Smoothelin-B deficiency results in reduced arterial contractility, hypertension, and cardiac hypertrophy in mice

BACKGROUND: Smoothelins are actin-binding proteins that are abundantly expressed in healthy visceral (smoothelin-A) and vascular (smoothelin-B) smooth muscle. Their expression is strongly associated with the contractile phenotype of smooth muscle cells. Analysis of mice lacking both smoothelins (Smtn-A/B(-/-) mice) previously revealed a critical role for smoothelin-A in intestinal smooth muscle contraction. Here, we report on the generation and cardiovascular phenotype of mice lacking only smoothelin-B (Smtn-B(-/-)). METHODS AND RESULTS: Myograph studies revealed that the contractile capacity of the saphenous and femoral arteries was strongly reduced in Smtn-B(-/-) mice, regardless of the contractile agonist used to trigger contraction. Arteries from Smtn-A/B(-/-) compound mutant mice exhibited a similar contractile deficit. Smtn-B(-/-) arteries had a normal architecture and expressed normal levels of other smooth muscle cell-specific genes, including smooth muscle myosin heavy chain, alpha-smooth muscle actin, and smooth muscle-calponin. Decreased contractility of Smtn-B(-/-) arteries was paradoxically accompanied by increased mean arterial pressure (20 mm Hg) and concomitant cardiac hypertrophy despite normal parasympathetic and sympathetic tone in Smtn-B(-/-) mice. Magnetic resonance imaging experiments revealed that cardiac function was not changed, whereas distension of the proximal aorta during the cardiac cycle was increased in Smtn-B(-/-) mice. However, isobaric pulse wave velocity and pulse pressure measurements indicated normal aortic distensibility. CONCLUSIONS: Collectively, our results identify smoothelins as key determinants of arterial smooth muscle contractility and cardiovascular performance. Studies on mutations in the Smtn gene or alterations in smoothelin levels in connection to hypertension in humans are warranted

The Nucleoporin Can/Nup214 Binds to Both the Cytoplasmic and the Nucleoplasmic Sides of the Nuclear Pore Complex in Overexpressing Cells

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Mitotic kinase cascades orchestrating timely disjunction and movement of centrosomes maintain chromosomal stability and prevent cancer

Centrosomes are microtubule-organizing centers that duplicate in S phase to form bipolar spindles that separate duplicated chromosomes faithfully into two daughter cells during cell division. Recent studies show that proper timing of centrosome dynamics, the disjunction and movement of centrosomes, is tightly linked to spindle symmetry, correct microtubule-kinetochore attachment, and chromosome segregation. Here, we review mechanisms that regulate centrosome dynamics, with emphasis on the roles of key mitotic kinases in the proper timing of centrosome dynamics and how aberrancies in these processes may cause chromosomal instability and cancer

Nuclear pore protein NUP88 activates anaphase-promoting complex to promote aneuploidy

Item does not contain fulltextThe nuclear pore complex protein NUP88 is frequently elevated in aggressive human cancers and correlates with reduced patient survival; however, it is unclear whether and how NUP88 overexpression drives tumorigenesis. Here, we show that mice overexpressing NUP88 are cancer prone and form intestinal tumors. To determine whether overexpression of NUP88 drives tumorigenesis, we engineered transgenic mice with doxycycline-inducible expression of Nup88. Surprisingly, NUP88 overexpression did not alter global nuclear transport, but was a potent inducer of aneuploidy and chromosomal instability. We determined that NUP88 and the nuclear transport factors NUP98 and RAE1 comprise a regulatory network that inhibits premitotic activity of the anaphase-promoting complex/cyclosome (APC/C). When overexpressed, NUP88 sequesters NUP98-RAE1 away from APC/CCDH1, triggering proteolysis of polo-like kinase 1 (PLK1), a tumor suppressor and multitasking mitotic kinase. Premitotic destruction of PLK1 disrupts centrosome separation, causing mitotic spindle asymmetry, merotelic microtubule-kinetochore attachments, lagging chromosomes, and aneuploidy. These effects were replicated by PLK1 insufficiency, indicating that PLK1 is responsible for the mitotic defects associated with NUP88 overexpression. These findings demonstrate that the NUP88-NUP98-RAE1-APC/CCDH1 axis contributes to aneuploidy and suggest that it may be deregulated in the initiating stages of a broad spectrum of human cancers

Magnetoresistivity of the spin-fluctuation materials titanium-beryllium (TiBe2) and uranium-aluminum (UAl2)

