Peptide ligands of the cardiac ryanodine receptor as super-resolution imaging probes

To study the structural basis of pathological remodelling and altered calcium channel functional states in the heart, we sought to re-purpose high-affinity ligands of the cardiac calcium channel, the ryanodine receptor (RyR2), into super-resolution imaging probes. Imperacalcin (IpCa), a scorpion toxin peptide which induces channel sub-conduction states, and DPc10, a synthetic peptide corresponding to a sequence of the RyR2, which replicates arrhythmogenic CPVT functional changes, were used in fluorescent imaging experiments. Isolated adult rat ventricular cardiomyocytes were saponin-permeabilised and incubated with each peptide. IpCa-A546 became sequestered into the mitochondria. This was prevented by treatment of the permeabilised cells with the ionophore FCCP, revealing a striated staining pattern in confocal imaging which had weak colocalisation with RyR2 clusters. Poor specificity (as an RyR2 imaging probe) was confirmed at higher resolution with expansion microscopy (proExM) (~70 nm). DPc10-FITC labelled a striated pattern, which had moderate colocalisation with RyR2 cluster labelling in confocal and proExM. There was also widespread non-target labelling of the Z-discs, intercalated discs, and nuclei, which was unaffected by incubation times or 10 mM caffeine. The inactive peptide mut-DPc10-FITC (which causes no functional effects) displayed a similar labelling pattern. Significant labelling of structures unrelated to RyR2 by both peptide conjugates makes their use as highly specific imaging probes of RyR2 in living isolated cardiomyocytes highly challenging. We investigated the native DPc10 sequence within the RyR2 structure to understand the domain interactions and proposed mechanism of peptide binding. The native DPc10 sequence does not directly interact with another domain, and but is downstream of one such domain interface. The rabbit Arg2475 (equivalent to human Arg2474, mutated in CPVT) in the native sequence is the most accessible portion and most likely location for peptide disturbance, suggesting FITC placement does not impact peptide binding

On realcompact topological vector spaces

[EN] This survey paper collects some of older and quite new concepts and results from descriptive set topology applied to study certain infinite-dimensional topological vector spaces appearing in Functional Analysis, including Frechet spaces, (L F)-spaces, and their duals, (D F)-spaces and spaces of continuous real-valued functions C(X) on a completely regular Hausdorff space X. Especially (L F)-spaces and their duals arise in many fields of Functional Analysis and its applications, for example in Distributions Theory, Differential Equations and Complex Analysis. The concept of a realcompact topological space, although originally introduced and studied in General Topology, has been also studied because of very concrete applications in Linear Functional Analysis.The research for the first named author was (partially) supported by Ministry of Science and Higher Education, Poland, Grant no. NN201 2740 33 and for the both authors by the project MTM2008-01502 of the Spanish Ministry of Science and Innovation.Kakol, JM.; López Pellicer, M. (2011). On realcompact topological vector spaces. Revista de la Real Academia de Ciencias Exactas, Fisicas y Naturales. Serie A. Matematicas. 105(1):39-70. https://doi.org/10.1007/s13398-011-0003-0S39701051Argyros S., Mercourakis S.: On weakly Lindelöf Banach spaces. Rocky Mountain J. Math. 23(2), 395–446 (1993). doi: 10.1216/rmjm/1181072569Arkhangel’skii, A. V.: Topological Function Spaces, Mathematics and its Applications, vol. 78, Kluwer, Dordrecht (1992)Batt J., Hiermeyer W.: On compactness in L p (μ, X) in the weak topology and in the topology σ(L p (μ, X), L p (μ,X′)). Math. Z. 182, 409–423 (1983)Baumgartner J.E., van Douwen E.K.: Strong realcompactness and weakly measurable cardinals. Topol. 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A century of trends in adult human height

Being taller is associated with enhanced longevity, and higher education and earnings. We reanalysed 1472 population-based studies, with measurement of height on more than 18.6 million participants to estimate mean height for people born between 1896 and 1996 in 200 countries. The largest gain in adult height over the past century has occurred in South Korean women and Iranian men, who became 20.2 cm (95% credible interval 17.5-22.7) and 16.5 cm (13.3-19.7) taller, respectively. In contrast, there was little change in adult height in some sub-Saharan African countries and in South Asia over the century of analysis. The tallest people over these 100 years are men born in the Netherlands in the last quarter of 20th century, whose average heights surpassed 182.5 cm, and the shortest were women born in Guatemala in 1896 (140.3 cm; 135.8-144.8). The height differential between the tallest and shortest populations was 19-20 cm a century ago, and has remained the same for women and increased for men a century later despite substantial changes in the ranking of countries

Sorcin links pancreatic β cell lipotoxicity to ER Ca2+ stores.

Preserving β cell function during the development of obesity and insulin resistance would limit the worldwide epidemic of type 2 diabetes (T2DM). Endoplasmic reticulum (ER) calcium (Ca(2+)) depletion induced by saturated free fatty acids and cytokines causes β cell ER stress and apoptosis, but the molecular mechanisms behind these phenomena are still poorly understood. Here, we demonstrate that palmitate-induced sorcin (SRI) down-regulation, and subsequent increases in glucose-6-phosphatase catalytic subunit-2 (G6PC2) levels contribute to lipotoxicity. SRI is a calcium sensor protein involved in maintaining ER Ca(2+) by inhibiting ryanodine receptor activity and playing a role in terminating Ca(2+)-induced Ca(2+) release. G6PC2, a GWAS gene associated with fasting blood glucose, is a negative regulator of glucose-stimulated insulin secretion (GSIS). High fat feeding in mice and chronic exposure of human islets to palmitate decreases endogenous SRI expression while levels of G6PC2 mRNA increase. Sorcin null mice are glucose intolerant, with markedly impaired GSIS and increased expression of G6pc2. Under high fat diet, mice overexpressing SRI in the β cell display improved glucose tolerance, fasting blood glucose and GSIS, whereas G6PC2 levels are decreased and cytosolic and ER Ca(2+) are increased in transgenic islets. SRI may thus provide a target for intervention in T2DM