The abundance of chlorine in the Earth's atmosphere increased considerably during the 1970s to 1990s, following large emissions of anthropogenic long-lived chlorine-containing source gases, notably ...the chlorofluorocarbons. The chemical inertness of chlorofluorocarbons allows their transport and mixing throughout the troposphere on a global scale, before they reach the stratosphere where they release chlorine atoms that cause ozone depletion. The large ozone loss over Antarctica was the key observation that stimulated the definition and signing in 1987 of the Montreal Protocol, an international treaty establishing a schedule to reduce the production of the major chlorine- and bromine-containing halocarbons. Owing to its implementation, the near-surface total chlorine concentration showed a maximum in 1993, followed by a decrease of half a per cent to one per cent per year, in line with expectations. Remote-sensing data have revealed a peak in stratospheric chlorine after 1996, then a decrease of close to one per cent per year, in agreement with the surface observations of the chlorine source gases and model calculations. Here we present ground-based and satellite data that show a recent and significant increase, at the 2σ level, in hydrogen chloride (HCl), the main stratospheric chlorine reservoir, starting around 2007 in the lower stratosphere of the Northern Hemisphere, in contrast with the ongoing monotonic decrease of near-surface source gases. Using model simulations, we attribute this trend anomaly to a slowdown in the Northern Hemisphere atmospheric circulation, occurring over several consecutive years, transporting more aged air to the lower stratosphere, and characterized by a larger relative conversion of source gases to HCl. This short-term dynamical variability will also affect other stratospheric tracers and needs to be accounted for when studying the evolution of the stratospheric ozone layer.
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Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Size-exclusion chromatography (SEC) is a method of choice for the analysis of protein aggregates in pharmaceuticals. The United States and European Pharmacopoeias currently use a SEC method with an ...acidic pH mobile phase to assess the content of aggregates in insulin formulations.
In this article, we analyzed aggregated human insulin samples and demonstrated that both methods under neutral conditions, namely neutral pH SEC (nSEC) and capillary gel electrophoresis (CGE), yield to similar aggregate content contrary to SEC under acidic conditions (aSEC). aSEC showed polymeric complexes that were not observed in nSEC and CGE. During method development, the effect on SEC profiles of arginine and acetonitrile were highlighted. In CGE, the effect of SDS on disruption of non-covalent insulin aggregates was confirmed and the benefit of sodium deoxycholate addition in sieving gel was discussed. The three methods were applied to the analysis of an insulin formulation and similar results to those obtained for human insulin as raw material were observed. Finally, the CGE method was used to study the stability of human insulin under different storage conditions.
In view of the obtained results one may question the relevance of the current pharmacopoeia method to study insulin aggregates by emphasizing the importance of the mobile phase composition and pH in SEC. The new CGE method developed is an easy method for studying non-covalent aggregates of insulin, which could be applied to other proteins.
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•In SEC, the mobile phase composition plays a major role on aggregation profile.•Acidic and neutral SEC methods give differences in insulin aggregation assessment.•Sodium deoxycholate in CGE enables the detection of non covalent aggregates.
With the emergence of more challenging targets, a relatively new approach, fragment-based drug discovery (FBDD), proved its efficacy and gained increasing importance in the pharmaceutical industry. ...FBDD identifies low molecular-weight (MW) ligands (fragments) that bind to biologically important macromolecules, then a structure-guided fragment growing or merging approach is performed, contributing to the quality of the lead. However, to select the appropriate fragment to be evolved, sensitive analytical screening methods must be used to measure the affinity in the μM or even mM range. In this particular context, we developed a robust and selective partial filling affinity CE (ACE) method for the direct binding screening of a small fragment library in order to identify new thrombin inhibitors. To demonstrate the accuracy of our assay, the complex dissociation constants of three known thrombin inhibitors, namely benzamidine, p-aminobenzamidine and nafamostat were determined and found to be in good concordance with the previously reported values. Finally, the screening of a small library was performed and demonstrated the high discriminatory power of our method towards weak binders compared to classical spectrophotometric activity assay, proving the interest of our method in the context of FBDD.
