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71.
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Nicolas C. Nicolaides Agaristi Lamprokostopoulou Alexandros Polyzos Tomoshige Kino Eleni Katsantoni Panagiota Triantafyllou Athanasios Christophoridis George Katzos Maria Dracopoulou Amalia Sertedaki George P. Chrousos Evangelia Charmandari 《European journal of clinical investigation》2015,45(12):1306-1315
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Georgia Trakada Paschalis Steiropoulos Paul Zarogoulidis Evangelia Nena Nikolaos Papanas Efstratios Maltezos Demosthenes Bouros 《Sleep & breathing》2014,18(1):53-58
Purpose
The purpose of this study was to investigate the role of a fatty meal before bedtime, on sleep characteristics and blood pressure in patients with obstructive sleep apnea (OSA).Methods
Recently diagnosed, by full polysomnography (PSG), patients with OSA (n?=?19) were included. These underwent PSG for additional two consecutive nights. Two hours before the PSG examination, a ham and cheese sandwich of 360 kcal was served to all patients, at first night, while a fatty meal of 1,800 kcal was served before the second PSG examination. Comparisons were performed between the last two examinations in terms of PSG data and morning and night blood pressure measurements.Results
After the fatty meal, a significant increase was observed in total sleep time (p?=?0.026) in the Apnea–Hypopnea Index (AHI) (p?=?0.015), as well as in the absolute number of obstructive and central apneas (p?=?0.032 and p?=?0.042, respectively) compared to the previous night. Conversely, distribution of sleep stages and indices of nocturnal hypoxia (average and minimum SpO2 and sleep time with SpO2?<?90 %) did not change significantly. Likewise, no significant change was observed in blood pressure measurements.Conclusions
Fatty meal intake before sleep can increase AHI in OSA patients, although it does not affect sleep architecture or indices of hypoxia. 相似文献75.
Christos Papadimitriou 《Proceedings of the National Academy of Sciences of the United States of America》2014,111(45):15881-15887
Algorithms, perhaps together with Moore’s law, compose the engine of the information technology revolution, whereas complexity—the antithesis of algorithms—is one of the deepest realms of mathematical investigation. After introducing the basic concepts of algorithms and complexity, and the fundamental complexity classes P (polynomial time) and NP (nondeterministic polynomial time, or search problems), we discuss briefly the P vs. NP problem. We then focus on certain classes between P and NP which capture important phenomena in the social and life sciences, namely the Nash equlibrium and other equilibria in economics and game theory, and certain processes in population genetics and evolution. Finally, an algorithm known as multiplicative weights update (MWU) provides an algorithmic interpretation of the evolution of allele frequencies in a population under sex and weak selection. All three of these equivalences are rife with domain-specific implications: The concept of Nash equilibrium may be less universal—and therefore less compelling—than has been presumed; selection on gene interactions may entail the maintenance of genetic variation for longer periods than selection on single alleles predicts; whereas MWU can be shown to maximize, for each gene, a convex combination of the gene’s cumulative fitness in the population and the entropy of the allele distribution, an insight that may be pertinent to the maintenance of variation in evolution.Information technology has inundated and changed our world, as it is transforming the ways we live, work, play, learn, interact, and understand science and the world around us. One driving force behind this deluge is quite obvious: Computer hardware has become more cheap, fast, and innovative over the past half century, riding as it does on the exponent of Moore’s law (1). Progress in efficient algorithms—methods for solving computational problems in ways that take full advantage of fast hardware—is arguably of even greater importance.Algorithms have been known since antiquity. In the third century BC Euclid wrote about his algorithm for finding the greatest common divisor of two integers. The French scholar G. Lamé noted in 1845 (2) that Euclid’s algorithm is efficient, because it terminates after a number of arithmetic operations that grow proportionately to the length of the input—what we call today the number of bits of the two numbers. [In fact, one of the very few works on the subject of algorithms that have been published in PNAS is a 1976 article by Andrew Yao and Donald Knuth, revisiting and refining that analysis (3).] In the ninth century CE, the Arab mathematician Al Khwarizmi codified certain elementary algorithms for adding, dividing, etc., decimal numbers—the precise algorithms we learn today at elementary school. In fact, these simple and powerful algorithms were a major incentive for the eventual adoption of the decimal number system in Europe (ca. 1500 CE), an innovation that helped precipitate a social and scientific revolution comparable in impact to the one we are living in now.The study of efficient algorithms—algorithms that perform the required tasks within favorable time limits—started in the 1950s, soon after the first computer, and is now a very well-developed mathematical field within computer science. By the 1960s, researchers had begun to measure algorithms by the criterion of polynomial time, that is, to consider an algorithm efficient, or satisfactory, if the total number of operations it performs is always bounded from above by a polynomial function (as opposed to an exponential function) of the size of the input. For example, sorting n numbers can be done with about n?log?n comparisons, whereas discovering the best alignment of two DNA sequences with n nucleotides can take in the worst case time proportional to n2 (but can be performed in linear time for sequences that do align well); these are both considered “satisfactory” according to this criterion. 相似文献
76.
