Two synthetic routes have been developed for the asymmetric syntheses of (2R,3S)- and (2S,3S)-3-hydroxyproline. The key synthetic step in each of these strategies is the conversion of protected ...α,δ-dihydroxy-β-amino esters (either 2,3-anti- or 2,3-syn-configured) into β,δ-dihydroxy-α-amino esters (protected forms thereof), via the intermediacy of the corresponding aziridinium ions. The products of these stereospecific rearrangements were then cyclized and deprotected to afford (2R,3S)-3-hydroxyproline and (2S,3S)-3-hydroxyproline as single diastereoisomers (>99:1 dr) in >26% overall yield.
High concentrations of volatile organic compounds (VOCs) associated with oil and natural gas extraction were measured during a strong temperature inversion in the winter of 2013 at a rural site in ...the Uintah Basin, Utah. During this period, photochemistry enhanced by the stagnant meteorological conditions and concentrated VOCs led to high ozone mixing ratios (150 ppbv). A simple analysis of aromatic VOCs measured by proton-transfer-reaction mass-spectrometry (PTR-MS) is used to estimate (1) VOC emission ratios (the ratio of two VOCs at the time of emission) relative to benzene, (2) aromatic VOC emission rates, and (3) ambient OH radical concentrations. These quantities are determined from a best fit to VOC : benzene ratios as a function of time. The main findings are that (1) emission ratios are consistent with contributions from both oil and gas producing wells; (2) the emission rate of methane (27-57 103 kg methane h-1), extrapolated from the emission rate of benzene (4.1 plus or minus 0.4 105 molecules cm-3 s-1), agrees with an independent estimate of methane emissions from aircraft measurements in 2012; and (3) calculated daily OH concentrations are low, peaking at 1 106 molecules cm-3, and are consistent with Master Chemical Mechanism (MCM) modeling. The analysis is extended to photochemical production of oxygenated VOCs measured by PTR-MS and is able to explain daytime variability of these species. It is not able to completely reproduce nighttime behavior, possibly due to surface deposition. Using results from this analysis, the carbon mass of secondary compounds expected to have formed by the sixth day of the stagnation event was calculated, then compared to the measured mass of primary and secondary compounds. Only 17% of the expected secondary carbon mass is accounted for by gas phase, aerosol, and snow organic carbon measurements. The disparity is likely due to substantial amounts of unquantified oxygenated products.
More than 40 model groups worldwide are participating in the Coupled Model Intercomparison Project Phase 6 (CMIP6), providing a new and rich source of information to better understand past, present, ...and future climate change. Here, we use the Earth System Model Evaluation Tool (ESMValTool) to assess the performance of the CMIP6 ensemble compared to the previous generations CMIP3 and CMIP5. While CMIP5 models did not capture the observed pause in the increase in global mean surface temperature between 1998 and 2013, the historical CMIP6 simulations agree well with the observed recent temperature increase, but some models have difficulties in reproducing the observed global mean surface temperature record of the second half of the twentieth century. While systematic biases in annual mean surface temperature and precipitation remain in the CMIP6 multimodel mean, individual models and high‐resolution versions of the models show significant reductions in many long‐standing biases. Some improvements are also found in the vertical temperature, water vapor, and zonal wind speed distributions, and root‐mean‐square errors for selected fields are generally smaller with reduced intermodel spread and higher average skill in the correlation patterns relative to observations. An emerging property of the CMIP6 ensemble is a higher effective climate sensitivity with an increased range between 2.3 and 5.6 K. A possible reason for this increase in some models is improvements in cloud representation resulting in stronger shortwave cloud feedbacks than in their predecessor versions.
Key Points
Temperature, water vapor, and zonal wind speed show improvements in CMIP6 with amplitudes of many long‐standing biases smaller than CMIP3/5
High‐resolution models show significant improvements in their historical CMIP6 simulations for temperature and precipitation mean biases
Spread in effective climate sensitivity in CMIP6 is larger than in previous phases
Iodide chemical ionization mass spectrometry (CIMS) is a common analytical
tool used in both laboratory and field experiments to measure a large suite
of atmospherically relevant compounds. Here, we ...describe a systematic ion
molecule reactor (IMR) temperature dependence of iodide CIMS analyte
sensitivity for a wide range of analytes in laboratory experiments. Weakly
bound iodide clusters, such as HCl, HONO, HCOOH, HCN, phenol, 2-nitrophenol,
and acyl peroxynitrate (PAN) detected via the peroxy radical cluster, all
exhibit strong IMR temperature dependence of sensitivity ranging from −3.4 % ∘C−1
to 5.9 % ∘C−1 (from 37 to 47 ∘C). Strongly
bound iodide clusters, such as Br2, N2O5, ClNO2, and PAN
detected via the carboxylate anion, all exhibit little to no IMR temperature
dependence ranging from 0.2 % ∘C−1 to −0.9 % ∘C−1 (from 37 to 47 ∘C). The IMR temperature relationships of weakly bound clusters
provide an estimate of net reaction enthalpy, and comparison with database
values indicates that these clusters are in thermal equilibrium. Ground site
HCOOH data collected in the summer of 2021 in Pasadena (CA) are corrected
and show a reversal in the diel cycle, emphasizing the importance of this
correction (35±6 % during the day, -26±2 % at night).
