Abstract Silk proteins are a promising material for drug delivery due to their aqueous processability, biocompatibility, and biodegradability. A simple aqueous preparation method for silk fibroin ...particles with controllable size, secondary structure and zeta potential is reported. The particles were produced by salting out a silk fibroin solution with potassium phosphate. The effect of ionic strength and pH of potassium phosphate solution on the yield and morphology of the particles was determined. Secondary structure and zeta potential of the silk particles could be controlled by pH. Particles produced by salting out with 1.25 m potassium phosphate pH 6 showed a dominating silk II (crystalline) structure whereas particles produced at pH 9 were mainly composed of silk I (less crystalline). The results show that silk I-rich particles possess chemical and physical stability and secondary structure which remained unchanged during post treatments even upon exposure to 100% ethanol or methanol. A model is presented to explain the process of particle formation based on intra- and intermolecular interactions of the silk domains, influenced by pH and kosmotropic salts. The reported silk fibroin particles can be loaded with small molecule model drugs, such as alcian blue, rhodamine B, and crystal violet, by simple absorption based on electrostatic interactions. In vitro release of these compounds from the silk particles depends on charge–charge interactions between the compounds and the silk. With crystal violet we demonstrated that the release kinetics are dependent on the secondary structure of the particles.
Major depression is characterized by a cluster of symptoms that includes hopelessness, low mood, feelings of worthlessness and inability to experience pleasure. The lifetime prevalence of major ...depression approaches 20%, yet current treatments are often inadequate both because of associated side effects and because they are ineffective for many people. In basic research, animal models are often used to study depression. Typically, experimental animals are exposed to acute or chronic stress to generate a variety of depression‐like symptoms. Despite its clinical importance, very little is known about the cellular and neural circuits that mediate these symptoms. Recent advances in circuit‐targeted approaches have provided new opportunities to study the neuropathology of mood disorders such as depression and anxiety. We review recent progress and highlight some studies that have begun tracing a functional neuronal circuit diagram that may prove essential in establishing novel treatment strategies in mood disorders. First, we shed light on the complexity of mesocorticolimbic dopamine (DA) responses to stress by discussing two recent studies reporting that optogenetic activation of midbrain DA neurons can induce or reverse depression‐related behaviors. Second, we describe the role of the lateral habenula circuitry in the pathophysiology of depression. Finally, we discuss how the prefrontal cortex controls limbic and neuromodulatory circuits in mood disorders.
Here we review recent advances aided by optogenetic tools in understanding mood disorders.
Storage capacity at CMS Tier-1 and Tier-2 sites reached over 100 Petabytes in 2014, and will be substantially increased during Run 2 data taking. The allocation of storage for the individual users ...analysis data, which is not accounted as a centrally managed storage space, will be increased to up to 40%. For comprehensive tracking and monitoring of the storage utilization across all participating sites, CMS developed a space monitoring system, which provides a central view of the geographically dispersed heterogeneous storage systems. The first prototype was deployed at pilot sites in summer 2014, and has been substantially reworked since then. In this paper we discuss the functionality and our experience of system deployment and operation on the full CMS scale.
We study sparsity constrained nonlinear optimization (SCNO) from a topological point of view. Special focus will be on M-stationary points from Burdakov et al. (SIAM J Optim 26:397–425, 2016), also ...introduced as NC\documentclass12pt{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$N^C$$\end{document}-stationary points in Pan et al. (J Oper Res Soc China 3:421–439, 2015). We introduce nondegenerate M-stationary points and define their M-index. We show that all M-stationary points are generically nondegenerate. In particular, the sparsity constraint is active at all local minimizers of a generic SCNO. Some relations to other stationarity concepts, such as S-stationarity, basic feasibility, and CW-minimality, are discussed in detail. By doing so, the issues of instability and degeneracy of points due to different stationarity concepts are highlighted. The concept of M-stationarity allows to adequately describe the global structure of SCNO along the lines of Morse theory. For that, we study topological changes of lower level sets while passing an M-stationary point. As novelty for SCNO, multiple cells of dimension equal to the M-index are needed to be attached. This intriguing fact is in strong contrast with other optimization problems considered before, where just one cell suffices. As a consequence, we derive a Morse relation for SCNO, which relates the numbers of local minimizers and M-stationary points of M-index equal to one. The appearance of such saddle points cannot be thus neglected from the perspective of global optimization. Due to the multiplicity phenomenon in cell-attachment, a saddle point may lead to more than two different local minimizers. We conclude that the relatively involved structure of saddle points is the source of well-known difficulty if solving SCNO to global optimality.
The prompt reconstruction of the data recorded from the Large Hadron Collider (LHC) detectors has always been addressed by dedicated resources at the CERN Tier-0. Such workloads come in spikes due to ...the nature of the operation of the accelerator and in special high load occasions experiments have commissioned methods to distribute (spill-over) a fraction of the load to sites outside CERN. The present work demonstrates a new way of supporting the Tier-0 environment by provisioning resources elastically for such spilled-over workflows onto the Piz Daint Supercomputer at CSCS. This is implemented using containers, tuning the existing batch scheduler and reinforcing the scratch file system, while still using standard Grid middleware. ATLAS, CMS and CSCS have jointly run selected prompt data reconstruction on up to several thousand cores on Piz Daint into a shared environment, thereby probing the viability of the CSCS high performance computer site as on demand extension of the CERN Tier-0, which could play a role in addressing the future LHC computing challenges for the high luminosity LHC.
