Pharmacological profiling of store-operated Ca(2+) entry in retinal arteriolar smooth muscle

Objective: Pharmacological profiling of store-operated Ca(2+) entry (SOCE) and molecular profiling of ORAI and TRPC expression in arterioles. 
Methods: Fura-2 based microfluorimetry was used to assess CPA-induced SOCE in rat retinal arteriolar myocytes. Arteriolar ORAI and TRP transcript expression were screened using RT-PCR. 
Results: SKF96365 and LOE908 blocked SOCE (IC(50) s of 1.2µM and 1.4µM, respectively). Gd(3+) and La(3+) potently inhibited SOCE (IC(50) s of 21nM and 42nM, respectively), but Ni(2+) showed lower potency (IC(50) = 11.6µM). 2-aminoethyldiphenyl borate (2APB) inhibited SOCE (IC(50) = 3.7µM) but enhanced basal influx (>100µM). Verapamil and nifedipine had no effect at concentrations that inhibit L-type Ca(2+) channels, but diltiazem inhibited SOCE by approximately 40% (=0.1µM). RT-PCR demonstrated transcript expression for ORAI 1, 2 and 3, and TRPC1, 3, 4 and 7. Transcripts for TRPV1 and 2, which are activated by 2APB, were also expressed. 
Conclusion: The pharmacological profile of SOCE in retinal arteriolar smooth muscle appears unique when compared to other vascular tissues. This suggests that the molecular mechanisms underlying SOCE can differ, even in closely related tissues. Taken together, the pharmacological and molecular data are most consistent with involvement of TRPC1 in SOCE, although involvement of ORAI or other TRPC channels cannot be excluded. © 2012 John Wiley & Sons Ltd.

Ca(2+) sparks promote myogenic tone in retinal arterioles

Background and Purpose: Ca(2+) imaging reveals subcellular Ca(2+) sparks and global Ca(2+) waves/oscillations in vascular smooth muscle. It is well established that Ca(2+) sparks can relax arteries, but we have previously reported that sparks can summate to generate Ca(2+) waves/oscillations in unpressurized retinal arterioles, leading to constriction. We have extended these studies to test the functional significance of Ca(2+) sparks in the generation of myogenic tone in pressurized arterioles.

Experimental Approach: Isolated retinal arterioles (25-40 μm external diameter) were pressurized to 70 mmHg, leading to active constriction. Ca(2+) signals were imaged from arteriolar smooth muscle in the same vessels using Fluo4 and confocal laser microscopy.

Key Results: Tone development was associated with an increased frequency of Ca(2+) sparks and oscillations. Vasomotion was observed in 40% of arterioles and was associated with synchronization of Ca(2+) oscillations, quantifiable as an increased cross-correlation coefficient. Inhibition of Ca(2+) sparks with ryanodine, tetracaine, cyclopiazonic acid or nimodipine, or following removal of extracellular Ca(2+) , resulted in arteriolar relaxation. Cyclopiazonic acid-induced dilatation was associated with decreased Ca(2+) sparks and oscillations but with a sustained rise in the mean global cytoplasmic [Ca(2+) ] ([Ca(2+) ]c ), as measured using Fura2 and microfluorimetry.

Conclusions and Implications: This study provides direct evidence that Ca(2+) sparks can play an excitatory role in pressurized arterioles, promoting myogenic tone. This contrasts with the generally accepted model in which sparks promote relaxation of vascular smooth muscle. Changes in vessel tone in the presence of cyclopiazonic acid correlated more closely with changes in spark and oscillation frequency than global [Ca(2+) ]c , underlining the importance of frequency-modulated signalling in vascular smooth muscle.