Finally, we recommend two approaches to minimize this effect in the field,
namely heating or cooling the IMR; the latter technique has the added benefit of
improving absolute sensitivity.
To maximise the effect of an antibiotic it is necessary to pay careful attention to dosing. The maintenance dose is determined by antibiotic clearance which is usually determined in young healthy ...adults with normal physiology. Antibiotic clearance in critically ill patients may increase or decrease due to altered physiology and the treatments that are administered. Clearance may also vary significantly over time in patients with critical illness. Advancing age and comorbidities, in particular chronic kidney disease, can also decrease antibiotic clearance. Therefore, it is complicated and arguably impossible to suggest generic guidelines for the dosing of antibiotics in critically ill patients. Factors that influence clearance must be identified and accounted for in each patient for a rational approach to dose adjustment of antibiotics in patients with critical illness. The necessary changes can be predicted by understanding pharmacokinetic concepts. It is necessary to quantify organ function in patients at multiple time points because this can be used to estimate antibiotic clearance and guide dose selection. For example, creatinine clearance should be calculated but methods used in ambulatory patients may not apply to patients with critical illness. If possible, therapeutic drug monitoring should be conducted to ensure that antibiotic concentration targets are achieved and also to guide titration of subsequent doses. If blood sampling is carefully planned it may be possible to directly measure antibiotic clearance for dose adjustment. The purpose of this article is to review the concept of clearance and to highlight circumstances where antibiotic clearance may be altered in patients with critical illness. Strategies for dose modification of antibiotics in critically ill patients will be discussed.
Recent preclinical studies revealed the efficacy of combined use of PI3K inhibitor BKM120 and PARP inhibitor Olaparib in breast and prostate cancers. The current study investigated the effect of such ...drug combination on ovarian cancer. Here we showed that combined inhibition of PI3K and PARP effectively synergized to inhibit proliferation, survival and invasion in the majority of ovarian cancer cell lines harboring PIK3CA mutations, including SKOV3, HEYA8, and IGROV1. Mechanistically, combined treatment of PARP and PI3K inhibitors resulted in an exacerbated DNA damage response and more substantially reduced AKT/mTOR signaling when compared to single-agent. Notably, ovarian cancer cells responsive to the PI3K/PARP combination displayed decreased BRCA1/2 expression upon drug treatment. Furthermore, the effect of the drug combination was corroborated in an intraperitoneal dissemination xenograft mouse model in which SKOV3 ovarian cancer cells responded with significantly decreased BRCA1 expression, suppressed PI3K/AKT signaling and reduced tumor burden. Collectively, our data suggested that combined inhibition of PI3K and PARP may be an effective therapeutic strategy for ovarian cancers with PIK3CA mutations and that the accompanied BRCA downregulation following PI3K inhibition could serve as a biomarker for the effective response to PARP inhibition.
Human epidermal growth factor receptor-2 (HER2) amplification/overexpression (HER2+) frequently co-occurs with PI3K pathway activation in breast tumors. PI3K signaling is most often activated by ...PIK3CA mutation or PTEN loss, which frequently results in sensitivity to p110α or p110β inhibitors, respectively. To examine the p110 isoform dependence in HER2+, PTEN-deficient tumors, we generated genetic mouse models of breast tumors driven by concurrent Her2 activation and Pten loss coupled with deletion of p110α or p110β. Ablation of p110α, but not p110β, significantly impaired the development of Her2+/Pten-null tumors in mice. We further show that p110α primarily mediates oncogenic signaling in HER2+/PTEN-deficient human cancers while p110β conditionally mediates PI3K/AKT signaling only upon HER2 inhibition. Combined HER2 and p110α inhibition effectively reduced PI3K/AKT signaling and growth of cancer cells both in vitro and in vivo. Addition of the p110β inhibitor to dual HER2 and p110α inhibition induced tumor regression in a xenograft model of HER2+/PTEN-deficient human cancers. Together, our data suggest that combined inhibition of HER2 and p110α/β may serve as a potent and durable therapeutic regimen for the treatment of HER2+, PTEN-deficient breast tumors.
