The Cγ Subunit is a Unique Isozyme of the cAMP-Dependent Protein Kinase

There are at least three isozymes (Cα, Cβ, and Cγ) of the mammalian catalytic (C) subunit of cAMP-dependent protein kinase (PKA) (Beebe, S., Oyen, O., Sandberg, M., Froysa, A., Hansson, V., and Jahnsen, T. (1990) Mol. Endocrinol. 4, 465-475). To compare the Cγ and Cα isozymes, the respective cDNAs were expressed in permanently transformed Kin-8 PKA-deficient Y1 adrenal cells using the mouse metallothionein promoter. The recombinant C subunits were characterized as immunoreactive, zinc-inducible, cAMP-dependent kinase activities. In contrast to Cα, histone was a better substrate than Leu-Arg-Arg-Ala-Ser-Leu-Gly (Kemptide) for Cγ. Furthermore, Cγ histone kinase activity was not inhibited by the protein kinase inhibitor peptide (5- 24 amide), which has been widely used as a PKA-specific inhibitor. The major Cγ peak (type I) eluted from DEAE-Sepharose at a higher NaCl concentration (120 mM) than the Cα type I eluted (70 mM). Cγ and Cα type II eluted between 220 and 240 mM NaCl. Cγ required higher concentrations of cAMP than Cα did for dissociation from the mutant type I holoenzyme. These differences provided a basis for the separation of the mutant RI-associated isozymes on DEAE-Sepharose. Both Cα (41-42 kDa) and Cγ (39-40 kDa) were identified by a C subunit antibody after sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunoblot analysis. Zinc induced the PKA-mediated rounding phenotype in Cγ and Cα clones, thereby restoring the cells to the parent Y1 adrenal cell phenotype. Collectively, these data indicate that Cγ is an active PKA C subunit but suggest that Cγ and Cα have different protein and peptide recognition determinants

Oceanic forcing of the global warming slowdown in multi-model simulations

Abstract Concurrent with the slowdown of global warming during 2002–2013, the wintertime land surface air temperatures over Eurasia, North America, Africa, Australia, South America, and Greenland experienced notable cooling trends. The oceanic effects on the continental cooling trends are here investigated using two sets of uncoupled experiments with six different climate models. Daily and annually varying sea ice is prescribed for both sets of experiments, while daily and annually varying SST is used in the first set (EXP1) and daily and annually repeating climatological mean SST in the second set (EXP2). All six models capture the slowdown of global-mean land surface air temperature during 2002–2013 winters in EXP1 only. The slowdown concurs with a negative phase of the Pacific Decadal Oscillation (PDO), indicating that PDO plays an important role in modulating the global warming signal. Not all ensemble members capture the cooling trends over the continents, suggesting additional contribution from internal atmospheric variability. KEYWORDS continental cooling, global warming, multi-model simulations, Pacific Decadal Oscillationpublished versio

1,1′-(4,4′-Bipiperidine-1,1′-di­yl)bis­(2,2,2-trifluoro­ethanone)

The title compound, C14H18F6N2O2, has a central center of symmetry with both piperidine rings occurring in regular chair conformations. Even though the structure is fairly compact with no sizable voids, the shortest H⋯O distance is as long as 2.58 Å

Precise determination of polarization fields in c-plane GaN/Al x Ga1-x N/GaN heterostructures with capacitance--voltage-measurements

Due to changes in the spontaneous and piezoelectric polarization, AlGaN/GaN heterostructures exhibit strong polarization fields at heterointerfaces. For quantum wells, the polarization fields lead to a strong band bending and a redshift of the emission wavelength, known as quantum-confined Stark effect. In this paper the polarization fields of thin AlGaN layers in a GaN matrix were determined by evaluating the changes in the depletion region width in comparison to a reference sample without heterostructure using capacitance-voltage-measurements. The polarization fields for Al0.09Ga0.91N (0.6 +/- 0.7 MV cm(-1)), Al0.26Ga0.74N (2.3 +/- 0.6 MV cm(-1)), Al0.34Ga0.66N (3.1 +/- 0.6 MV cm(-1)), Al0.41Ga0.59N (4.0 +/- 0.7 MV cm(-1)) and Al0.47Ga0.53N (5.0 +/- 0.8 MV cm(-1)) heterostructures were determined. The results of the field strength and field direction of all samples are in excellent agreement with values predicted by theory and a capacitance-voltage based Poisson-carrier transport simulation approach giving experimental evidence for a nonlinear increasing polarization field with Al-concentration. (C) 2019 The Japan Society of Applied Physic

Reconciling conflicting evidence for the cause of the observed early 21st century Eurasian cooling

