Daytime CO2 urban surface fluxes from airborne measurements, eddy-covariance observations and emissions inventory in Greater London

Airborne measurements within the urban mixing layer (360 m) over Greater London are used to quantify CO2 emissions at the meso-scale. Daytime CO2 fluxes, calculated by the Integrative Mass Boundary Layer (IMBL) method, ranged from 46 to 104 μmol CO2 m−2 s−1 for four days in October 2011. The day-to-day variability of IMBL fluxes is at the same order of magnitude as for surface eddy-covariance fluxes observed in central London. Compared to fluxes derived from emissions inventory, the IMBL method gives both lower (by −37%) and higher (by 19%) estimates. The sources of uncertainty of applying the IMBL method in urban areas are discussed and guidance for future studies is given

The Impact of Insulin Pump Therapy on Glycemic Profiles in Patients with Type 2 Diabetes: Data from the OpT2mise Study

Background: The OpT2mise randomized trial was designed to compare the effects of continuous subcutaneous insulin infusion (CSII) and multiple daily injections (MDI) on glucose profiles in patients with type 2 diabetes. Research Design and Methods: Patients with glycated hemoglobin (HbA1c) levels of ≥8% (64 mmol/mol) and ≤12% (108 mmol/mol) despite insulin doses of 0.7-1.8 U/kg/day via MDI were randomized to CSII (n=168) or continued MDI (n=163). Changes in glucose profiles were evaluated using continuous glucose monitoring data collected over 6-day periods before and 6 months after randomization. Results: After 6 months, reductions in HbA1c levels were significantly greater with CSII (-1.1±1.2% [-12.0±13.1 mmol/mol]) than with MDI (-0.4±1.1% [-4.4±12.0 mmol/mol]) (P<0.001). Similarly, compared with patients receiving MDI, those receiving CSII showed significantly greater reductions in 24-h mean sensor glucose (SG) (treatment difference, -17.1 mg/dL; P=0.0023), less exposure to SG >180 mg/dL (-12.4%; P=0.0004) and SG >250 mg/dL (-5.5%; P=0.0153), and more time in the SG range of 70-180 mg/dL (12.3%; P=0.0002), with no differences in exposure to SG<70 mg/dL or in glucose variability. Changes in postprandial (4-h) glucose area under the curve >180 mg/dL were significantly greater with CSII than with MDI after breakfast (-775.9±1,441.2 mg/dL/min vs. -160.7±1,074.1 mg/dL/min; P=0.0015) and after dinner (-731.4±1,580.7 mg/dL/min vs. -71.1±1,083.5 mg/dL/min; P=0.0014). Conclusions: In patients with suboptimally controlled type 2 diabetes, CSII significantly improves selected glucometrics, compared with MDI, without increasing the risk of hypoglycemia

A meta-analysis of two randomised trials of early chemotherapy in asymptomatic metastatic colorectal cancer

This report constitutes a prospectively planned meta-analysis combining two almost identical trials undertaken in Australasia and Canada to study the effect of starting chemotherapy immediately in asymptomatic patients with metastatic colorectal cancer. Patients (n=168) were randomised to receive either immediate or delayed treatment (at onset of predefined symptoms). Australasian patients received either weekly 5-fluorouracil and leucovorin (500 and 20 mg m−2, respectively) (n=59) or the daily × 5 Mayo Clinic schedule (425 and 20 mg m−2, respectively) (n=42). Canadian patients were treated with the Mayo schedule (n=67). Otherwise, the two studies were almost identical in design and each used the European Organisation for the Research and Treatment of Cancer (EORTC) QLQ-C30 instrument for measuring quality of life (QoL). Treatment was continued until 6 months had elapsed or disease progression occurred. Low accrual led to trial suspension before the predetermined sample size for either study was reached. Median survival was not significantly better with immediate treatment (median 13.0 vs 11.0 months; hazard ratio, 1.15; 95% confidence interval (CI) 0.79–1.72; P=0.49). There was no statistically significant difference in progression-free survival (time from randomisation until first evidence of progression after chemotherapy, 10.2 vs 10.8 months; hazard ratio, 1.08; 95% CI 0.71–1.64; P=0.73). There was no difference in overall QoL or its individual domains between the two treatment strategies at baseline or at any subsequent time point. Early treatment of asymptomatic patients with metastatic colorectal cancer did not provide a survival benefit or improved QoL compared to withholding treatment until symptoms occurred

ACTRIS ACSM intercomparison - Part 2: Intercomparison of ME-2 organic source apportionment results from 15 individual, co-located aerosol mass spectrometers

