PCSK9: A Multi-Faceted Protein That Is Involved in Cardiovascular Biology.

Pro-protein convertase subtilisin/kexin type 9 (PCSK9) is secreted mostly by hepatocytes and to a lesser extent by the intestine, pancreas, kidney, adipose tissue, and vascular cells. PCSK9 has been known to interact with the low-density lipoprotein receptor (LDLR) and chaperones the receptor to its degradation. In this manner, targeting PCSK9 is a novel attractive approach to reduce hyperlipidaemia and the risk for cardiovascular diseases. Recently, it has been recognised that the effects of PCSK9 in relation to cardiovascular complications are not only LDLR related, but that various LDLR-independent pathways and processes are also influenced. In this review, the various LDLR dependent and especially independent effects of PCSK9 on the cardiovascular system are discussed, followed by an overview of related PCSK9-polymorphisms and currently available and future therapeutic approaches to manipulate PCSK9 expression

Protein complex directs hemoglobin-to-hemozoin formation in Plasmodium falciparum

Malaria parasites use hemoglobin (Hb) as a major nutrient source in the intraerythrocytic stage, during which heme is converted to hemozoin (Hz). The formation of Hz is essential for parasite survival, but to date, the underlying mechanisms of Hb degradation and Hz formation are poorly understood. We report the presence of a ∼200-kDa protein complex in the food vacuole that is required for Hb degradation and Hz formation. This complex contains several parasite proteins, including falcipain 2/2', plasmepsin II, plasmepsin IV, histo aspartic protease, and heme detoxification protein. The association of these proteins is evident from coimmunoprecipitation followed by mass spectrometry, coelution from a gel filtration column, cosedimentation on a glycerol gradient, and in vitro protein interaction analyses. To functionally characterize this complex, we developed an in vitro assay using two of the proteins present in the complex. Our results show that falcipain 2 and heme detoxification protein associate with each other to efficiently convert Hb to Hz. We also used this in vitro assay to elucidate the modes of action of chloroquine and artemisinin. Our results reveal that both chloroquine and artemisinin act during the heme polymerization step, and chloroquine also acts at the Hb degradation step. These results may have important implications in the development of previously undefined antimalarials

Detection of short-period coronal oscillations during the total solar eclipse of 24 october, 1995

An experiment to search for short-period oscillations in the solar corona was conducted during the total solar eclipse of 1995 October 24 at Kalpi, India. The intensity in the continuum, centred around 5500 Å and with a passband having a half-width of 240 Å, was recorded at a counting rate of 20 Hz using a thermoelectric-liquid cooled photomultiplier. The power-spectrum analysis of the data reveals that most of the power is contained in 6 frequencies below 0.2 Hz. A least-square analysis gives the periods of the 6 frequency components to be 56.5, 19.5, 13.5, 8.0, 6.1, and 5.3 s. These oscillations are found to be sinusoidal, and their amplitudes are found to lie in the range 0.2-1.3% of the coronal brightness. Assuming these oscillations to be fast magnetosonic modes, the calculations indicate the availability of enough flux for the heating of the active regions in the solar corona

Adaptive stiffness in lattice metastructures through tensile-buckling inspired topology morphing

This paper explores the use of simultaneous tensile buckling of unit cells to induce a transformation in lattice topology. Under tension, unit cells undergo passive transformation from a rectangle-like to a triangle-/pentagon-like topology, with an associated change in the effective stiffness properties. This behaviour is investigated through finite element analysis and experiments, with analytical results providing insights into the observed behaviour. The analysis identifies (i) that the initial unit cell topology (rectangular) is dominated by membrane effects, (ii) the transformation phase is associated with negative stiffness, and (iii) once formed, the new topology (triangular/pentagonal) exhibits increased stiffness in both compression and tension. Finite element analysis confirms that the unit cell behaviour is also preserved in lattices. Under tension, the lattice undergoes a seven-fold increase in stiffness as it transitions from its initial to the new topology, with a regime of negative stiffness during this transformation accounting for approximately 82% of its total elastic deformation. This new approach to elastically tailor the nonlinear response of (meta-)materials/structures has the potential to contribute to the development of novel tensile energy absorbers

Topological Metal MoP Nanowire for Interconnect

The increasing resistance of Cu interconnects for decreasing dimensions is a major challenge in continued downscaling of integrated circuits beyond the 7-nm technology node as it leads to unacceptable signal delays and power consumption in computing. The resistivity of Cu increases due to electron scattering at surfaces and grain boundaries of the interconnects at the nanoscale. Topological semimetals, owing to their topologically protected surface states and suppressed electron backscattering, are promising material candidates to potentially replace current Cu interconnects as low-resistance interconnects. Here, we report the attractive resistivity scaling of topological metal MoP nanowires and show that the resistivity values are comparable to those of Cu interconnects below 500 nm$^2$ cross-section areas. More importantly, we demonstrate that the dimensional scaling of MoP nanowires, in terms of line resistance versus total cross-sectional area, is superior to those of effective Cu and barrier-less Ru interconnects, suggesting MoP is an attractive solution to the current scaling challenge of Cu interconnects.Comment: 4 figure

Community health workers and accountability: Reflections from an international "think-in"

