A pathway converting C16 and C18 fatty acids to alkanes or alkenes, involving the light-dependent transformation of cis-vaccenic acid into 7-heptadecene, is present in various microalgae.
Microalgae ...are considered a promising platform for the production of lipid-based biofuels. While oil accumulation pathways are intensively researched, the possible existence of a microalgal pathways converting fatty acids into alka(e)nes has received little attention. Here, we provide evidence that such a pathway occurs in several microalgal species from the green and the red lineages. In
Chlamydomonas reinhardtii
(Chlorophyceae), a C17 alkene,
n
-heptadecene, was detected in the cell pellet and the headspace of liquid cultures. The
Chlamydomonas
alkene was identified as 7-heptadecene, an isomer likely formed by decarboxylation of cis-vaccenic acid. Accordingly, incubation of intact
Chlamydomonas
cells with per-deuterated D
31
-16:0 (palmitic) acid yielded D
31
-18:0 (stearic) acid, D
29
-18:1 (oleic and cis-vaccenic) acids, and D
29
-heptadecene. These findings showed that loss of the carboxyl group of a C
18
monounsaturated fatty acid lead to heptadecene formation. Amount of 7-heptadecene varied with growth phase and temperature and was strictly dependent on light but was not affected by an inhibitor of photosystem II. Cell fractionation showed that approximately 80% of the alkene is localized in the chloroplast. Heptadecane, pentadecane, as well as 7- and 8-heptadecene were detected in
Chlorella variabilis NC64A
(Trebouxiophyceae) and several
Nannochloropsis
species (Eustigmatophyceae). In contrast,
Ostreococcus tauri
(Mamiellophyceae) and the diatom
Phaeodactylum tricornutum
produced C
21
hexaene, without detectable C
15
-C
19
hydrocarbons. Interestingly, no homologs of known hydrocarbon biosynthesis genes were found in the
Nannochloropsis
,
Chlorella
, or
Chlamydomonas
genomes. This work thus demonstrates that microalgae have the ability to convert C
16
and C
18
fatty acids into alka(e)nes by a new, light-dependent pathway.
Objectives
Cytochrome P450 2B6 (CYP2B6) is responsible for the metabolic clearance of efavirenz and single nucleotide polymorphisms (SNPs) in the CYP2B6 gene are associated with efavirenz ...pharmacokinetics. Since the constitutive androstane receptor (CAR) and the pregnane X receptor (PXR) correlate with CYP2B6 in liver, and a CAR polymorphism (rs2307424) and smoking correlate with efavirenz plasma concentrations, we investigated their association with early (<3 months) discontinuation of efavirenz therapy.
Methods
Three hundred and seventy-three patients initiating therapy with an efavirenz-based regimen were included (278 white patients and 95 black patients; 293 male). DNA was extracted from whole blood and genotyping for CYP2B6 (516G → T, rs3745274), CAR (540C → T, rs2307424) and PXR (44477T → C, rs1523130; 63396C → T, rs2472677; and 69789A → G, rs763645) was conducted. Binary logistic regression using the backwards method was employed to assess the influence of SNPs and demographics on early discontinuation.
Results
Of the 373 patients, 131 withdrew from therapy within the first 3 months. Black ethnicity odds ratio (OR) = 0.27; P = 0.0001, CYP2B6 516TT (OR = 2.81; P = 0.006), CAR rs2307424 CC (OR = 1.92; P = 0.007) and smoking status (OR = 0.45; P = 0.002) were associated with discontinuation within 3 months.
Conclusions
These data indicate that genetic variability in CYP2B6 and CAR contributes to early treatment discontinuation for efavirenz-based antiretroviral regimens. Further studies are now required to define the clinical utility of these associations.
Background And Objectives
Because of extensive first‐pass metabolism, oral bioavailability of sildenafil reaches only 40%. Formation of the primary metabolite, N‐desmethylsildenafil, is mainly ...mediated by the cytochrome P450 enzyme CYP3A4. In this study we investigated the influence of grapefruit juice, containing inhibitors of intestinal CYP3A4, on the pharmacokinetics of sildenafil and N‐desmethylsildenafil.
Methods
In a randomized crossover study, 24 healthy white male volunteers received single 50‐mg doses of sildenafil. Two doses each of 250 ml grapefruit juice or water, respectively, were administered 1 hour before and together with the drug. Plasma concentrations of sildenafil and N‐desmethylsildenafil were determined up to 24 hours post dose by use of liquid chromatography–tandem mass spectrometry (limit of quantification, 1 ng/ml).
Results
Grapefruit juice changed the area under the sildenafil plasma concentration–time curve from time zero to infinity AUC(0‐∞) from 620 1.53 ng/ml • h to 761 1.58 ng/ml • h (geometric mean with geometric standard deviation), corresponding to a 23% increase (90% confidence interval, 13%‐33%). N‐Desmethylsildenafil AUC(0‐∞) increased by 24% (90% confidence interval, 17%‐32%). Maximum plasma concentrations (Cmax) of sildenafil and N‐desmethylsildenafil were essentially unchanged. There was a trend toward a prolonged time to reach Cmax during the grapefruit juice period (from a median of 0.75 hour to a median of 1.13 hours), corresponding to an increase by 0.25 hour (90% confidence interval, 0–0.63 hour). Interindividual variability was pronounced in both periods.