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•Affinity capillary electrophoresis is used in the context of fragment-based drug discovery.•The developed direct binding-screening assay takes into account aspecific interactions.•Dissociation constants calculated are similar to the one of the literature.•Weak binders are better discriminated by ACE compared to spectrophotometric activity assay.
Ground-based Fourier transform infrared (FTIR) measurements of solar absorption spectra can provide ozone total columns with a precision of 2% but also independent partial column amounts in about ...four vertical layers, one in the troposphere and three in the stratosphere up to about 45km, with a precision of 5-6%. We use eight of the Network for the Detection of Atmospheric Composition Change (NDACC) stations having a long-term time series of FTIR ozone measurements to study the total and vertical ozone trends and variability, namely, Ny-Aalesund (79 degree N), Thule (77 degree N), Kiruna (68 degree N), Harestua (60 degree N), Jungfraujoch (47 degree N), Izana (28 degree N), Wollongong (34 degree S) and Lauder (45 degree S). The length of the FTIR time series varies by station but is typically from about 1995 to present. We applied to the monthly means of the ozone total and four partial columns a stepwise multiple regression model including the following proxies: solar cycle, quasi-biennial oscillation (QBO), El Nino-Southern Oscillation (ENSO), Arctic and Antarctic Oscillation (AO/AAO), tropopause pressure (TP), equivalent latitude (EL), Eliassen-Palm flux (EPF), and volume of polar stratospheric clouds (VPSC). At the Arctic stations, the trends are found mostly negative in the troposphere and lower stratosphere, very mixed in the middle stratosphere, positive in the upper stratosphere due to a large increase in the 1995-2003 period, and non-significant when considering the total columns. The trends for mid-latitude and subtropical stations are all non-significant, except at Lauder in the troposphere and upper stratosphere and at Wollongong for the total columns and the lower and middle stratospheric columns where they are found positive. At Jungfraujoch, the upper stratospheric trend is close to significance (+0.9 plus or minus 1.0% decade-1). Therefore, some signs of the onset of ozone mid-latitude recovery are observed only in the Southern Hemisphere, while a few more years seem to be needed to observe it at the northern mid-latitude station.
► The CSP was evaluated in the polar organic solvent mode. ► The studied CSP has high chiral discrimination ability for acidic compounds. ► Acidic and basic mobile phase additives have a strong ...impact on enantioresolution. ► After optimization, the 12 tested compounds were all enantioseparated. ► Generic conditions were proposed for rapid method development.
The LC enantioseparation of chiral acidic and zwitterionic drugs selected as model compounds was optimized using chlorine containing cellulose based chiral stationary phases and polar organic mobile phases. The main solvent of the mobile phase was acetonitrile, the temperature was settled at 25°C and a stationary phase with cellulose tris(3-chloro-4-methylphenylcarbamate) as chiral selector (3-Cl-4-Me-PC) was selected. In the screening step, the nature and concentration of both acidic and basic additives were found to have a significant effect on retention, selectivity and resolution. Acetic acid (AcA) was selected as acidic additive for the optimization step since it could lead to the enantioseparation of more acidic compounds than trifluoroacetic acid (TFA) and formic acid (FA), while among the three basic additives tested, diethylamine (DEA) most often gave better results with respect to enantioresolution and selectivity than butylamine (BuA) and triethylamine (TEA). The optimization was performed using a central composite face-centered design with two factors, namely the concentration of acetic acid (0.1–0.3%) and the concentration of DEA (0.01–0.1%) in the mobile phase. On the basis of the results obtained in the screening and optimization steps, a strategy for the rapid development of methods for the enantioseparation of acidic or neutral compounds was proposed.