Community health workers (CHWs) are frequently put forward as a remedy for lack of health system capacity, including challenges associated with health service coverage and with low community engagement in the health system, and expected to enhance or embody health system accountability. During a ‘think in’, held in June of 2017, a diverse group of practitioners and researchers discussed the topic of CHWs and their possible roles in a larger “accountability ecosystem.” This jointly authored commentary resulted from our deliberations. While CHWs are often conceptualized as cogs in a mechanistic health delivery system, at the end of the day, CHWs are people embedded in families, communities, and the health system. CHWs’ social position and professional role influence how they are treated and trusted by the health sector and by community members, as well as when, where, and how they can exercise agency and promote accountability. To that end, we put forward several propositions for further conceptual development and research related to the question of CHWs and accountability.publishedVersio

1D-confined crystallization routes for tungsten phosphides

Topological materials confined in one-dimension (1D) can transform computing technologies, such as 1D topological semimetals for nanoscale interconnects and 1D topological superconductors for fault-tolerant quantum computing. As such, understanding crystallization of 1D-confined topological materials is critical. Here, we demonstrate 1D-confined crystallization routes during template-assisted nanowire synthesis where we observe diameter-dependent phase selectivity for topological metal tungsten phosphides. A phase bifurcation occurs to produce tungsten monophosphide and tungsten diphosphide at the cross-over nanowire diameter of ~ 35 nm. Four-dimensional scanning transmission electron microscopy was used to identify the two phases and to map crystallographic orientations of grains at a few nm resolution. The 1D-confined phase selectivity is attributed to the minimization of the total surface energy, which depends on the nanowire diameter and chemical potentials of precursors. Theoretical calculations were carried out to construct the diameter-dependent phase diagram, which agrees with experimental observations. Our find-ings suggest a new crystallization route to stabilize topological materials confined in 1D.Comment: 5 figure

Community health workers and accountability: reflections from an international “think-in”

Community health workers (CHWs) are frequently put forward as a remedy for lack of health system capacity, including challenges associated with health service coverage and with low community engagement in the health system, and expected to enhance or embody health system accountability. During a ‘think in’, held in June of 2017, a diverse group of practitioners and researchers discussed the topic of CHWs and their possible roles in a larger “accountability ecosystem.” This jointly authored commentary resulted from our deliberations. While CHWs are often conceptualized as cogs in a mechanistic health delivery system, at the end of the day, CHWs are people embedded in families, communities, and the health system. CHWs’ social position and professional role influence how they are treated and trusted by the health sector and by community members, as well as when, where, and how they can exercise agency and promote accountability. To that end, we put forward several propositions for further conceptual development and research related to the question of CHWs and accountability

Near-zero negative real permittivity in far ultraviolet: extending plasmonics and photonics with B1-MoNx

CMOS-compatible, refractory conductors are emerging as the materials that will advance novel concepts into real, practical plasmonic technologies. From the available pallet of materials, those with negative real permittivity at very short wavelengths are extremely rare; importantly, they are vulnerable to oxidation—upon exposure to far-UV radiation—and nonrefractory. Epitaxial, substoichiometric, cubic MoN (B1-MoNx) films exhibit resistivity as low as 250 μΩ cm and negative real permittivity for experimental wavelengths as short as 155 nm, accompanied with unparalleled chemical and thermal stabilities, which are reported herein. Finite-difference time domain calculations suggest that B1-MoNx operates as an active plasmonic element deeper in the UV (100–200 nm) than any other known material, apart from Al, while being by far more stable and abundant than any other UV plasmonic conductor. Unexpectedly, the unique optical performance of B1-MoNx is promoted by nitrogen vacancies, thus changing the common perception on the role of defects in plasmonic materials

Plasmonic tunnel junctions for single-molecule redox chemistry

Nanoparticles attached just above a flat metallic surface can trap optical fields in the nanoscale gap. This enables local spectroscopy of a few molecules within each coupled plasmonic hotspot, with near thousand-fold enhancement of the incident fields. As a result of non-radiative relaxation pathways, the plasmons in such sub-nanometre cavities generate hot charge carriers, which can catalyse chemical reactions or induce redox processes in molecules located within the plasmonic hotspots. Here, surface-enhanced Raman spectroscopy allows us to track these hot-electron-induced chemical reduction processes in a series of different aromatic molecules. We demonstrate that by increasing the tunnelling barrier height and the dephasing strength, a transition from coherent to hopping electron transport occurs, enabling observation of redox processes in real time at the single-molecule level.We acknowledge financial support from EPSRC grants EP/G060649/1, EP/I012060/1, EP/L027151/1, ERC grant LINASS 320503. F.B. acknowledges support from the Winton Programme for the Physics of Sustainability. S.J.B. thanks the European Commission for a Marie Curie Fellowship (NANOSPHERE, 658360). M.K. thanks the European Commission for a Marie Curie Fellowship (SPARCLEs, 7020005). P.N. acknowledges support from the Harvard University Center for the Environment (HUCE). R.C. acknowledges support from the Dr Manmohan Singh scholarship from St John’s College. C.C. acknowledges support from the UK National Physical Laboratories. R.S. acknowledges computational resources provided by the Center for Computational Innovations (CCI) at Rensselaer Polytechnic Institute