Knowledge Formation and the Great Divergence between China and Europe: Manuscripts and Printed Books, ca. 581–1840

Literature dealing with the history of Chinese printed books and printing is voluminous. Yet studies of how knowledge in general and utilitarian forms of knowledge in particular were generated, accumulated and circulated by printed books and their relationship with the long-term socio-economic transformation of China are rare. This paper aims to open up the subject by examining the long-term trends in the production of manuscripts and books and focusing on the connections between the generation and dissemination of useful knowledge in China and the production and circulation of printed books over the centuries and dynasties from circa 581 to 1840 compared to Europe. It connects trends in this indicator for knowledge formation and diffusion to economic growth, urbanization, changes in higher forms of education, the rise of literacy, the development of printing technologies, and changes in perceptions of the natural world. It concludes that human capital formation in China probably proceeded at a slower rate,which is relevant for narratives of the “divergence” between China and Europe.

Switching between molecular switch types by module rearrangement:Ca -enabled, H-driven 'off-on-off', H-driven YES and PASS 0 as well as H, Ca-driven AND logic operations

Several logic gates and switches can be accessed from two different combinations of a single set of fluorophore, receptor and spacer components.

Composer in Interview: Pierre Boulez

Interview with composer Pierre Boulez

Comparison of progenitor mass estimates for the type IIP SN 2012A

We present the one-year long observing campaign of SN 2012A which exploded in the nearby (9.8 Mpc) irregular galaxy NGC 3239. The photometric evolution is that of a normal type IIP supernova. The absolute maximum magnitude, with MB = -16.23 +- 0.16 mag. SN2012A reached a peak luminosity of about 2X10**42 erg/s, which is brighter than those of other SNe with a similar 56Ni mass. The latter was estimated from the luminosity in the exponential tail of the light curve and found to be M(56Ni) = 0.011 +-0.004 Msun. The spectral evolution of SN 2012A is also typical of SN IIP, from the early spectra dominated by a blue continuum and very broad (~10**4 km/s) Balmer lines, to the late-photospheric spectra characterized by prominent P-Cygni features of metal lines (Fe II, Sc II, Ba II, Ti II, Ca II, Na ID). The photospheric velocity is moderately low, ~3X10**3 km/s at 50 days, for the low optical depth metal lines. The nebular spectrum obtained 394 days after the shock breakout shows the typical features of SNe IIP and the strength of the [O I] doublet suggests a progenitor of intermediate mass, similar to SN 2004et (~15 Msun). A candidate progenitor for SN 2012A has been identified in deep, pre-explosion K'-band Gemini North (NIRI) images, and found to be consistent with a star with a bolometric magnitude -7.08+-0.36 (log L/Lsun = 4.73 +- 0.14$ dex). The magnitude of the recovered progenitor in archival images points toward a moderate-mass 10.5 (-2/+4.5) Msun star as the precursor of SN 2012A. The explosion parameters and progenitor mass were also estimated by means of a hydrodynamical model, fitting the bolometric light curve, the velocity and the temperature evolution. We found a best fit for a kinetic energy of 0.48 foe, an initial radius of 1.8X10**13 cm and ejecta mass of 12.5 Msun.

Electron excitation of Ca XVII

Electron-excitation collision strengths have been calculated for transitions between the ten lowest levels of Ca XVII (2sS, 2s2p P, 2s2p P, 2pP 2p D, 2pS ). At high impact energies, where all the channels are open, the calculation was carried out in the LS-coupling approximation by means of the R-matrix method. Transitions between the fine structure levels were then determined by application of a unitary transformation to the LS-coupled K-matrices. At low impact energies, where some of the channels may be closed, an extension of the R-matrix method was employed to take account of relativistic effects directly in the scattering equations. In general, results are in good agreement with recent distorted-wave calculations. Electron-excitation rates are given for a range of electron temperatures.