•Sample and mobile phase composition were optimised for RP-LC–MS peptide analysis.•Multivariate analysis was used for experimental condition optimisation.•Peak splitting can be avoided using ...appropriate sample composition.•Sample dissolution medium influences sensitivity.•Generic conditions lead to high peak efficiency and sensitivity for most peptides.
Because the chromatographic behaviour of peptides is totally different from that of small molecules, a good understanding of the mechanisms that occur from injection to detection in reversed-phase LC–MS is strongly recommended to successfully develop not only qualitative but also quantitative methods. In this study, design of experiments was used in order to investigate the influence of the experimental parameters, i.e. sample and mobile phase composition, on a peptide mixture covering a wide range of molecular weights, isoelectric points and hydropathies. First, a screening design was developed to identify the significant factors concerning mobile phase (ion-pairing reagent nature and concentration) and sample composition (organic modifier proportion and ion-pairing reagent nature) on retention and response intensity (sensitivity). Then, after having selected the experimental domain and the significant factors, a full factorial design was used to further investigate the role of the considered factors and their interactions. Interestingly, ion-pairing reagent nature present in the sample had a tremendous effect on retention and response intensity. Optimal conditions leading to good sensitivity and adequate peptide retention without band splitting were selected and could be used as starting point for rapid method development using classical solvents and ion-pairing reagents.
Some hypotheses are still necessary in order to access the ball bearing Newtonian equilibrium with quasi-static methods. Among these hypotheses are the values of the transverse loads within ball/race ...contacts. Those loads are due to the gyroscopic torques. Nowadays, the transverse loads are estimated without any equilibrium criterion by the specialized literature. Moreover, the race control assumption is often employed in addition to the hypotheses made about the transverse loads. The paper describes a new method to compute the transverse loads without using the race control assumption. Then, a correlation between the ball bearing kinematics and the transverse loads is established. It leads to an accurate and efficient computational method to access the Newtonian equilibrium of high speed ball bearings.
•A new method to compute ball/race transverse loads in ball bearings is described.•Transverse loads are due to gyroscopic torque at high speed.•The method discards usual hypotheses regarding race control and transverse loads.•It also demonstrates the link between the kinematics and the transverse loads.
As an ubiquitous product of the oxidation of many volatile organic compounds (VOCs), formaldehyde (HCHO) plays a key role as a short-lived and reactive intermediate in the atmospheric photo-oxidation ...pathways leading to the formation of tropospheric ozone and secondary organic aerosols. In this study, HCHO profiles have been successfully retrieved from ground-based Fourier transform infrared (FTIR) solar spectra and UV-visible Multi-AXis Differential Optical Absorption Spectroscopy (MAX-DOAS) scans recorded during the July 2010–December 2012 time period at the Jungfraujoch station (Swiss Alps, 46.5° N, 8.0° E, 3580 m a.s.l.). Analysis of the retrieved products has revealed different vertical sensitivity between both remote sensing techniques. Furthermore, HCHO amounts simulated by two state-of-the-art chemical transport models (CTMs), GEOS-Chem and IMAGES v2, have been compared to FTIR total columns and MAX-DOAS 3.6–8 km partial columns, accounting for the respective vertical resolution of each ground-based instrument. Using the CTM outputs as the intermediate, FTIR and MAX-DOAS retrievals have shown consistent seasonal modulations of HCHO throughout the investigated period, characterized by summertime maximum and wintertime minimum. Such comparisons have also highlighted that FTIR and MAX-DOAS provide complementary products for the HCHO retrieval above the Jungfraujoch station. Finally, tests have revealed that the updated IR parameters from the HITRAN 2012 database have a cumulative effect and significantly decrease the retrieved HCHO columns with respect to the use of the HITRAN 2008 compilation.