Nathaniel V. Nucci Brian Fuglestad Evangelia A. Athanasoula A. Joshua Wand 《Proceedings of the National Academy of Sciences of the United States of America》2014,111(38):13846-13851
It is well known that high hydrostatic pressures can induce the unfolding of proteins. The physical underpinnings of this phenomenon have been investigated extensively but remain controversial. Changes in solvation energetics have been commonly proposed as a driving force for pressure-induced unfolding. Recently, the elimination of void volumes in the native folded state has been argued to be the principal determinant. Here we use the cavity-containing L99A mutant of T4 lysozyme to examine the pressure-induced destabilization of this multidomain protein by using solution NMR spectroscopy. The cavity-containing C-terminal domain completely unfolds at moderate pressures, whereas the N-terminal domain remains largely structured to pressures as high as 2.5 kbar. The sensitivity to pressure is suppressed by the binding of benzene to the hydrophobic cavity. These results contrast to the pseudo-WT protein, which has a residual cavity volume very similar to that of the L99A–benzene complex but shows extensive subglobal reorganizations with pressure. Encapsulation of the L99A mutant in the aqueous nanoscale core of a reverse micelle is used to examine the hydration of the hydrophobic cavity. The confined space effect of encapsulation suppresses the pressure-induced unfolding transition and allows observation of the filling of the cavity with water at elevated pressures. This indicates that hydration of the hydrophobic cavity is more energetically unfavorable than global unfolding. Overall, these observations point to a range of cooperativity and energetics within the T4 lysozyme molecule and illuminate the fact that small changes in physical parameters can significantly alter the pressure sensitivity of proteins.The destabilization of proteins by pressure is a fundamental and highly informative probe of their structural free energy landscape but remains inadequately understood (1). The underlying determinants of pressure-induced unfolding have recently been a subject of several detailed investigations (2–10). Fundamentally, pressure-induced unfolding of proteins results from the population of nonnative conformations having a lower total system volume than the native structure seen at ambient pressure. Various mechanisms for pressure-induced unfolding have been proposed including changes in water structure that weaken the hydrophobic effect at high pressure (11, 12), increases in solvent density at the protein surface that contribute to a reduction in the total volume of the protein–water system (13, 14), and the elimination of cavities in the protein interior through exposure to solvent (3). With the development of high-pressure sample cells compatible with modern solution NMR probes (15), detailed measurements of proteins unfolding under pressure with atomic resolution have now become possible (5, 16–18). Recent studies of staphylococcal nuclease (SNase) compellingly argue that the filling of void volumes present in the native state is the primary determinant of pressure-induced unfolding (4–6). A critical aspect of a “destruction of voids” mechanism for pressure-induced unfolding of proteins is whether the voids or cavities are occupied with water in the folded state. Early investigations of buried hydrophobic pockets indicated that even large cavities are typically not hydrated, whereas hydrophilic cavities generally are occupied by water (19, 20). Many of the key studies impacting this question used the L99A single-point mutant of the model enzyme T4 lysozyme (20).The L99A mutation creates an internal cavity with an estimated volume of ∼150–160 Å3, large enough to accommodate three or four water molecules (21) (Fig. 1). Crystallographic investigation found no electron density within this pocket at ambient pressure (22, 23). In contrast, solution NMR and molecular-dynamics simulations suggest that the region of the protein around the hydrophobic pocket is highly dynamic, possibly to the extent that the pocket may be transiently accessible to solvent (22, 24–27). Crystallographic studies conducted at high pressure conversely suggested that the region around the pocket is rigid and exhibits increasing rigidity with increased pressure (23). Electron density also increased within the cavity as the hydrostatic pressure was increased (22), consistent with a pressure-induced filling of the hydrophobic cavity with water molecules. In contrast, fluorescence and small-angle X-ray scattering studies in bulk solution demonstrated that the protein is unfolded at these elevated pressures (2), suggesting that the crystal packing effects stabilize the protein. The hydrophobic cavity also provides a general, moderate-affinity binding site for small, relatively nonpolar ligands (28).Open in a separate windowFig. 