High-field magnetoresistivity (MR) measurements are presented for high-purity samples of TiBe2 and UAl2. The MR of TiBe2 gives strong evidence for scattering due to spin fluctuations. The peculiar features in the MR around 5 T are apparently connected to the maxima in the susceptibility and may provide a clue to a theoretical description of the contributions of spin fluctuations to the resistivity. A value for the spin-fluctuation temperature is obtained and it is in agreement with earlier estimates. The MR of UAl2 is consistent with the behavior of a compensated metal. From the high-field behavior of the MR we expect to observe de Haas–van Alphen oscillations above approximately 10 T, but up to 40 T no signals are found. A small negative MR at higher temperatures may be due to spin-fluctuation scattering, but the evidence is not as clear as for TiBe2

The Fermi surface of indium-bismuth (In5Bi3) from DHVA measurements

De Haas van Alphen data on In5Bi3 single crystals in magnetic fields up to 35 T are presented. A Fermi surface model is proposed based on symmetry considerations, on the angle dependency of the data and on the compensation of electron- and hole-pieces. The model is additionally based on the observation of high effective masses for the dominant pieces of the Fermi surface, indicating a flat character of the corresponding energy bands

Observation of the magnetic field dependence of the cyclotron mass in the Kondo lattice cerium boride (CeB6)

Low-temperature, high-field deHaas–van Alphen measurements are presented which show that the conduction-electron mass in the Kondo lattice CeB6 decreases strongly with field. This field dependence is consistent with recent specific-heat results. The geometry of the Fermi surface does not depend on field. Thus we observe a reduction in the many-body enhancement of the electronic density of states at the Fermi energy which is described by a change of the itinerant-electron mass alone; the number of particles and the occupation of states in k space remain unchanged. We argue that CeB6 represents a different limit of heavy-fermion behavior as compared to UPt3

Magnetic field dependence of the cyclotron effective mass in the Kondo lattice cerium hexaboride

We report the first observation of a field-dependent mass in a hybridizing f-electron system. CeB6 is an ordered moment heavy fermion system with an electronic specific heat coefficient of order 225–300 mJ/mole K2. Using the de Haas–van Alphen effect at temperatures as low as 60 mK in steady magnetic fields as large as 22 T, we observe a cyclotron orbit of frequency 8680 T for fields along the [100] direction. The mass of this orbit was measured at eight fixed fields and found to decrease from 18me to 8me as the field increases from 12 to 22 T. The observed Fermi surface is very similar to that of LaB6, indicating that the f-electrons are largely local rather than itinerant in CeB6, a picture confirmed by bandstructure calculations. The observed field dependence of the cyclotron mass is consistent with the low-energy scale of the system as measured, for example, by the Kondo temperature. Our results are compared with Fermi surface observations in other heavy fermion systems. Journal of Applied Physics is copyrighted by The American Institute of Physics

A de Haas-van Alphen study of the field dependence of the Fermi surface in ZrZn2

Pulsed field de Haas-van Alphen measurements of the Gamma centred part of the Fermi surface in ZrZn2 are presented for fields up to 35T. The spin-split Fermi surface was found to be field dependent. It is argued that the observed de Haas-van Alphen frequency is different from the frequency defined by the Onsager relation. An expression is derived based on the Stoner-Wohlfarth model which describes the difference in spin-up and spin-down frequencies as a function of field strength. The observed difference in the effective mass for the two spin directions can also be explained by this model and it compares well with band structure calculations. An anomalous behaviour of the second harmonic of the majority surface de Haas-van Alphen frequency was observed. A search for other frequencies was carried out but in spite of the high sensitivity, in terms of m*TD, no other orbits were seen

Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline

Item does not contain fulltextCellular senescence, which is characterized by an irreversible cell-cycle arrest(1) accompanied by a distinctive secretory phenotype(2), can be induced through various intracellular and extracellular factors. Senescent cells that express the cell cycle inhibitory protein p16(INK4A) have been found to actively drive naturally occurring age-related tissue deterioration(3,4) and contribute to several diseases associated with ageing, including atherosclerosis(5) and osteoarthritis(6). Various markers of senescence have been observed in patients with neurodegenerative diseases(7-9); however, a role for senescent cells in the aetiology of these pathologies is unknown. Here we show a causal link between the accumulation of senescent cells and cognition-associated neuronal loss. We found that the MAPT(P301S)PS19 mouse model of tau-dependent neurodegenerative disease(10) accumulates p16(INK4A)-positive senescent astrocytes and microglia. Clearance of these cells as they arise using INK-ATTAC transgenic mice prevents gliosis, hyperphosphorylation of both soluble and insoluble tau leading to neurofibrillary tangle deposition, and degeneration of cortical and hippocampal neurons, thus preserving cognitive function. Pharmacological intervention with a first-generation senolytic modulates tau aggregation. Collectively, these results show that senescent cells have a role in the initiation and progression of tau-mediated disease, and suggest that targeting senescent cells may provide a therapeutic avenue for the treatment of these pathologies