire calibration data that account for both temperature and concentration

The Association between Early-life Relative Telomere Length and Childhood Neurodevelopment

Purpose: To examine the association between telomere length and neurodevelopment in children. Methods: We examined the relationship between relative telomere length (rTL) and neurodevelopmental outcomes at 9 and 30 months, and 5 years of age in children enrolled in the Seychelles Child Development Study Nutrition Cohort 1 (NC1). Relative telomere length was measured in cord blood and in child blood at age five. Multivariable linear regression examined associations between neurodevelopmental outcomes and rTL adjusting for relevant covariates. Results: Mean rTL was 1.18 at birth and 0.71 at age five. Increased cord blood rTL was associated with better scores on two neurodevelopmental tests, the psychomotor developmental index (β = 4.01; 95% confidence interval (CI) = 0.17, 7.85) at age 30 months, and the Woodcock Johnson test of achievement letter-word score (β = 2.88; CI = 1.21–4.56) at age five. The Woodcock Johnson test of achievement letter-word score remained statistically significant after two outliers were excluded (β = 2.83; CI = 0.69, 4.97); the psychomotor developmental index did not (β = 3.62; CI = −1.28, 8.52). None of the neurodevelopmental outcomes at age five were associated with five-year rTL. Conclusion: Although increased cord blood rTL was associated with better test scores for a few neurodevelopmental outcomes, this study found little consistent evidence of an association between rTL and neurodevelopment. Future studies with a larger sample size, longer follow-up, and other relevant biological markers (e.g. oxidative stress) are needed to clarify the role of rTL in neurodevelopment and its relevance as a potential surrogate measure for oxidative stress in the field of developmental neurotoxicity

A multicentre validation of Metasin: a molecular assay for the intraoperative assessment of sentinel lymph nodes from breast cancer patients

Aims: Treatment strategies for breast cancer continue to evolve. No uniformity exists in the UK for the management of node‐positive breast cancer patients. Most centres continue to use conventional histopathology of sampled sentinel lymph nodes (SLNs), which requires delayed axillary clearance in up to 25% of patients. Some use touch imprint cytology or frozen section for intraoperative testing, although both have inherent sensitivity issues. An intraoperative molecular diagnostic approach helps to overcome some of these limitations. The aim of this study was to assess the clinical effectiveness of Metasin, a molecular method for the intraoperative evaluation of SLNs. Methods and results: RNA from 3296 lymph nodes from 1836 patients undergoing SLN assessment was analysed with Metasin. Alternate slices of tissue were examined in parallel by histology. Cases deemed to be discordant were analysed by protein gel electrophoresis. There was concordance between Metasin and histology in 94.1% of cases, with a sensitivity of 92% [95% confidence interval (CI) 88–94%] and a specificity of 97% (95% CI 95–97%). Positive and negative predictive values were 88% and 98%, respectively. Over half of the discordant cases (4.4%) were ascribed to tissue allocation bias (TAB). Conclusions: Clinical validation of the Metasin assay suggests that it is sufficiently sensitive and specific to make it fit for purpose in the intraoperative setting