1,277 research outputs found
Towards Automated Benchmarking of Atomistic Forcefields: Neat Liquid Densities and Static Dielectric Constants from the ThermoML Data Archive
Atomistic molecular simulations are a powerful way to make quantitative
predictions, but the accuracy of these predictions depends entirely on the
quality of the forcefield employed. While experimental measurements of
fundamental physical properties offer a straightforward approach for evaluating
forcefield quality, the bulk of this information has been tied up in formats
that are not machine-readable. Compiling benchmark datasets of physical
properties from non-machine-readable sources require substantial human effort
and is prone to accumulation of human errors, hindering the development of
reproducible benchmarks of forcefield accuracy. Here, we examine the
feasibility of benchmarking atomistic forcefields against the NIST ThermoML
data archive of physicochemical measurements, which aggregates thousands of
experimental measurements in a portable, machine-readable, self-annotating
format. As a proof of concept, we present a detailed benchmark of the
generalized Amber small molecule forcefield (GAFF) using the AM1-BCC charge
model against measurements (specifically bulk liquid densities and static
dielectric constants at ambient pressure) automatically extracted from the
archive, and discuss the extent of available data. The results of this
benchmark highlight a general problem with fixed-charge forcefields in the
representation low dielectric environments such as those seen in binding
cavities or biological membranes
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Exploration of PET and MRI radiomic features for decoding breast cancer phenotypes and prognosis.
Radiomics is an emerging technology for imaging biomarker discovery and disease-specific personalized treatment management. This paper aims to determine the benefit of using multi-modality radiomics data from PET and MR images in the characterization breast cancer phenotype and prognosis. Eighty-four features were extracted from PET and MR images of 113 breast cancer patients. Unsupervised clustering based on PET and MRI radiomic features created three subgroups. These derived subgroups were statistically significantly associated with tumor grade (p = 2.0 × 10-6), tumor overall stage (p = 0.037), breast cancer subtypes (p = 0.0085), and disease recurrence status (p = 0.0053). The PET-derived first-order statistics and gray level co-occurrence matrix (GLCM) textural features were discriminative of breast cancer tumor grade, which was confirmed by the results of L2-regularization logistic regression (with repeated nested cross-validation) with an estimated area under the receiver operating characteristic curve (AUC) of 0.76 (95% confidence interval (CI) = [0.62, 0.83]). The results of ElasticNet logistic regression indicated that PET and MR radiomics distinguished recurrence-free survival, with a mean AUC of 0.75 (95% CI = [0.62, 0.88]) and 0.68 (95% CI = [0.58, 0.81]) for 1 and 2 years, respectively. The MRI-derived GLCM inverse difference moment normalized (IDMN) and the PET-derived GLCM cluster prominence were among the key features in the predictive models for recurrence-free survival. In conclusion, radiomic features from PET and MR images could be helpful in deciphering breast cancer phenotypes and may have potential as imaging biomarkers for prediction of breast cancer recurrence-free survival
Ambient seismic noise tomography of Canada and adjacent regions: Part I. Crustal structures
This paper presents the first continental-scale study of the crust and upper mantle shear velocity (V_s) structure of Canada and adjacent regions using ambient noise tomography. Continuous waveform data recorded between 2003 and 2009 with 788 broadband seismograph stations in Canada and adjacent regions were used in the analysis. The higher primary frequency band of the ambient noise provides better resolution of crustal structures than previous tomographic models based on earthquake waveforms. Prominent low velocity anomalies are observed at shallow depths (<20 km) beneath the Gulf of St. Lawrence in east Canada, the sedimentary basins of west Canada, and the Cordillera. In contrast, the Canadian Shield exhibits high crustal velocities. We characterize the crust-mantle transition in terms of not only its depth and velocity but also its sharpness, defined by its thickness and the amount of velocity increase. Considerable variations in the physical properties of the crust-mantle transition are observed across Canada. Positive correlations between the crustal thickness, Moho velocity, and the thickness of the transition are evident throughout most of the craton except near Hudson Bay where the uppermost mantle V_s is relatively low. Prominent vertical V_s gradients are observed in the midcrust beneath the Cordillera and beneath most of the Canadian Shield. The midcrust velocity contrast beneath the Cordillera may correspond to a detachment zone associated with high temperatures immediately beneath, whereas the large midcrust velocity gradient beneath the Canadian Shield probably represents an ancient rheological boundary between the upper and lower crust
Polarization and relaxation of radon
Investigations of the polarization and relaxation of Rn by spin
exchange with laser optically pumped rubidium are reported. On the order of one
million atoms per shot were collected in coated and uncoated glass cells.