The vascular targeting agent combretastatin-A4 and a novel cis-Restricted {beta}-Lactam Analogue, CA-432, induce apoptosis in human chronic myeloid leukemia cells and ex vivo patient samples including those displaying multidrug resistance

Combretastatin-A4 (CA-4) is a natural derivative of the African willow tree Combretum caffrum. CA-4 is one of the most potent antimitotic components of natural origin, but it is, however, intrinsically unstable. A novel series of CA-4 analogs incorporating a 3,4-diaryl-2-azetidinone (β-lactam) ring were designed and synthesized with the objective to prevent cis -trans isomerization and improve the intrinsic stability without altering the biological activity of CA-4. Evaluation of selected β-lactam CA-4 analogs demonstrated potent antitubulin, antiproliferative, and antimitotic effects in human leukemia cells. A lead β-lactam analog, CA-432, displayed comparable antiproliferative activities with CA-4. CA-432 induced rapid apoptosis in HL-60 acute myeloid leukemia cells, which was accompanied by depolymerization of the microtubular network, poly(ADP-ribose) polymerase cleavage, caspase-3 activation, and Bcl-2 cleavage. A prolonged G(2)M cell cycle arrest accompanied by a sustained phosphorylation of mitotic spindle checkpoint protein, BubR1, and the antiapoptotic proteins Bcl-2 and Bcl-x(L) preceded apoptotic events in K562 chronic myeloid leukemia (CML) cells. Molecular docking studies in conjunction with comprehensive cell line data rule out CA-4 and β-lactam derivatives as P-glycoprotein substrates. Furthermore, both CA-4 and CA-432 induced significantly more apoptosis compared with imatinib mesylate in ex vivo samples from patients with CML, including those positive for the T315I mutation displaying resistance to imatinib mesylate and dasatinib. In summary, synthetic intrinsically stable analogs of CA-4 that display significant clinical potential as antileukemic agents have been designed and synthesized.

SN 2009ip at late times - an interacting transient at+2 years

We present photometric and spectroscopic observations of the interacting transient SN 2009ip taken during the 2013 and 2014 observing seasons. We characterize the photometric evolution as a steady and smooth decline in all bands, with a decline rate that is slower than expected for a solely Co-56-powered supernova at late phases. No further outbursts or eruptions were seen over a two year period from 2012 December until 2014 December. SN 2009ip remains brighter than its historic minimum from pre-discovery images. Spectroscopically, SN 2009ip continues to be dominated by strong, narrow (less than or similar to 2000 km s(-1)) emission lines of H, He, Ca, and Fe. While we make tenuous detections of [Fe II] lambda 7155 and [O I] lambda lambda 6300, 6364 lines at the end of 2013 June and the start of 2013 October, respectively, we see no strong broad nebular emission lines that could point to a core-collapse origin. In general, the lines appear relatively symmetric, with the exception of our final spectrum in 2014 May, when we observe the appearance of a redshifted shoulder of emission at +550 km s(-1). The lines are not blueshifted, and we see no significant near-or mid-infrared excess. From the spectroscopic and photometric evolution of SN 2009ip until 820 d after the start of the 2012a event, we still see no conclusive evidence for core-collapse, although whether any such signs could be masked by ongoing interaction is unclear.

Apprentissage par problèmes étude exploratoire de son application partielle au collégial

Les débats actuels sur l'avenir des cégeps portent essentiellement sur une caractéristique: l'efficacité de l'enseignement. La mondialisation des marchés et les développements scientifiques et technologiques ont des incidences sur les programmes de formation et les stratégies éducatives. De nombreuses réflexions alimentent notre engagement pédagogique: peut-on, simultanément, concilier tous les objectifs d'une formation de qualité au cégep? Peut-on, à l'intérieur d'un programme professionnel reconnu comme étant"lourd", réaliser une formation qui doit être à la fois fondamentale, générale et polyvalente tout en permettant l'acquisition de connaissances très spécifiques à la profession? Comment éviter que cette acquisition se fasse au détriment du développement personnel? Comment répondre aux aspirations d'une formation collégiale qui se veut de qualité, tout en tenant compte des besoins nécessaires à l'intégration sociale et des caractéristiques imposées par le marché du travail: la capacité d'adaptation, la capacité de faire des choix fondés sur un système de valeurs et sur un esprit critique et enfin, la capacité d'ouverture à la diversité?"--Résumé abrégé par UMI.