1.Hydration of T4 lysozyme L99A at ambient pressure (∼1 bar). A backbone ribbon representation of L99A [Protein Data Bank (PDB) ID code 1L90 (63)] is shown with the N-terminal domain (residues 13–65) illustrated in blue, and the C-terminal domain (residues 1–12 and 66–164) is colored green. The hydrophobic pocket created by the L99A mutation is shown as orange mesh, and the three tryptophan side chains are shown as stick representations. The helices are numbered as a reference for discussion in the text. Cyan spheres are shown at the positions of amide hydrogens where an NOE to the water resonance was detected. Yellow spheres indicate the positions of amide hydrogens within NOE distance (5 Å) of the interior of the hydrophobic pocket, but outside NOE distance to the protein surface. These are the sites where detection of NOEs to the water resonance would indicate hydration of the pocket. No NOE cross-peaks from these sites to the water resonance were observed, suggesting that the pocket is not hydrated at ambient pressure.T4 lysozyme is one of the smallest known proteins to contain more than one cooperative folding unit. The folding of WT T4 lysozyme has been examined in detail by using hydrogen–deuterium exchange approaches and has been shown to contain two domains that fold cooperatively and with distinct free energy profiles (29–32). The N-terminal domain is ∼6 kcal/mol less stable than the C-terminal domain. The cavity created by the L99A mutation is in the center of the C-terminal domain. The thermal stability of the L99A mutant is reduced compared with the WT protein by 16 °C (5 kcal/mol) (33), an effect that is partially abrogated by binding hydrophobic ligands to the cavity (28, 34).The L99A mutant of T4 lysozyme provides a unique system to examine the hydration of internal pockets and the details of pressure-induced unfolding. In principle, protein–water interactions can be characterized by solution NMR methods (35), but severe artifacts often render the approach quite limited (36). Recently, it has been shown that various advantageous properties of proteins and water encapsulated within reverse micelles largely overcome these artifacts (37, 38). Here, we use this approach to directly measure the hydration of the internal cavity. High-pressure NMR is used to examine the pressure-induced response of the protein in bulk solution and under confinement by the reverse micelle. We demonstrate that the hydrophobic pocket appears to be essentially dehydrated at ambient pressure (∼1 bar) and that the pressure response of the protein is an unfolding of the C-terminal domain only, representing an inversion of the relative stability of the domains as a result of the cavity-creating mutation. This result is in contrast to the unfolding of the cysteine-free WT (WT*) protein, which shows only the earliest stages of pressure-induced subglobal unfolding. Furthermore, the L99A mutant with benzene occupying the cavity shows no evidence of pressure unfolding. Nanoscale confinement of the protein also suppresses the L99A pressure-induced unfolding transition (Pu) as a result of the restriction of conformational space imposed by the reverse micelle. In lieu of the pressure unfolding transition, the volume reduction imposed by increasing pressure is compensated for in the reverse micelle by progressively increasing incorporation of water into the cavity interior, essentially recapitulating the observations from high-pressure crystallography in a solution measurement. These findings have important implications with respect to the nature of pressure-induced unfolding, the roles of cavities in protein structural stability, and the effects of confinement, a critical parameter when considering the intracellular milieu, in which proteins must fold and carry out their functions. 相似文献
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Heart disease remains the leading cause of death and disability in the Western world. Current therapies aim at treating the symptoms rather than the subcellular mechanisms, underlying the etiology and pathological remodeling in heart failure. A universal characteristic, contributing to the decreased contractile performance in human and experimental failing hearts, is impaired calcium sequestration into the sarcoplasmic reticulum (SR). SR calcium uptake is mediated by a Ca(2+)-ATPase (SERCA2), whose activity is reversibly regulated by phospholamban (PLN). Dephosphorylated PLN is an inhibitor of SERCA and phosphorylation of PLN relieves this inhibition. However, the initial simple view of a PLN/SERCA regulatory complex has been modified by our recent identification of SUMO, S100 and the histidine-rich Ca-binding protein as regulators of SERCA activity. In addition, PLN activity is regulated by 2 phosphoproteins, the inhibitor-1 of protein phosphatase 1 and the small heat shock protein 20, which affect the overall SERCA-mediated Ca-transport. This review will highlight the regulatory mechanisms of cardiac contractility by the multimeric SERCA/PLN-ensemble and the potential for new therapeutic avenues targeting this complex by using small molecules and gene transfer methods. 相似文献
79.
Breen DM Dolinsky VW Zhang H Ghanim H Guo J Mroziewicz M Tsiani EL Bendeck MP Dandona P Dyck JR Heximer SP Giacca A 《Atherosclerosis》2012,222(2):375-381
Revascularization procedures used for treatment of atherosclerosis often result in restenosis. Resveratrol (RSV), an antioxidant with cardiovascular benefits, decreases neointimal formation after arterial injury by a mechanism that is still not fully clarified. Our main objective was to address the role of nitric oxide synthases (NOSes) and more specifically the endothelial-NOS (eNOS) isoform as a mediator of this effect. RSV (4 mg/kg/day, s.c.) alone or in combination with the NOS inhibitor N-nitro-L-arginine methyl ester (L-NAME) (2 mg/kg/day, s.c.) was given to Sprague-Dawley rats beginning at 3 days before arterial (carotid or aortic) injury. RSV reduced neointimal formation by 50% (P<0.01), decreased intimal cell proliferation by 37% (P<0.01) and reduced inflammatory markers such as PECAM and MMP-9 mRNA. These effects of RSV were all abolished by coadministration of l-NAME. Oral RSV (beginning at 5 days before arterial injury) reduced neointimal thickness after femoral wire injury in mice, however this effect was not observed in eNOS knockout mice. This is the first report of RSV decreasing neointimal cell proliferation and neointimal growth through an eNOS-dependent mechanism. 相似文献
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