29 research outputs found

    The relationship between the diagonal and the bar constructions on a bisimplicial set

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    AbstractThe aim of this paper is to prove that the homotopy type of any bisimplicial set X is modelled by the simplicial set W¯X, the bar construction on X. We stress the interest of this result by showing two relevant theorems which now become simple instances of it; namely, the Homotopy colimit theorem of Thomason, for diagrams of small categories, and the generalized Eilenberg–Zilber theorem of Dold–Puppe for bisimplicial Abelian groups. Among other applications, we give an algebraic model for the homotopy theory of (not necessarily path-connected) spaces whose homotopy groups vanish in degree 4 and higher

    Prelamin A mediates myocardial inflammation in dilated and HIV-associated cardiomyopathies

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    Cardiomyopathies are complex heart muscle diseases that can be inherited or acquired. Dilated cardiomyopathy can result from mutations in LMNA, encoding the nuclear intermediate filament proteins lamin A/C. Some LMNA mutations lead to accumulation of the lamin A precursor, prelamin A, which is disease causing in a number of tissues, yet its impact upon the heart is unknown. Here, we discovered myocardial prelamin A accumulation occurred in a case of dilated cardiomyopathy, and we show that a potentially novel mouse model of cardiac-specific prelamin A accumulation exhibited a phenotype consistent with inflammatory cardiomyopathy, which we observed to be similar to HIV-associated cardiomyopathy, an acquired disease state. Numerous HIV protease therapies are known to inhibit ZMPSTE24, the enzyme responsible for prelamin A processing, and we confirmed that accumulation of prelamin A occurred in HIV+ patient cardiac biopsies. These findings (a) confirm a unifying pathological role for prelamin A common to genetic and acquired cardiomyopathies; (b) have implications for the management of HIV patients with cardiac disease, suggesting protease inhibitors should be replaced with alternative therapies (i.e., nonnucleoside reverse transcriptase inhibitors); and (c) suggest that targeting inflammation may be a useful treatment strategy for certain forms of inherited cardiomyopathy

    Riociguat treatment in patients with chronic thromboembolic pulmonary hypertension: Final safety data from the EXPERT registry

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    Objective: The soluble guanylate cyclase stimulator riociguat is approved for the treatment of adult patients with pulmonary arterial hypertension (PAH) and inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH) following Phase

    Impact of site-specific phosphorylation of protein kinase A sites Ser(23) and Ser(24) of cardiac troponin I in human cardiomyocytes

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    PKA-mediated phosphorylation of contractile proteins upon β-adrenergic stimulation plays an important role in the regulation of cardiac performance. Phosphorylation of the PKA sites (Se

    Three-dimensional model study of the Antarctic ozone hole in 2002 and comparison with 2000

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    An offline 3D chemical transport model (CTM) has been used to study the evolution of the Antarctic ozone hole during the sudden warming event of 2002 and to compare it with similar simulations for 2000. The CTM has a detailed stratospheric chemistry scheme and was forced by ECMWF and Met Office analyses. Both sets of meteorological analyses permit the CTM to produce a good simulation of the evolution of the 2002 vortex and its breakup, based on O3 comparisons with Total Ozone Mapping Spectrometer (TOMS) column data, sonde data, and first results from the Environmental Satellite–Michelson Interferometer for Passive Atmospheric Sounding (ENVISAT–MIPAS) instrument. The ozone chemical loss rates in the polar lower stratosphere in September 2002 were generally less than in 2000, because of the smaller average active chlorine, although around the time of the warming, the largest vortex chemical loss rates were similar to those in 2000 (i.e., −2.6 DU day−1 between 12 and 26 km). However, the disturbed vortex of 2002 caused a somewhat larger influence of polar processing on Southern Hemisphere (SH) midlatitudes in September. Overall, the calculations show that the average SH chemical O3 loss (poleward of 30°S) by September was ∼20 DU less in 2002 compared with 2000. A significant contribution to the much larger observed polar O3 column in September 2002 was due to the enhanced descent at the vortex edge and increased horizontal transport, associated with the distorted vortex

    Length-dependent activation is modulated by cardiac troponin I bisphosphorylation at Ser23 and Ser24 but not by Thr143 phosphorylation

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    Frank-Starling's law reflects the ability of the heart to adjust the force of its contraction to changes in ventricular filling, a property based on length-dependent myofilament activation (LDA). The threonine at amino acid 143 of cardiac troponin I (cTnI) is prerequisite for the length-dependent increase in C

    Phosphorylation of protein kinase C sites Ser42/44 decreases Ca2+-sensitivity and blunts enhanced length-dependent activation in response to protein kinase A in human cardiomyocytes

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    Protein kinase C (PKC)-mediated phosphorylation of troponin I (cTnI) at Ser42/44 is increased in heart failure. While studies in rodents demonstrated that PKC-mediated Ser42/44 phosphorylation decreases maximal force and ATPase activity, PKC incubation of human cardiomyocytes did not affect maximal force. We investigated whether Ser42/44 pseudo-phosphorylation affects force development and ATPase activity using troponin exchange in human myocardium. Additionally, we studied if pseudo-phosphorylated Ser42/44 modulates length-dependent activation of force, which is regulated by protein kinase A (PKA)-mediated cTnI-Ser23/24 phosphorylation. Isometric force was measured in membrane-permeabilized cardiomyocytes exchanged with human recombinant wild-type troponin or troponin mutated at Ser42/44 or Ser23/24 into aspartic acid (D) or alanine (A) to mimic phosphorylation and dephosphorylation, respectively. In troponin-exchanged donor cardiomyocytes experiments were repeated after PKA incubation. ATPase activity was measured in troponin-exchanged cardiac muscle strips. Compared to wild-type, 42D/44D decreased C

    A novel phosphorylation site, Serine 199, in the C-terminus of cardiac troponin I regulates calcium sensitivity and susceptibility to calpain-induced proteolysis

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    Phosphorylation of cardiac troponin I (cTnI) by protein kinase C (PKC) is implicated in cardiac dysfunction. Recently, Serine 199 (Ser199) was identified as a target for PKC phosphorylation and increased Ser199 phosphorylation occurs in end-stage failing compared with non-failing human myocardium. The functional consequences of cTnI-Ser199 phosphorylation in the heart are unknown. Therefore, we investigated the impact of phosphorylation of cTnI-Ser199 on myofilament function in human cardiac tissue and the susceptibility of cTnI to proteolysis. cTnI-Ser199 was replaced by aspartic acid (199D) or alanine (199A) to mimic phosphorylation and dephosphorylation, respectively, with recombinant wild-type (Wt) cTn as a negative control. Force development was measured at various [C
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