Gamma-ray anisotropies were measured as a signal of the alignment (second order
moment of the polarization) resulting from the combination of polarization and
quadrupole relaxation at the cell walls. The temperature dependence over the
range 130C to 220C shows the anisotropies increasing with
increasing temperature as the ratio of the spin exchange polarization rate to
the wall relaxation rate increases faster than the rubidium polarization
decreases. Polarization relaxation rates for coated and uncoated cells are
presented. In addition, improved limits on the multipole mixing ratios of some
of the main gamma-ray transitions have been extracted. These results are
promising for electric dipole moment measurements of octupole-deformed
Rn and other isotopes, provided sufficient quantities of the rare
isotopes can be produced.Comment: 4 pages, 4 figure
Justifications-on-demand as a device to promote shifts of attention associated with relational thinking in elementary arithmetic
Student responses to arithmetical questions that can be solved by using arithmetical structure can serve to reveal the extent and nature of relational, as opposed to computational thinking. Here, student responses to probes which require them to justify-on-demand are analysed using a conceptual framework which highlights distinctions between different forms of attention. We analyse a number of actions observed in students in terms of forms of attention and shifts between them: in the short-term (in the moment), medium-term (over several tasks), and long-term (over a year). The main factors conditioning students´ attention and its movement are identified and some didactical consequences are proposed
pirfenidone in patients with idiopathic pulmonary fibrosis and more advanced lung function impairment
Abstract Background Patients with idiopathic pulmonary fibrosis (IPF) demonstrate a range of lung function impairment. However, the efficacy of antifibrotics compared with placebo has not been assessed in patients with more advanced disease. This post-hoc analysis investigated the efficacy and safety of pirfenidone versus placebo in patients with IPF and more advanced lung function impairment, defined as percent predicted forced vital capacity (%FVC) Methods Patients randomised to pirfenidone 2,403 mg/day or placebo in the ASCEND (NCT01366209) and CAPACITY (NCT00287716; NCT00287729) trials with more advanced baseline lung function impairment (pirfenidone, n = 90; placebo, n = 80) were included. Mortality, lung function, hospitalisation, exercise capacity and dyspnoea were investigated over 52 weeks. Results At Week 52 versus placebo, pirfenidone was associated with significantly lower risks of all-cause mortality (hazard ratio [HR] 0.28; 95% confidence interval [CI] 0.09–0.86; p=0.0180), ≥10% absolute %FVC decline or all-cause mortality (HR 0.40; 95% CI 0.23–0.69; p=0.0006) and ≥10% absolute %FVC decline or respiratory-related hospitalisation or all-cause mortality (HR 0.46; 95% CI 0.28–0.76; p=0.0018). At Week 52, median treatment differences favouring pirfenidone were 36.7 m for 6-min walk distance and −8.0 points for the University of California—San Diego Shortness of Breath Questionnaire total score. Treatment-emergent adverse events (TEAEs) led to discontinuation in 14.4% and 21.3% of patients with pirfenidone and placebo, respectively. Conclusion Pirfenidone demonstrated clinically relevant benefits across multiple domains in patients with IPF and more advanced disease without an increased risk of discontinuation due to TEAEs. Clinical trials registration clinicaltrials. gov (ASCEND: NCT01366209; CAPACITY: NCT00287716; NCT00287729)
Supplementary guidance: listening to staff: Autumn 2017
Kinases play a critical
role in cellular signaling and are dysregulated
in a number of diseases, such as cancer, diabetes, and neurodegeneration.
Therapeutics targeting kinases currently account for roughly 50% of
cancer drug discovery efforts. The ability to explore human kinase
biochemistry and biophysics in the laboratory is essential to designing
selective inhibitors and studying drug resistance. Bacterial expression
systems are superior to insect or mammalian cells in terms of simplicity
and cost effectiveness but have historically struggled with human
kinase expression. Following the discovery that phosphatase coexpression
produced high yields of Src and Abl kinase domains in bacteria, we
have generated a library of 52 His-tagged human kinase domain constructs
that express above 2 μg/mL of culture in an automated bacterial
expression system utilizing phosphatase coexpression (YopH for Tyr
kinases and lambda for Ser/Thr kinases). Here, we report a structural
bioinformatics approach to identifying kinase domain constructs previously
expressed in bacteria and likely to express well in our protocol,
experiments demonstrating our simple construct selection strategy
selects constructs with good expression yields in a test of 84 potential
kinase domain boundaries for Abl, and yields from a high-throughput
expression screen of 96 human kinase constructs. Using a fluorescence-based
thermostability assay and a fluorescent ATP-competitive inhibitor,
we show that the highest-expressing kinases are folded and have well-formed
ATP binding sites. We also demonstrate that these constructs can enable
characterization of clinical mutations by expressing a panel of 48
Src and 46 Abl mutations. The wild-type kinase construct library is
available publicly via Addgene
Sex-specific associations of comorbidome and pulmorbidome with mortality in chronic obstructive pulmonary disease : results from COSYCONET
In patients with COPD, it has not been comprehensively assessed whether the predictive value
of comorbidities for mortality difers between men and women. We therefore aimed to examine
sex diferences of COPD comorbidities in regard with prognosis by classifying comorbidities into a
comorbidome related to extrapulmonary disorders and a pulmorbidome, referring to pulmonary
disorders. The study population comprised 1044 women and 1531 men with the diagnosis of
COPD from COSYCONET, among them 2175 of GOLD grades 1–4 and 400 at risk. Associations
of comorbidities with mortality were studied using Cox regression analysis for men and women
separately. During the follow-up (median 3.7 years) 59 women and 159 men died. In men, obesity,
hypertension, coronary artery disease, liver cirrhosis, osteoporosis, kidney disease, anaemia
and increased heart rate (HR) predict mortality, in women heart failure, hyperuricemia, mental
disorders, kidney disease and increased HR (p< 0.05 each). Regarding the pulmorbidome, signifcant
predictors in men were impairment in difusion capacity and hyperinfation, in women asthma and
hyperinfation. Similar results were obtained when repeating the analyses in GOLD 1–4 patients only.
Gender diferences should be considered in COPD risk assessment for a tailored approach towards the
treatment of COPD
Randomised Phase I/II trial assessing the safety and efficacy of radiolabelled anti-carcinoembryonic antigen I131 KAb201 antibodies given intra-arterially or intravenously in patients with unresectable pancreatic adenocarcinoma
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