A new approach for the design of alloys is presented in this study. These “high‐entropy alloys” with multi‐principal elements were synthesized using well‐developed processing technologies. ...Preliminary results demonstrate examples of the alloys with simple crystal structures, nanostructures, and promising mechanical properties. This approach may be opening a new era in materials science and engineering.
ABSTRACT
We report on the determination of electron densities, and their impact on the outflow masses and rates, measured in the central few hundred parsecs of 11 local luminous active galaxies. We ...show that the peak of the integrated line emission in the active galactic nuclei (AGN) is significantly offset from the systemic velocity as traced by the stellar absorption features, indicating that the profiles are dominated by outflow. In contrast, matched inactive galaxies are characterized by a systemic peak and weaker outflow wing. We present three independent estimates of the electron density in these AGN, discussing the merits of the different methods. The electron density derived from the S ii doublet is significantly lower than that found with a method developed in the last decade using auroral and transauroral lines, as well as a recently introduced method based on the ionization parameter. The reason is that, for gas photoionized by an AGN, much of the S ii emission arises in an extended partially ionized zone where the implicit assumption that the electron density traces the hydrogen density is invalid. We propose ways to deal with this situation and we derive the associated outflow rates for ionized gas, which are in the range 0.001–0.5 M⊙ yr−1 for our AGN sample. We compare these outflow rates to the relation between $\dot{M}_{\rm out}$ and LAGN in the literature, and argue that it may need to be modified and rescaled towards lower mass outflow rates.
The “magic methyl” effect, a dramatic boost in the potency of biologically active compounds from the incorporation of a single methyl group, provides a simple yet powerful strategy employed by ...medicinal chemists in the drug discovery process. Despite significant advances, methodologies that enable the selective C(sp3)–H methylation of structurally complex medicinal agents remain very limited. In this work, we disclose a modular, efficient, and selective strategy for the α-methylation of protected amines (i.e., amides, carbamates, and sulfonamides) by means of electrochemical oxidation. Mechanistic analysis guided our development of an improved electrochemical protocol on the basis of the classic Shono oxidation reaction, which features broad reaction scope, high functional group compatibility, and operational simplicity. Importantly, this reaction system is amenable to the late-stage functionalization of complex targets containing basic nitrogen groups that are prevalent in medicinally active agents. When combined with organozinc-mediated C–C bond formation, our protocol enabled the direct methylation of a myriad of amine derivatives including those that have previously been explored for the “magic methyl” effect. This synthesis strategy thus circumvents multistep de novo synthesis that is currently necessary to access such compounds and has the potential to accelerate drug discovery efforts.
Chronic hypoxia causes pulmonary hypertension with vascular remodeling, increase in vascular tone, and altered reactivity to agonists. These changes involve alterations in multiple Ca(2+) pathways in ...pulmonary arterial smooth muscle cells (PASMCs). We have previously shown that vanilloid (TRPV)- and melastatin-related transient receptor potential (TRPM) channels are expressed in pulmonary arteries (PAs). Here we found that TRPV4 was the only member of the TRPV and TRPM subfamilies upregulated in PAs of chronic hypoxic rats. The increase in TRPV4 expression occurred within 1 day of hypoxia exposure, indicative of an early hypoxic response. TRPV4 in PASMCs were found to be mechanosensitive. Osmo-mechanical stress imposed by hypotonic solution activated Ca(2+) transients; they were inhibited by TRPV4 specific short interfering RNA, the TRPV blocker ruthenium red, and the cytochrome P450 epoxygenase inhibitor N-(methylsulfonyl)-2-(2-propynyloxy)-benzenehexanamide. Consistent with TRPV4 upregulation, the Ca(2+) response induced by the TRPV4 agonist 4α-phorbol 12,13-didecanoate and hypotonicity was potentiated in hypoxic PASMCs. Moreover, a significant myogenic tone, sensitive to ruthenium red, was observed in pressurized endothelium denuded small PAs of hypoxic but not normoxic rats. The elevated basal intracellular Ca(2+) concentration in hypoxic PASMCs was also reduced by ruthenium red. In extension of these results, the development of pulmonary hypertension, right heart hypertrophy, and vascular remodeling was significantly delayed and suppressed in hypoxic trpv4(-/-) mice. These results suggest the novel concept that TRPV4 serves as a signal pathway crucial for the development of hypoxia-induced pulmonary hypertension. Its upregulation may provide a pathogenic feed-forward mechanism that promotes pulmonary hypertension via facilitated Ca(2+) influx, subsequently enhanced myogenic tone and vascular remodeling.
In this paper, we consider the state controllability of networked systems, where the network topology is directed and weighted and the nodes are higher-dimensional linear time-invariant (LTI) ...dynamical systems. We investigate how the network topology, the node-system dynamics, the external control inputs, and the inner interactions affect the controllability of a networked system, and show that for a general networked multi-input/multi-output (MIMO) system: (1) the controllability of the overall network is an integrated result of the aforementioned relevant factors, which cannot be decoupled into the controllability of individual node-systems and the properties solely determined by the network topology; (2) if the network topology is uncontrollable by external inputs, then the networked system with identical nodes will be uncontrollable, even if it is structurally controllable; (3) with a controllable network topology, controllability and observability of the nodes together are necessary for the controllability of the networked systems under some mild conditions, but nevertheless they are not sufficient.