Chemically resolved atmospheric aerosol data sets from the largest intercomparison of the Aerodyne aerosol chemical speciation monitors (ACSMs) performed to date were collected at the French atmospheric supersite SIRTA. In total 13 quadrupole ACSMs (Q-ACSM) from the European ACTRIS ACSM network, one time-of-flight ACSM (ToF-ACSM), and one high-resolution ToF aerosol mass spectrometer (AMS) were operated in parallel for about 3 weeks in November and December~2013. Part 1 of this study reports on the accuracy and precision of the instruments for all the measured species. In this work we report on the intercomparison of organic components and the results from factor analysis source apportionment by positive matrix factorisation (PMF) utilising the multilinear engine 2 (ME-2). Except for the organic contribution of mass-to-charge ratio m/z 44 to the total organics (f44), which varied by factors between 0.6 and 1.3 compared to the mean, the peaks in the organic mass spectra were similar among instruments. The m/z 44 differences in the spectra resulted in a variable f44 in the source profiles extracted by ME-2, but had only a minor influence on the extracted mass contributions of the sources. The presented source apportionment yielded four factors for all 15 instruments: hydrocarbon-like organic aerosol (HOA), cooking-related organic aerosol (COA), biomass burning-related organic aerosol (BBOA) and secondary oxygenated organic aerosol (OOA). ME-2 boundary conditions (profile constraints) were optimised individually by means of correlation to external data in order to achieve equivalent / comparable solutions for all ACSM instruments and the results are discussed together with the investigation of the influence of alternative anchors (reference profiles). A comparison of the ME-2 source apportionment output of all 15 instruments resulted in relative standard deviations (SD) from the mean between 13.7 and 22.7 % of the source's average mass contribution depending on the factors (HOA: 14.3 ± 2.2 %, COA: 15.0 ± 3.4 %, OOA: 41.5 ± 5.7 %, BBOA: 29.3 ± 5.0 %). Factors which tend to be subject to minor factor mixing (in this case COA) have higher relative uncertainties than factors which are recognised more readily like the OOA. Averaged over all factors and instruments the relative first SD from the mean of a source extracted with ME-2 was 17.2 %

An iPSC model of hereditary sensory neuropathy-1 reveals L-serine-responsive deficits in neuronal ganglioside composition and axoglial interactions.

Hereditary sensory neuropathy type 1 (HSN1) is caused by mutations in the SPTLC1 or SPTLC2 sub-units of the enzyme serine palmitoyltransferase, resulting in the production of toxic 1-deoxysphingolipid bases (DSBs). We used induced pluripotent stem cells (iPSCs) from patients with HSN1 to determine whether endogenous DSBs are neurotoxic, patho-mechanisms of toxicity and response to therapy. HSN1 iPSC-derived sensory neurons (iPSCdSNs) endogenously produce neurotoxic DSBs. Complex gangliosides, which are essential for membrane micro-domains and signaling, are reduced, and neurotrophin signaling is impaired, resulting in reduced neurite outgrowth. In HSN1 myelinating cocultures, we find a major disruption of nodal complex proteins after 8 weeks, which leads to complete myelin breakdown after 6 months. HSN1 iPSC models have, therefore, revealed that SPTLC1 mutation alters lipid metabolism, impairs the formation of complex gangliosides, and reduces axon and myelin stability. Many of these changes are prevented by l-serine supplementation, supporting its use as a rational therapy

Application of the PM6 semi-empirical method to modeling proteins enhances docking accuracy of AutoDock

<p>Abstract</p> <p>Background</p> <p>Molecular docking methods are commonly used for predicting binding modes and energies of ligands to proteins. For accurate complex geometry and binding energy estimation, an appropriate method for calculating partial charges is essential. AutoDockTools software, the interface for preparing input files for one of the most widely used docking programs AutoDock 4, utilizes the Gasteiger partial charge calculation method for both protein and ligand charge calculation. However, it has already been shown that more accurate partial charge calculation - and as a consequence, more accurate docking- can be achieved by using quantum chemical methods. For docking calculations quantum chemical partial charge calculation as a routine was only used for ligands so far. The newly developed Mozyme function of MOPAC2009 allows fast partial charge calculation of proteins by quantum mechanical semi-empirical methods. Thus, in the current study, the effect of semi-empirical quantum-mechanical partial charge calculation on docking accuracy could be investigated.</p> <p>Results</p> <p>The docking accuracy of AutoDock 4 using the original AutoDock scoring function was investigated on a set of 53 protein ligand complexes using Gasteiger and PM6 partial charge calculation methods. This has enabled us to compare the effect of the partial charge calculation method on docking accuracy utilizing AutoDock 4 software. Our results showed that the docking accuracy in regard to complex geometry (docking result defined as accurate when the RMSD of the first rank docking result complex is within 2 Å of the experimentally determined X-ray structure) significantly increased when partial charges of the ligands and proteins were calculated with the semi-empirical PM6 method.</p> <p>Out of the 53 complexes analyzed in the course of our study, the geometry of 42 complexes were accurately calculated using PM6 partial charges, while the use of Gasteiger charges resulted in only 28 accurate geometries. The binding affinity estimation was not influenced by the partial charge calculation method - for more accurate binding affinity prediction development of a new scoring function for AutoDock is needed.</p> <p>Conclusion</p> <p>Our results demonstrate that the accuracy of determination of complex geometry using AutoDock 4 for docking calculation greatly increases with the use of quantum chemical partial charge calculation on both the ligands and proteins.</p