Storage capacity at CMS Tier-1 and Tier-2 sites reached over 100 Petabytes in 2014, and will be substantially increased during Run 2 data taking. The allocation of storage for the individual users ...analysis data, which is not accounted as a centrally managed storage space, will be increased to up to 40%. For comprehensive tracking and monitoring of the storage utilization across all participating sites, CMS developed a space monitoring system, which provides a central view of the geographically dispersed heterogeneous storage systems. The first prototype was deployed at pilot sites in summer 2014, and has been substantially reworked since then. In this paper we discuss the functionality and our experience of system deployment and operation on the full CMS scale.
We consider the class of mathematical programs with orthogonality type constraints. Orthogonality type constraints appear by reformulating the sparsity constraint via auxiliary binary variables and ...relaxing them afterwards. For mathematical programs with orthogonality type constraints a necessary optimality condition in terms of T-stationarity is stated. The justification of T-stationarity is threefold. First, it allows to capture the global structure of mathematical programs with orthogonality type constraints in terms of Morse theory, i. e. deformation and cell-attachment results are established. For that, nondegeneracy for the T-stationary points is introduced and shown to hold generically. Second, we prove that Karush-Kuhn-Tucker points of the Scholtes-type regularization converge to T-stationary points of mathematical programs with orthogonality type constraints. This is done under the tailored linear independence constraint qualification, which turns out to be a generic property too. Third, we show that T-stationarity applied to the relaxation of sparsity constrained nonlinear optimization naturally leads to its M-stationary points. Moreover, we argue that all T-stationary points of this relaxation become degenerate.
We study the problem of sparse recovery in the context of compressed sensing. This is to minimize the sensing error of linear measurements by sparse vectors with at most s non-zero entries. We ...develop the so-called critical point theory for sparse recovery. This is done by introducing nondegenerate M-stationary points which adequately describe the global structure of this non-convex optimization problem. We show that all M-stationary points are generically nondegenerate. In particular, the sparsity constraint is active at all local minimizers of a generic sparse recovery problem. Additionally, the equivalence of strong stability and nondegeneracy for M-stationary points is shown. We claim that the appearance of saddle points - these are M-stationary points with exactly s−1 non-zero entries - cannot be neglected. For this purpose, we derive a so-called Morse relation, which gives a lower bound on the number of saddle points in terms of the number of local minimizers. The relatively involved structure of saddle points can be seen as a source of well-known difficulty by solving the problem of sparse recovery to global optimality.
Abstract
Background and aims
Cytotoxic CD8+ T cells mediate myocardial damage in patients with virus induced myocarditis, plaque erosion during acute coronary syndrome, and promote adverse ...post-ischemic cardiac remodeling. There is emerging evidence to support a link between inflammation and atrial fibrillation (AF). Protease-activated receptor 1 (PAR1) is the thrombin receptor expressed on platelets, but it is also expressed in endothelial cells, vascular smooth muscle cells, cardiac fibroblasts, and CD8+ T cells. The role of CD8+ T cells and PAR1 in atrial myopathy and early AF have not been studied.
Methods
In 80 non-anticoagulated patients with a first documented episode of AF, and 20 control subjects without AF but with a comparable cardiovascular risk profile (e.g. SCORE2, CHA2DS2-VASc, p>0.05), we studied PAR1-related cytotoxic T cell activity in the first hours (up to 24 h) of AF clinical manifestation. The Apolipoprotein E–knock out (ApoEko) mouse is a commonly used model of metabolic syndrome that develops atrial myopathy (structural correlate of AF). ApoEko male mice (Apoetm1Unc with a C57BL/6 genetic background) were fed for six weeks with a standard chew, western-type diet (high fat and high sucrose = WD) ± the specific PAR1 inhibitor vorapaxar.
Results
High levels of circulating, activated CD8+ T cells (CD8+CD57+ T cells with pro-inflammatory and high cytotoxic properties) were present in patients with early AF (flow cytometry). Stimulation of cytotoxic T cells, that expressed the thrombin receptor PAR1, that were isolated from patients with new onset of AF, released pro-inflammatory cytokines (e.g. IFN-γ, TNF-α). Enhanced cytotoxic activity of CD8+ T cells was suggested by elevated plasma levels of effector molecules (e.g. granulysin and granzyme).
In ApoEko mice fed a WD, atrial myopathy as the structural correlate for AF, was paralleled by increased expression of effector molecules that were associated with CD8+ T cell activity (like perforin, granzyme A, granzyme B, IFN-γ). Cytotoxic T cell activity disrupted the release of the potective atrial natriuretic peptide, ANP, and increased signaling pathways associated with atrial fibrosis (e.g. TGF-β, cTGF, TGF-β receptor). The specific PAR1 inhibitor, vorapaxar, reduced inflammatory T cell activity, transcription of fibrotic mediators, and reconstituted ANP secretion in atria of ApoEko mice.
Conclusions
Targeting the FXa/FIIa-PAR1-CD8+ axis might be a promising approach to reduce atrial fibrosis and inflammation.
Funding Acknowledgement
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): BIH Charité Clinician Scientist Program
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