209 research outputs found
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Lipotoxicity: a driver of heart failure with preserved ejection fraction?
Heart failure with preserved ejection fraction (HFpEF) is a growing public health concern, with rising incidence alongside high morbidity and mortality. However, the pathophysiology of HFpEF is not yet fully understood. The association between HFpEF and the metabolic syndrome (MetS) suggests that dysregulated lipid metabolism could drive diastolic dysfunction and subsequent HFpEF. Herein we summarise recent advances regarding the pathogenesis of HFpEF in the context of MetS, with a focus on impaired lipid handling, myocardial lipid accumulation and subsequent lipotoxicity.We thank the British Heart Foundation [grant numbers RG/18/7/33636 and FS/17/61/33473]; the Cambridge BHF Centre of Research Excellence [grant number RE/18/1/34212]; and the Medical Research Council [grant number MC UU 12012/2] for funding this work
Far-Field Wavefront Control of Nonlinear Luminescence in Disordered Gold Metasurfaces
We demonstrate the local optimization of nonlinear luminescence from disordered gold metasurfaces by shaping the phase of femtosecond excitation. This process is enabled by the far-field wavefront control of plasmonic modes delocalized over the sample surface, leading to a coherent enhancement of subwavelength electric fields. In practice, the increase in nonlinear luminescence is strongly sensitive to both the nanometer-scale morphology and the level of structural complexity of the gold metasurface. We typically observe a 2 orders of magnitude enhancement of the luminescence signal for an optimized excitation wavefront compared to a random one. These results demonstrate how disordered metasurfaces made of randomly coupled plasmonic resonators, together with wavefront shaping, provide numerous degrees of freedom to program locally optimized nonlinear responses and optical hotspots
Developments and the preliminary tests of Resistive GEMs manufactured by a screen printing technology
We report promising initial results obtained with new resistive-electrode GEM
(RETGEM) detectors manufactured, for the first time, using screen printing
technology. These new detectors allow one to reach gas gains nearly as high as
with ordinary GEM-like detectors with metallic electrodes; however, due to the
high resistivity of its electrodes the RETGEM, in contrast to ordinary
hole-type detectors, has the advantage of being fully spark protected. We
discovered that RETGEMs can operate stably and at high gains in noble gases and
in other badly quenched gases, such as mixtures of noble gases with air and in
pure air; therefore, a wide range of practical applications, including
dosimetry and detection of dangerous gases, is foreseeable. To promote a better
understanding of RETGEM technology some comparative studies were completed with
metallic-electrode thick GEMs. A primary benefit of these new RETGEMs is that
the screen printing technology is easily accessible to many research
laboratories. This accessibility encourages the possibility to manufacture
these GEM-like detectors with the electrode resistivity easily optimized for
particular experimental or practical applications
Co3O4 Nanocrystals on Graphene as a Synergistic Catalyst for Oxygen Reduction Reaction
Catalysts for oxygen reduction and evolution reactions are at the heart of
key renewable energy technologies including fuel cells and water splitting.
Despite tremendous efforts, developing oxygen electrode catalysts with high
activity at low costs remains a grand challenge. Here, we report a hybrid
material of Co3O4 nanocrystals grown on reduced graphene oxide (GO) as a
high-performance bi-functional catalyst for oxygen reduction reaction (ORR) and
oxygen evolution reaction (OER). While Co3O4 or graphene oxide alone has little
catalytic activity, their hybrid exhibits an unexpected, surprisingly high ORR
activity that is further enhanced by nitrogen-doping of graphene. The
Co3O4/N-doped graphene hybrid exhibits similar catalytic activity but superior
stability to Pt in alkaline solutions. The same hybrid is also highly active
for OER, making it a high performance non-precious metal based bi-catalyst for
both ORR and OER. The unusual catalytic activity arises from synergetic
chemical coupling effects between Co3O4 and graphene.Comment: published in Nature Material
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SREBP1-induced fatty acid synthesis depletes macrophages antioxidant defences to promote their alternative activation
Macrophages exhibit a spectrum of activation states ranging from classical to alternative activation1. Alternatively, activated macrophages are involved in diverse pathophysiological processes such as confining tissue parasites2, improving insulin sensitivity3 or promoting an immune tolerant microenvironment that facilitates tumour growth and metastasis4. Recently, the role of metabolism regulating macrophage function has come into focus as both the classical and alternative activation programmes require specific regulated metabolic reprogramming5. While most of the studies regarding immunometabolism have focussed on the catabolic pathways activated to provide energy, little is known about the anabolic pathways mediating macrophage alternative activation. In this study, we show that the anabolic transcription factor sterol regulatory element binding protein 1 (SREBP1) is activated in response to the canonical Th2 cytokine interleukin 4 (IL-4) to trigger the de novo lipogenesis (DNL) programme, as a necessary step for macrophage alternative activation. Mechanistically, DNL consumes NADPH, partitioning it away from cellular antioxidant defences and raising ROS levels. ROS serves as a second messenger, signalling sufficient DNL, and promoting macrophage alternative activation. The pathophysiological relevance of this mechanism is validated by showing that SREBP1/DNL is essential for macrophage alternative activation in vivo in a helminth infection model.This work was supported by the British Heart Foundation (RG/18/7/33636), the MRC (MC_UU_00014/2) and the FP7 MITIN (223450). K.P. was a recipient of a fellowship from the Wellcome Trust. A.N.J.M. and E.J. are supported by the Wellcome Trust (100963/Z/13/Z) and the MRC (U105178805). J.L. is a recipient fellowship of the British Heart Foundation. A.D. was a Marie-Curie Early-Stage Researcher supported by the European Unionâs Horizon 2020 research and innovation programme (675585 Marie-Curie ITN âSymBioSysâ) to J.S.