We present a method for harmonized retrieval of integrated water vapor (IWV) from existing, long-term, measurement records at the ground-based mid-infrared solar FTIR spectrometry stations of the ...Network for the Detection of Atmospheric Composition Change (NDACC). Correlation of IWV from FTIR with radiosondes shows an ideal slope of 1.00(3). This optimum matching is achieved via tuning one FTIR retrieval parameter, i.e., the strength of a Tikhonov regularization constraining the derivative (with respect to height) of retrieved water profiles given in per cent difference relative to an a priori profile. All other FTIR-sonde correlation parameters (intercept=0.02(12) mm, bias=0.02(5) mm, standard deviation of coincident IWV differences (stdv)=0.27 mm, R=0.99) are comparable to or better than results for all other ground-based IWV sounding techniques given in the literature. An FTIR-FTIR side-by-side intercomparison reveals a strong exponential increase in stdv as a function of increasing temporal mismatch starting at Δt≈1 min. This is due to atmospheric water vapor variability. Based on this result we derive an upper limit for the precision of the FTIR IWV retrieval for the smallest Δt(=3.75 min) still giving a statistically sufficient sample (32 coincidences), i.e., precision(IWVFTIR)<0.05 mm (or 2.2% of the mean IWV). The bias of the IWV retrievals from the two different FTIR instruments is nearly negligible (0.02(1) mm). The optimized FTIR IWV retrieval is set up in the standard NDACC algorithm SFIT 2 without changes to the code. A concept for harmonized transfer of the retrieval between different stations deals with all relevant control parameters; it includes correction for differing spectral point spacings (via regularization strength), and final quality selection of the retrievals (excluding the highest residuals (measurement minus model), 5% of the total). As first application examples long-term IWV data sets are retrieved from the FTIR records of the Zugspitze (47.4° N, 11.0° E, 2964 m a.s.l.) and Jungfraujoch (46.5° N, 8.0° E, 3580 m a.s.l.) NDACC sites. Station-trend analysis comprises a linear fit after subtracting an intra-annual model (3 Fourier components) and constructing an uncertainty interval 95% confidence via bootstrap resampling. For the Zugspitze a significant trend of 0.79 0.65, 0.92 mm/decade is found for the time interval 1996–2008, whereas for the Jungfraujoch no significant trend is found. This confirms recent findings that strong variations of IWV trends do occur above land on the local to regional scale (≈250 km) in spite of homogeneous surface temperature trends. This paper provides a basis for future exploitation of more than a dozen existing, multi-decadal FTIR measurement records around the globe for climate studies.
Ropivacaine is the first enantiomerically pure long-acting local anaesthetic used for surgical anaesthesia and post-operative pain relief.
A liquid chromatographic (LC) method using acetonitrile as ...the main solvent and cellulose tris(4-chloro-3-methylphenylcarbamate) coated on silica as chiral stationary phase was successfully developed and applied for the enantiomeric purity determination of S-ropivacaine in a pharmaceutical formulation (Naropin®). The key role played by the acidic additive (trifluoroacetic acid or formic acid) in the enantioseparation of basic drugs in these LC systems was demonstrated by the reversal of ropivacaine enantiomers elution order observed when both acids were compared. In order to elute the enantiomeric impurity (R-ropivacaine) before S-ropivacaine, formic acid (FA) was selected. The temperature and the percentages of acidic additive and hexane in the mobile phase were found to significantly influence the retention and resolution of these enantiomers. The optimized mobile phase consisted of ACN/0.1% DEA/0.2% FA/5% hexane (v/v/v/v). The temperature was set at 35°C to avoid the interference from a peak system related to the presence of water in the sample on ropivacaine enantiomers.
The LC method was then fully validated applying the strategy based on total measurement error and accuracy profiles. The accuracy profile obtained by linear regression after square root transformation was selected, the acceptance limits being settled at ±10% for the intended use of this analytical method. The relative bias was lower than 1.5%, while the RSD values for repeatability and intermediate precision were both below 1.0%. The limit of detection (LOD) and the limit of quantification (LOQ) were found to be about 0.2 and 1.0μg/mL, respectively, corresponding to 0.02 and 0.1% of the enantiomeric impurity in S-ropivacaine.
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