ACTRIS ACSM intercomparison - Part 2 : Intercomparison of ME-2 organic source apportionment results from 15 individual, co-located aerosol mass spectrometers

Chemically resolved atmospheric aerosol data sets from the largest intercomparison of the Aerodyne aerosol chemical speciation monitors (ACSMs) performed to date were collected at the French atmospheric supersite SIRTA. In total 13 quadrupole ACSMs (Q-ACSM) from the European ACTRIS ACSM network, one time-of-flight ACSM (ToF-ACSM), and one high-resolution ToF aerosol mass spectrometer (AMS) were operated in parallel for about 3 weeks in November and December similar to 2013. Part 1 of this study reports on the accuracy and precision of the instruments for all the measured species. In this work we report on the intercomparison of organic components and the results from factor analysis source apportionment by positive matrix factorisation (PMF) utilising the multilinear engine 2 (ME-2). Except for the organic contribution of mass-to-charge ratio m/z 44 to the total organics (f(44)), which varied by factors between 0.6 and 1.3 compared to the mean, the peaks in the organic mass spectra were similar among instruments. The m/z 44 differences in the spectra resulted in a variable f(44) in the source profiles extracted by ME-2, but had only a minor influence on the extracted mass contributions of the sources. The presented source apportionment yielded four factors for all 15 instruments: hydrocarbon-like organic aerosol (HOA), cooking-related organic aerosol (COA), biomass burning-related organic aerosol (BBOA) and secondary oxygenated organic aerosol (OOA). ME-2 boundary conditions (profile constraints) were optimised individually by means of correlation to external data in order to achieve equivalent / comparable solutions for all ACSM instruments and the results are discussed together with the investigation of the influence of alternative anchors (reference profiles). A comparison of the ME-2 source apportionment output of all 15 instruments resulted in relative standard deviations (SD) from the mean between 13.7 and 22.7 % of the source's average mass contribution depending on the factors (HOA: 14.3 +/- 2.2 %, COA: 15.0 +/- 3.4 %, OOA: 41.5 +/- 5.7 %, BBOA: 29.3 +/- 5.0 %). Factors which tend to be subject to minor factor mixing (in this case COA) have higher relative uncertainties than factors which are recognised more readily like the OOA. Averaged over all factors and instruments the relative first SD from the mean of a source extracted with ME-2 was 17.2 %.Peer reviewe

ACTRIS ACSM intercomparison - Part 1 : Reproducibility of concentration and fragment results from 13 individual Quadrupole Aerosol Chemical Speciation Monitors (Q-ACSM) and consistency with co-located instruments

As part of the European ACTRIS project, the first large Quadrupole Aerosol Chemical Speciation Monitor (Q-ACSM) intercomparison study was conducted in the region of Paris for 3 weeks during the late-fall-early-winter period (November-December 2013). The first week was dedicated to the tuning and calibration of each instrument, whereas the second and third were dedicated to side-by-side comparison in ambient conditions with co-located instruments providing independent information on submicron aerosol optical, physical, and chemical properties. Near real-time measurements of the major chemical species (organic matter, sulfate, nitrate, ammonium, and chloride) in the non-refractory submicron aerosols (NR-PM1) were obtained here from 13 Q-ACSM. The results show that these instruments can produce highly comparable and robust measurements of the NR-PM1 total mass and its major components. Taking the median of the 13 Q-ACSM as a reference for this study, strong correlations (r(2) > 0.9) were observed systematically for each individual Q-ACSM across all chemical families except for chloride for which three Q-ACSMs showing weak correlations partly due to the very low concentrations during the study. Reproducibility expanded uncertainties of Q-ACSM concentration measurements were determined using appropriate methodologies defined by the International Standard Organization (ISO 17025, 1999) and were found to be 9, 15, 19, 28, and 36% for NR-PM1, nitrate, organic matter, sulfate, and ammonium, respectively. However, discrepancies were observed in the relative concentrations of the constituent mass fragments for each chemical component. In particular, significant differences were observed for the organic fragment at mass-to-charge ratio 44, which is a key parameter describing the oxidation state of organic aerosol. Following this first major intercomparison exercise of a large number of Q-ACSMs, detailed intercomparison results are presented, along with a discussion of some recommendations about best calibration practices, standardized data processing, and data treatment.Peer reviewe