It is now well established that the Arctic is warming at a faster rate than the global average. This warming, which has been accompanied by a dramatic decline in sea ice, has been linked to cooling over the Eurasian subcontinent over recent decades, most dramatically during the period 1998–2012. This is a counter-intuitive impact under global warming given that land regions should warm more than ocean (and the global average). Some studies have proposed a causal teleconnection from Arctic sea-ice retreat to Eurasian wintertime cooling; other studies argue that Eurasian cooling is mainly driven by internal variability. Overall, there is an impression of strong disagreement between those holding the “ice-driven” versus “internal variability” viewpoints. Here, we offer an alternative framing showing that the sea ice and internal variability views can be compatible. Key to this is viewing Eurasian cooling through the lens of dynamics (linked primarily to internal variability with some potential contribution from sea ice; cools Eurasia) and thermodynamics (linked to sea-ice retreat; warms Eurasia). This approach, combined with recognition that there is uncertainty in the hypothesized mechanisms themselves, allows both viewpoints (and others) to co-exist and contribute to our understanding of Eurasian cooling. A simple autoregressive model shows that Eurasian cooling of this magnitude is consistent with internal variability, with some periods exhibiting stronger cooling than others, either by chance or by forced changes. Rather than posit a “yes-or-no” causal relationship between sea ice and Eurasian cooling, a more constructive way forward is to consider whether the cooling trend was more likely given the observed sea-ice loss, as well as other sources of low-frequency variability. Taken in this way both sea ice and internal variability are factors that affect the likelihood of strong regional cooling in the presence of ongoing global warming.</p

Reconciling conflicting evidence for the cause of the observed early 21st century Eurasian cooling

It is now well established that the Arctic is warming at a faster rate than the global average. This warming, which has been accompanied by a dramatic decline in sea ice, has been linked to cooling over the Eurasian subcontinent over recent decades, most dramatically during the period 1998–2012. This is a counter-intuitive impact under global warming given that land regions should warm more than ocean (and the global average). Some studies have proposed a causal teleconnection from Arctic sea-ice retreat to Eurasian wintertime cooling; other studies argue that Eurasian cooling is mainly driven by internal variability. Overall, there is an impression of strong disagreement between those holding the “ice-driven” versus “internal variability” viewpoints. Here, we offer an alternative framing showing that the sea ice and internal variability views can be compatible. Key to this is viewing Eurasian cooling through the lens of dynamics (linked primarily to internal variability with some potential contribution from sea ice; cools Eurasia) and thermodynamics (linked to sea-ice retreat; warms Eurasia). This approach, combined with recognition that there is uncertainty in the hypothesized mechanisms themselves, allows both viewpoints (and others) to co-exist and contribute to our understanding of Eurasian cooling. A simple autoregressive model shows that Eurasian cooling of this magnitude is consistent with internal variability, with some periods exhibiting stronger cooling than others, either by chance or by forced changes. Rather than posit a “yes-or-no” causal relationship between sea ice and Eurasian cooling, a more constructive way forward is to consider whether the cooling trend was more likely given the observed sea-ice loss, as well as other sources of low-frequency variability. Taken in this way both sea ice and internal variability are factors that affect the likelihood of strong regional cooling in the presence of ongoing global warming.publishedVersio

SIRT1 Activation by a c-MYC Oncogenic Network Promotes the Maintenance and Drug Resistance of Human FLT3-ITD Acute Myeloid Leukemia Stem Cells

SummaryThe FLT3-ITD mutation is frequently observed in acute myeloid leukemia (AML) and is associated with poor prognosis. In such patients, FLT3 tyrosine kinase inhibitors (TKIs) are only partially effective and do not eliminate the leukemia stem cells (LSCs) that are assumed to be the source of treatment failure. Here, we show that the NAD-dependent SIRT1 deacetylase is selectively overexpressed in primary human FLT3-ITD AML LSCs. This SIRT1 overexpression is related to enhanced expression of the USP22 deubiquitinase induced by c-MYC, leading to reduced SIRT1 ubiquitination and enhanced stability. Inhibition of SIRT1 expression or activity reduced the growth of FLT3-ITD AML LSCs and significantly enhanced TKI-mediated killing of the cells. Therefore, these results identify a c-MYC-related network that enhances SIRT1 protein expression in human FLT3-ITD AML LSCs and contributes to their maintenance. Inhibition of this oncogenic network could be an attractive approach for targeting FLT3-ITD AML LSCs to improve treatment outcomes