-R. A.K. is supported by the Wellcome Trust (106260/Z/14/Z) and an ERC award (648889). P.F. is supported by the Science Foundation Ireland (10/IN.1/B3004). The IMS Genomics and Transcriptomics and Histology cores (B.M.-A., B.Y.H.L. and M.K.M.) are funded by the UK MRC Metabolic Disease Unit (MRC_MC_UU_12012/5) and a Wellcome Trust Strategic Award (100574/Z/12/Z). The Disease Model Core is part of the MRC Metabolic Diseases Unit (MRC_MC_UU_12012/5) and Wellcome Trust Strategic Award (100574/Z/12/Z)
Lipodystrophy-Linked LMNA p.R482W Mutation Induces Clinical Early Atherosclerosis and In Vitro Endothelial Dysfunction
ObjectiveâSome mutations in LMNA, encoding A-type lamins, are responsible for Dunnigan-type-familial partial lipodystrophy (FPLD2), with altered fat distribution and metabolism. The high prevalence of early and severe cardiovascular outcomes in these patients suggests that, in addition to metabolic risk factors, FPLD2-associated LMNA mutations could have a direct role on the vascular wall cells.
Approach and ResultsâWe analyzed the cardiovascular phenotype of 19 FPLD2 patients aged >30 years with LMNA p.R482 heterozygous substitutions, and the effects of p.R482W-prelamin-A overexpression in human coronary artery endothelial cells. In 68% of FPLD2 patients, early atherosclerosis was attested by clinical cardiovascular events, occurring before the age of 45 in most cases. In transduced endothelial cells, exogenous wild-type-prelamin-A was correctly processed and localized, whereas p.R482W-prelamin-A accumulated abnormally at the nuclear envelope. Patientsâ fibroblasts also showed a predominant nuclear envelope distribution with a decreased rate of prelamin-A maturation. Only p.R482W-prelamin-A induced endothelial dysfunction, with decreased production of NO, increased endothelial adhesion of peripheral blood mononuclear cells, and cellular senescence. p.R482W-prelamin-A also induced oxidative stress, DNA damages, and inflammation. These alterations were prevented by treatment of endothelial cells with pravastatin, which inhibits prelamin-A farnesylation, or with antioxidants. In addition, pravastatin allowed the correct relocalization of p.R482W-prelamin-A within the endothelial cell nucleus. These data suggest that farnesylated p.R482W-prelamin-A accumulation at the nuclear envelope is a toxic event, leading to cellular oxidative stress and endothelial dysfunction.
ConclusionsâLMNA p.R482 mutations, responsible for FPLD2, exert a direct proatherogenic effect in endothelial cells, which could contribute to patientsâ early atherosclerosis
Electrode Polarization Effects in Broadband Dielectric Spectroscopy
In the present work, we provide broadband dielectric spectra showing strong
electrode polarization effects for various materials, belonging to very
different material classes. This includes both ionic and electronic conductors
as, e.g., salt solutions, ionic liquids, human blood, and
colossal-dielectric-constant materials. These data are intended to provide a
broad data base enabling a critical test of the validity of phenomenological
and microscopic models for electrode polarization. In the present work, the
results are analyzed using a simple phenomenological equivalent-circuit
description, involving a distributed parallel RC circuit element for the
modeling of the weakly conducting regions close to the electrodes. Excellent
fits of the experimental data are achieved in this way, demonstrating the
universal applicability of this approach. In the investigated ionically
conducting materials, we find the universal appearance of a second dispersion
region due to electrode polarization, which is only revealed if measuring down
to sufficiently low frequencies. This indicates the presence of a second
charge-transport process in ionic conductors with blocking electrodes.Comment: 9 pages, 6 figures, experimental data are provided in electronic form
(see "Data Conservancy"
Colossal dielectric constants in transition-metal oxides
Many transition-metal oxides show very large ("colossal") magnitudes of the
dielectric constant and thus have immense potential for applications in modern
microelectronics and for the development of new capacitance-based
energy-storage devices. In the present work, we thoroughly discuss the
mechanisms that can lead to colossal values of the dielectric constant,
especially emphasising effects generated by external and internal interfaces,
including electronic phase separation. In addition, we provide a detailed
overview and discussion of the dielectric properties of CaCu3Ti4O12 and related
systems, which is today's most investigated material with colossal dielectric
constant. Also a variety of further transition-metal oxides with large
dielectric constants are treated in detail, among them the system La2-xSrxNiO4
where electronic phase separation may play a role in the generation of a
colossal dielectric constant.Comment: 31 pages, 18 figures, submitted to Eur. Phys. J. for publication in
the Special Topics volume "Cooperative Phenomena in Solids: Metal-Insulator
Transitions and Ordering of Microscopic Degrees of Freedom
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