This paper describes the issues relating to the measurement of nanoparticle size, shape and dispersion when evaluating the toxicity of nanoparticles. Complete characterization of these materials ...includes much more than size, size distribution and shape; nonetheless, these attributes are usually the essential foundation. The measurement of particle size, particularly at scales of 100 nm or less, can be challenging under the best of conditions. Measurements that are routine in the laboratory setting become even more difficult when made under the physiological conditions relevant to toxicity studies, where the environment of the particles can be quite complex. Passive and active cellular responses, as well as the presence of a variety of nano-scale biological structures, often complicate the collection and interpretation of size and shape data. In this paper, we highlight several of the common issues faced when characterizing nanoparticles for toxicity testing and suggest general protocols to address these problems.
There is a need to develop new ways of protecting plants against aphid attack. Here, we investigated the effect of a plant defence activator,
cis
-jasmone (CJ), in a range of cultivars of
Brassica ...napus, Brassica rapa
and
Brassica oleracea
. Plants were sprayed with
cis
-jasmone or blank formulation and then tested with peach potato aphids (
Myzus persicae
Sulzer) (Hemiptera: Aphididae) and their parasitoid
Diaeretiella rapae
(M'Intosh) (Hymenoptera: Braconidae). CJ treated plants had significantly lower aphid settlement than control plants in a settlement bioassay. Conversely, in a foraging bioassay,
D. rapae
parasitoids spent a significantly longer time foraging on CJ treated plants. Our results reveal that CJ treatment makes plants less attractive to and less suitable for
M. persicae
but more attractive to
D. rapae
in a range of brassica cultivars. It is likely that these effects are due to changes in volatile emission indicating activation of defence and presence of conspecific competitors to aphids but presence of prey to parasitoids. Increases in volatile emission were found in CJ induced plants but varied with genotype. Among the synthetic volatile compounds that were induced in the headspace of CJ treated brassica cultivars, methyl isothiocyanate, methyl salicylate and
cis
-jasmone were most repellent to aphids. These results build on earlier studies in
Arabidopsis
and show that tritrophic interactions are influenced by CJ in a wide range of brassica germplasm. The implication is that CJ is a promising treatment that could be used in brassica crops as part of an integrated pest management system.
Ethylene glycol (EG) is metabolized into glycolate and oxalate and may cause metabolic acidemia, neurotoxicity, acute kidney injury (AKI), and death. Historically, treatment of EG toxicity included ...supportive care, correction of acid-base disturbances and antidotes (ethanol or fomepizole), and extracorporeal treatments (ECTRs), such as hemodialysis. With the wider availability of fomepizole, the indications for ECTRs in EG poisoning are debated. We conducted systematic reviews of the literature following published EXTRIP methods to determine the utility of ECTRs in the management of EG toxicity. The quality of the evidence and the strength of recommendations, either strong ("we recommend") or weak/conditional ("we suggest"), were graded according to the GRADE approach. A total of 226 articles met inclusion criteria. EG was assessed as dialyzable by intermittent hemodialysis (level of evidence = B) as was glycolate (Level of evidence = C). Clinical data were available for analysis on 446 patients, in whom overall mortality was 18.7%. In the subgroup of patients with a glycolate concentration ≤ 12 mmol/L (or anion gap ≤ 28 mmol/L), mortality was 3.6%; in this subgroup, outcomes in patients receiving ECTR were not better than in those who did not receive ECTR. The EXTRIP workgroup made the following recommendations for the use of ECTR in addition to supportive care over supportive care alone in the management of EG poisoning (very low quality of evidence for all recommendations): i) Suggest ECTR if fomepizole is used and EG concentration > 50 mmol/L OR osmol gap > 50; or ii) Recommend ECTR if ethanol is used and EG concentration > 50 mmol/L OR osmol gap > 50; or iii) Recommend ECTR if glycolate concentration is > 12 mmol/L or anion gap > 27 mmol/L; or iv) Suggest ECTR if glycolate concentration 8-12 mmol/L or anion gap 23-27 mmol/L; or v) Recommend ECTR if there are severe clinical features (coma, seizures, or AKI). In most settings, the workgroup recommends using intermittent hemodialysis over other ECTRs. If intermittent hemodialysis is not available, CKRT is recommended over other types of ECTR. Cessation of ECTR is recommended once the anion gap is < 18 mmol/L or suggested if EG concentration is < 4 mmol/L. The dosage of antidotes (fomepizole or ethanol) needs to be adjusted during ECTR.
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