Ductility of wide-beam RC frames as lateral resisting system

[EN] Some Mediterranean seismic codes consider wide-beam reinforced concrete moment resisting frames (WBF) as horizontal load carrying systems that cannot guarantee high ductility performances. Conversely, Eurocode 8 allows High Ductility Class (DCH) design for such structural systems. Code prescriptions related to WBF are systematically investigated. In particular, lesson learnt for previous earthquakes, historical reasons, and experimental and numerical studies underpinning specific prescriptions on wide beams in worldwide seismic codes are discussed. Local and global ductility of WBF are then analytically investigated through (1) a parametric study on chord rotations of wide beams with respect to that of deep beams, and (2) a spectral-based comparison of WBF with conventional reinforced concrete moment resisting frames (i.e. with deep beams). Results show that the set of prescriptions given by modern seismic codes provides sufficient ductility to WBF designed in DCH. In fact, global capacity of WBF relies more on the lateral stiffness of the frames and on the overstrength of columns rather than on the local ductility of wide beams, which is systematically lower with respect to that of deep beams.Gómez-Martínez, F.; Alonso Durá, A.; De Luca, F.; Verderame, GM. (2016). Ductility of wide-beam RC frames as lateral resisting system. Bulletin of Earthquake Engineering. 14(6):1545-1569. doi:10.1007/s10518-016-9891-xS15451569146ACI (1989) Building code requirements for reinforced concrete (ACI 318-89). ACI Committee 318, American Concrete Institute, Farmington Hills, Michigan, USAACI (2008) Building code requirements for structural concrete (ACI 318-08) and commentary (318-08). ACI Committee 318, American Concrete Institute, Farmington Hills, Michigan, USAACI-ASCE (1991) Recommendations for design of beam-column connections in monolithic reinforced concrete structures (ACI 352R-91). 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J Earthquake Eng 11:493–511Benavent-Climent A, Zahran R (2010) An energy-based procedure for the assessment of seismic capacity of existing frames: application to RC wide beam systems in Spain. Soil Dyn Earthq Eng 30:354–367Benavent-Climent A, Cahís X, Zahran R (2009) Exterior wide beam-column connections in existing RC frames subjected to lateral earthquake loads. Eng Struct 31:1414–1424Benavent-Climent A, Cahís X, Vico JM (2010) Interior wide beam-column connections in existing RC frames subjected to lateral earthquake loading. Bull Earthq Eng 8:401–420BHRC (2004) Iranian Code of Practice for Seismic Resistant Design of Buildings. Standard Nº 2800, 3rd edn. Building and Housing Research Center, TehranBorzi B, Elnashai AS (2000) Refined force reduction factors for seismic design. Eng Struct 22:1244–1260Borzi B, Pinho R, Crowley H (2008) Simplified pushover-based vulnerability analysis for large-scale assessment of RC buildings. 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Informes de la Construcción 66(533):e008 (in Spanish)Domínguez D, López-Almansa F, Benavent-Climent A (2016) Would RC wide-beam buildings in Spain have survived Lorca earthquake (11-05-2011)? Eng Struct 108:134–154Dönmez C (2013) Seismic Performance of Wide-Beam Infill-Joist Block RC Frames in Turkey. J Perform Constr Facil 29(1):04014026Fadwa I, Ali TA, Nazih E, Sara M (2014) Reinforced concrete wide and conventional beam-column connections subjected to lateral load. Eng Struct 76:34–48Fardis MN (2009) Seismic design, assessment and retrofitting of concrete, Buildings edn. Springer, LondonGentry TR, Wight JK (1992) Reinforced concrete wide beam-column connections under earthquake-type loading. Report no. UMCEE 92-12. Department of Civil and Environmental Engineering, University of Michigan, Ann Arbor, Michigan, USAGómez-Martínez F (2015) FAST simplified vulnerability approach for seismic assessment of infilled RC MRF buildings and its application to the 2011 Lorca (Spain) earthquake. Ph.D. Thesis, Polytechnic University of Valencia, SpainGómez-Martínez F, Pérez García A, De Luca F, Verderame GM (2015a) Comportamiento de los edificios de HA con tabiquería durante el sismo de Lorca de 2011: aplicación del método FAST. Informes de la Construcción 67(537):e065 (in Spanish)Gómez-Martínez F, Pérez-García A, Alonso Durá A, Martínez Boquera A, Verderame GM (2015b) Eficacia de la norma NCSE-02 a la luz de los daños e intervenciones tras el sismo de Lorca de 2011. In: Proceedings of Congreso Internacional sobre Intervención en Obras Arquitectónicas tras Sismo: L’Aquila (2009), Lorca (2011) y Emilia Romagna (2012), May 13–14, Murcia, Spain (in Spanish)Gómez-Martínez F, Verderame GM, De Luca F, Pérez-García A, Alonso-Durá, A (2015c). High ductility seismic performances of wide-beam RC frames. In; XVI Convegno ANIDIS. September 13–17, L'Aquila, ItalyHawkins NM, Mitchell D (1979) Progressive collapse of flat plate structures. 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