Transient receptor potential melastatin- (TRPM) and vanilloid-related (TRPV) channels are nonselective cation channels pertinent to diverse physiological functions. Multiple TRPM and TRPV channel ...subtypes have been identified and cloned in different tissues. However, their information in vascular tissue is scant. In this study, we sought to identify TRPM and TRPV channel subtypes expressed in rat deendothelialized intralobar pulmonary arteries (PAs) and aorta. With RT-PCR, mRNA of TRPM2, TRPM3, TRPM4, TRPM7, and TRPM8 of TRPM family and TRPV1, TRPV2, TRPV3, and TRPV4 of TRPV family were detected in both PAs and aorta. Quantitative real-time RT-PCR showed that TRPM8 and TRPV4 were the most abundantly expressed TRPM and TRPV subtypes, respectively. Moreover, Western blot analysis verified expression of TRPM2, TRPM8, TRPV1, and TRPV4 proteins in both types of vascular tissue. To examine the functional activities of these channels, we monitored intracellular Ca(2+) transients (Ca(2+)(i)) in pulmonary arterial smooth muscle cells (PASMCs) and aortic smooth muscle cells (ASMCs). The TRPM8 agonist menthol (300 muM) and the TRPV4 agonist 4alpha-phorbol 12,13-didecanoate (1 muM) evoked significant increases in Ca(2+)(i) in PASMCs and ASMCs. These Ca(2+) responses were abolished in the absence of extracellular Ca(2+) or the presence of 300 muM Ni(2+) but were unaffected by 1 muM nifedipine, suggesting Ca(2+) influx via nonselective cation channels. Hence, for the first time, our results indicate that multiple functional TRPM and TRPV channels are coexpressed in rat intralobar PAs and aorta. These novel Ca(2+) entry pathways may play important roles in the regulation of pulmonary and systemic circulation.
ABSTRACT
We report on our combined analysis of HST, VLT/MUSE, VLT/SINFONI, and ALMA observations of the local Seyfert 2 galaxy, NGC 5728 to investigate in detail the feeding and feedback of the ...active galactic nucleus (AGN). The data sets simultaneously probe the morphology, excitation, and kinematics of the stars, ionized gas, and molecular gas over a large range of spatial scales (10 pc to 10 kpc). NGC 5728 contains a large stellar bar that is driving gas along prominent dust lanes to the inner 1 kpc where the gas settles into a circumnuclear ring. The ring is strongly star forming and contains a substantial population of young stars as indicated by the lowered stellar velocity dispersion and gas excitation consistent with H ii regions. We model the kinematics of the ring using the velocity field of the CO (2–1) emission and stars and find it is consistent with a rotating disc. The outer regions of the disc, where the dust lanes meet the ring, show signatures of inflow at a rate of 1 M$\odot$ yr−1. Inside the ring, we observe three molecular gas components corresponding to the circular rotation of the outer ring, a warped disc, and the nuclear stellar bar. The AGN is driving an ionized gas outflow that reaches a radius of 250 pc with a mass outflow rate of 0.08 M$\odot$ yr−1 consistent with its luminosity and scaling relations from previous studies. While we observe distinct holes in CO emission which could be signs of molecular gas removal, we find that largely the AGN is not disrupting the structure of the circumnuclear region.
Abdominal aortic aneurysm (AAA) is a complex disease which is incompletely accounted for. Basement membrane (BM) Collagen IV (COL4A1/A2) is abundant in the artery wall, and several lines of evidence ...indicate a protective role of baseline COL4A1/A2 in AAA development. Using Col4a1/a2 hemizygous knockout mice (Col4a1/a2
, 129Svj background) we show that partial Col4a1/a2 deficiency augmented AAA formation. Although unchallenged aortas were morphometrically and biomechanically unaffected by genotype, explorative proteomic analyses of aortas revealed a clear reduction in BM components and contractile vascular smooth muscle cell (VSMC) proteins, suggesting a central effect of the BM in maintaining VSMCs in the contractile phenotype. These findings were translated to human arteries by showing that COL4A1/A2 correlated to BM proteins and VSMC markers in non-lesioned internal mammary arteries obtained from coronary artery bypass procedures. Moreover, in human AAA tissue, MYH11 (VSMC marker) was depleted in areas of reduced COL4 as assessed by immunohistochemistry. Finally, circulating COL4A1 degradation fragments correlated with AAA progression in the largest Danish AAA cohort, suggesting COL4A1/A2 proteolysis to be an important feature of AAA formation. In sum, we identify COL4A1/A2 as a critical regulator of VSMC phenotype and a protective factor in AAA formation.
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