A new look at diastole

The isovolumic period following systolic ejection is associated with untwisting of the apex that follows systolic torsion of the left ventricle, with simultaneous generation of negative pressures in the left ventricle. Previous studies have described this period as isovolumic relaxation, and have regarded the untwisting as entirely caused by restoring elastic forces. However, evidence from several sources indicates that some ventricular muscle is still contracting during this period, and that this muscle is subepicardial muscle or the ascending spiral segment of the ventricular myocardial band that extends from the apex up along the left ventricular epicardium and the right ventricular side of the septum to the root of the aorta. It is possible that diastolic dysfunction is due to defective incoordination of muscle contraction between the ascending and descending segments of this band rather than to defective passive restoring forces.     

Non‐invasive in vivo imaging of early metabolic tumor response to therapies targeting choline metabolism

The cholinic phenotype, characterized by elevated phosphocholine and a high production of total‐choline (tCho)‐containing metabolites, is a metabolic hallmark of cancer. It can be exploited for targeted therapy. Non‐invasive imaging biomarkers are required to evaluate an individual's response to targeted anticancer agents that usually do not rapidly cause tumor shrinkage. Because metabolic changes can manifest at earlier stages of therapy than changes in tumor size, the aim of the current study was to evaluate ¹H‐MRS and diffusion‐weighted MRI (DW‐MRI) as markers of tumor response to the modulation of the choline pathway in mammary tumor xenografts. Inhibition of choline kinase activity was achieved with the direct pharmacological inhibitor H‐89, indirect inhibitor sorafenib and down‐regulation of choline‐kinase α (ChKA) expression using specific short‐hairpin RNA (shRNA). While all three strategies significantly decreased tCho tumor content in vivo, only sorafenib and anti‐ChKA shRNA significantly repressed tumor growth. The increase of apparent‐diffusion‐coefficient of water (ADCw) measured by DW‐MRI, was predictive of the induced necrosis and inhibition of the tumor growth in sorafenib treated mice, while the absence of change in ADC values in H89 treated mice predicted the absence of effect in terms of tumor necrosis and tumor growth. In conclusion, ¹H‐choline spectroscopy can be useful as a pharmacodynamic biomarker for choline targeted agents, while DW‐MRI can be used as an early marker of effective tumor response to choline targeted therapies. DW‐MRI combined to choline spectroscopy may provide a useful non‐invasive marker for the early clinical assessment of tumor response to therapies targeting choline signaling.     

Seasonal mercury exposure and oxidant-antioxidant status of James Bay sport fishermen

The effects of a moderate seasonal exposure to methylmercury on plasma low-density lipoprotein (LDL) oxidation and cardiovascular risk indices are not known. The objective of the study was to assess the effects of a seasonal exposure to mercury at similar dose reported to increase cardiovascular risk through fish consumption. Effects on lipoprotein cholesterol and fatty acid profiles, LDL oxidation, and blood oxidant-antioxidant balance were to be assessed in sport fishermen presenting normal blood selenium and omega-3 fatty acid contents. Thirty-one healthy James Bay sport fishermen were assessed for within-subject longitudinal seasonal variations in hair and blood mercury, plasma oxidized LDL, lipophilic antioxidants, homocysteine, blood selenium, and glutathione peroxidase and reductase activities determined before and after the fishing season and compared by matched-pair tests. Hair mercury doubled during the fishing season (2.8+/-0.4 microg/g, P<.0001). Baseline blood selenium, homocysteine, and erythrocyte fatty acid profiles did not change. Plasma high-density lipoprotein cholesterol increased (+5%, P=.05), whereas very low-density lipoprotein cholesterol and oxidized LDL decreased (-8%, P=.05; -18%, P=.008). Blood glutathione peroxidase (+9.7%, P=.001), glutathione reductase (+7.2%, P<.0001), and total glutathione (+45% P<.0001) increased during the fishing season. Plasma total coenzyme Q10 (+13%, P=.02), ubiquinone-10 (+67%, P=.03), and beta-carotene (+46%, P=.01) also increased, whereas vitamin E status was unaffected. Pairwise correlations revealed no association between mercury exposure and any of the biomarkers investigated. In contrast, strong predictors of cardiovascular risk such as high-density lipoprotein cholesterol, oxidized LDL, and glutathione peroxidase improved during the fishing season despite elevated methylmercury exposure. The beneficial effects of seasonal fishing activity and fish consumption on cardiovascular health may suppress detrimental effects of concomitant moderate methylmercury exposure.     

Cosmogenic nuclide dating of Sahelanthropus tchadensis and Australopithecus bahrelghazali: Mio-Pliocene hominids from Chad

Ages were determined at two hominid localities from the Chad Basin in the Djurab Desert (Northern Chad). In the Koro Toro fossiliferous area, KT 12 locality (16°00′N, 18°53′E) was the site of discovery of Australopithecus bahrelghazali (Abel) and in the Toros-Menalla fossiliferous area, TM 266 locality (16°15′N, 17°29′E) was the site of discovery of Sahelanthropus tchadensis (Toumaï). At both localities, the evolutive degree of the associated fossil mammal assemblages allowed a biochronological estimation of the hominid remains: early Pliocene (3–3.5 Ma) at KT 12 and late Miocene (≈7 Ma) at TM 266. Atmospheric ¹⁰Be, a cosmogenic nuclide, was used to quasicontinuously date these sedimentary units. The authigenic ¹⁰Be/⁹Be dating of a pelite relic within the sedimentary level containing Abel yields an age of 3.58 ± 0.27 Ma that points to the contemporaneity of Australopithecus bahrelghazali (Abel) with Australopithecus afarensis (Lucy). The 28 ¹⁰Be/⁹Be ages obtained within the anthracotheriid unit containing Toumaï bracket, by absolute dating, the age of Sahelanthropus tchadensis to lie between 6.8 and 7.2 Ma. This chronological constraint is an important cornerstone both for establishing the earliest stages of hominid evolution and for new calibrations of the molecular clock.     

COPI coat assembly occurs on liquid-disordered domains and the associated membrane deformations are limited by membrane tension

Cytoplasmic coat proteins are required for cargo selection and budding of tubulovesicular transport intermediates that shuttle between intracellular compartments. To better understand the physical parameters governing coat assembly and coat-induced membrane deformation, we have reconstituted the Arf1-dependent assembly of the COPI coat on giant unilamellar vesicles by using fluorescently labeled Arf1 and coatomer. Membrane recruitment of Arf1-GTP occurs exclusively on disordered lipid domains and does not induce optically visible membrane deformation. In the presence of Arf1-GTP, coatomer self-assembles into weakly curved coats on membranes under high tension, while it induces extensive membrane deformation at low membrane tension. These deformations appear to have a composition different from the parental membrane because they are protected from phase transition. These findings suggest that the COPI coat is adapted to liquid disordered membrane domains where it could promote lipid sorting and that its mechanical effects can be tuned by membrane tension.