Conclusions
Grapefruit juice increases sildenafil bioavailability and tends to delay sildenafil absorption. Sildenafil pharmacokinetics may become less predictable with grapefruit juice. Although patients usually will not be endangered by concomitant use of grapefruit juice, it seems advisable to avoid this combination.
Clinical Pharmacology & Therapeutics (2002) 71, 21–29; doi: 10.1067/mcp.2002.121236
As a fundamental building block for quantum computation and communication protocols, the correct verification of the two-photon interference (TPI) contrast between two independent quantum light ...sources is of utmost importance. Here, we experimentally demonstrate how frequently present blinking dynamics and changes in emitter brightness critically affect the Hong–Ou–Mandel-type (HOM) correlation histograms of remote TPI experiments measured via the commonly utilized setup configuration. We further exploit this qualitative and quantitative explanation of the observed correlation dynamics to establish an alternative interferometer configuration, which is overcoming the discussed temporal fluctuations, giving rise to an error-free determination of the remote TPI visibility. We prove full knowledge of the obtained correlation by reproducing the measured correlation statistics via Monte Carlo simulations. As an exemplary system, we make use of two pairs of remote semiconductor quantum dots; however, the same conclusions apply for TPI experiments with flying qubits from any kind of remote solid-state quantum emitters.
We propose using virtual reality (VR) as a design tool for sketching and simulating spatially-aware interactive spaces. Using VR, designers can quickly experience their envisioned spaces and ...interactions by simulating technologies such as motion tracking, multiple networked devices, or unusual form factors such as spherical touchscreens or bezel-less display tiles. Design ideas can be rapidly iterated without restrictions by the number, size, or shape and availability of devices or sensors in the lab. To understand the potentials and challenges of designing in VR, we conducted a user study with 12 interaction designers. As their tool, they used a custom-built virtual design environment with finger tracking and physics simulations for natural interactions with virtual devices and objects. Our study identified the designers' experience of space in relation to their own bodies and playful design explorations as key opportunities. Key challenges were the complexities of building a usable yet versatile VR-based "World Editor".
Purpose In Caco-2 cells, folate uptake via the proton-coupled folate transporter (PCFT) increases significantly by a 3-day treatment with 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). Additionally, mRNA ...content and protein expression of the transporter OATP1A2 were increased up to ninefold with 1,25(OH)2D3. We investigated whether these in vitro findings can be confirmed in humans in vivo. Methods Ten healthy volunteers (six women) received 5 mg folic acid orally once before and once together with the last intake of a 10-day course of 0.5 mug 1,25(OH)2D3 orally. One hundred twenty milligrams fexofenadine, an OATP1A2 substrate, was taken in 1 day before the first folic acid intake, and again on the ninth day of 1,25(OH)2D3 intake. Duodenal biopsies were taken for transporter mRNA assessments once before and once on the ninth or tenth day of the vitamin D3 course. Serum folic acid and fexofenadine concentrations were quantified with a chemiluminescence immunoassay and LC-MS/MS, respectively. Pharmacokinetics were compared between periods with standard bioequivalence approaches. Results While geometric mean folic acid AUC0-2h, which mainly reflects absorption, was 0.403 and 0.414 mg/L·h before and after the vitamin D3 course (geometric mean ratio (GMR), 1.027; 90 % confidence interval (90 % CI), 0.788-1.340), the geometric mean fexofenadine AUC0-2h was 1.932 and 2.761 mg/L·h, respectively (GMR, 1.429; 90 % CI, 0.890-2.294). PCFT- and OATP1A2-mRNA expressions in duodenal biopsies were essentially unchanged. Conclusions No significant changes in folic acid and fexofenadine absorption were observed after a 10-day course of 1,25(OH)2D3 in humans in vivo. This study underlines the importance of confirming in vitro findings in vivo in humans.
Solid tumors, such as hepato-pancreato-biliary cancer, develop tumor hypoxia with tumor growth. Despite advances in surgery, a majority of these patients are in an unresectable condition. At this ...stage standard cytotoxic chemotherapy regimens are applied with limited success. Novel biological treatment options based on an antiangiogenic mechanism of action neglect other hypoxia mediated mechanisms (e.g. epithelial-mesenchymal transition, Warburg effect, and immunological response) leading to an increased invasiveness with a poor outcome. The novel antihypoxic molecule myo-inositoltrispyrophosphate (ITPP, OXY111A) acts as an allosteric effector of hemoglobin and promotes normoxia in hypoxic tumors. In preclinical studies, tumor growth was reduced and survival prolonged. Additionally, a beneficial side effect profile was observed.
In this first Ib/IIa clinical trial we will assess safety and tolerability of OXY111A as well as a proof of concept regarding efficacy in patients with non-resectable primary and secondary tumors of the liver, pancreas, and biliary tract. The study design is exploratory, prospective, open-labelled and mono-centric. The study is divided in a dose escalation part with a maximum of 48 subjects and an extension part, in which 21 subjects will be included.
The novel antihypoxic compound OXY111A has been tested in several cancer animal models showing beneficial effects for both survival and low side effect profiles. This first in patient application of OXY111A will reveal potential beneficial outcomes if anti-hypoxic therapy is added to standard cytotoxic treatment in patients with primary and secondary hepatopancreatobiliary tumors.
Institution Ethical Board Approval ID: KEK-ZH-Nr. 2014-0374; Swiss regulatory authority Swissmedic (2015DR1009); ClinicalTrials.gov Identifier: NCT02528526 , prospectively registered on November 11
, 2014.
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