Particle Diffusion and Acceleration by Shock Wave in Magnetized Filamentary Turbulence

We expand the off-resonant scattering theory for particle diffusion in magnetized current filaments that can be typically compared to astrophysical jets, including active galactic nucleus jets. In a high plasma beta region where the directional bulk flow is a free-energy source for establishing turbulent magnetic fields via current filamentation instabilities, a novel version of quasi-linear theory to describe the diffusion of test particles is proposed. The theory relies on the proviso that the injected energetic particles are not trapped in the small-scale structure of magnetic fields wrapping around and permeating a filament but deflected by the filaments, to open a new regime of the energy hierarchy mediated by a transition compared to the particle injection. The diffusion coefficient derived from a quasi-linear type equation is applied to estimating the timescale for the stochastic acceleration of particles by the shock wave propagating through the jet. The generic scalings of the achievable highest energy of an accelerated ion and electron, as well as of the characteristic time for conceivable energy restrictions, are systematically presented. We also discuss a feasible method of verifying the theoretical predictions. The strong, anisotropic turbulence reflecting cosmic filaments might be the key to the problem of the acceleration mechanism of the highest energy cosmic rays exceeding 100 EeV (10^{20} eV), detected in recent air shower experiments.Comment: 39 pages, 2 figures, accepted for publication in Ap

Formulacija i evaluacija monolitnih matriksnih polimernih filmova za transdermalnu isporuku nitrendipina

The objective of the present work was to develop a suitable transdermal drug delivery system for nitrendipine. Polymeric films of nitrendipine were prepared by the film casting technique (glass ring) on mercury substrate. They were evaluated for physicochemical parameters, in vitro release and ex vivo permeation (heat separated human epidermis). Release of the drug from the films followed anomalous transport (0.5 < n < 1). Polymeric combination containing Eudragit RL 100:PVP K 30 in 4:6 ratio showed the best results. Maximum drug release and skin permeability coefficient in 48 h were 85.8 % and 0.0142 cm h-1, respectively, in formulation C3 (Eudragit RL 100: Plasdone S 630; 4:6) and 88.0 % and 0.0155 cm h-1, respectively, in formulation D3 (Eudragit RL 100: PVP K 30; 4:6). FTIR and TLC studies indicated no drug and polymer interaction.Cilj rada bio je razvoj transdermalnog sustava nitrendipina. Polimerni filmovi nitrendipina pripravljeni su metodom lijevanja (stakleni prsten) na podlozi od žive. Ispitivani su fizičkokemijski parametri, in vitro oslobađanje i ex vivo permeacija (toplinom odvojena humana epiderma). Oslobađanje lijeka iz filmova slijedilo je anomalni transport (0,5 < n < 1). Najbolji rezultati postignuti su kombinacijom polimera Eudragit RL 100 i PVP K 30 u omjeru 4:6. Maksimalno oslobađanje ljekovite tvari i najbolji koeficijent permeacije kroz kožu tijekom 48 h bio je 85,8 %, odnosno 0,0142 cm h1 za formulaciju C3 (Eudragit RL 100 : Plasdone S 630; 4:6) i 88,0 %, odnosno 0,0155 cm h1 za formulaciju D3 (Eudragit RL 100 : PVP K 30; 4:6). FTIR i TLC ukazuju na to da nema interakcije između ljekovite tvari i polimera

Guideline for the diagnosis and treatment of Faecal Incontinence-A UEG/ESCP/ESNM/ESPCG collaboration

INTRODUCTION The goal of this project was to create an up-to-date joint European clinical practice guideline for the diagnosis and treatment of faecal incontinence (FI), using the best available evidence. These guidelines are intended to help guide all medical professionals treating adult patients with FI (e.g., general practitioners, surgeons, gastroenterologists, other healthcare workers) and any patients who are interested in information regarding the diagnosis and management of FI. METHODS These guidelines have been created in cooperation with members from the United European Gastroenterology (UEG), European Society of Coloproctology (ESCP), European Society of Neurogastroenterology and Motility (ESNM) and the European Society for Primary Care Gastroenterology (ESPCG). These members made up the guideline development group (GDG). Additionally, a patient advisory board (PAB) was created to reflect and comment on the draft guidelines from a patient perspective. Relevant review questions were established by the GDG along with a set of outcomes most important for decision making. A systematic literature search was performed using these review questions and outcomes as a framework. For each predefined review question, the study or studies with the highest level of study design were included. If evidence of a higher-level study design was available, no lower level of evidence was sought or included. Data from the studies were extracted by two reviewers for each predefined important outcome within each review question. Where possible, forest plots were created. After summarising the results for each review question, a systematic quality assessment using the GRADE (Grading of Recommendations, Assessment, Development and Evaluations) approach was performed. For each review question, we assessed the quality of evidence for every predetermined important outcome. After evidence review and quality assessment were completed, recommendations could be formulated. The wording used for each recommendation was dependent on the level of quality of evidence. Lower levels of evidence resulted in weaker recommendations and higher levels of evidence resulted in stronger recommendations. Recommendations were discussed within the GDG to reach consensus. RESULTS These guidelines contain 45 recommendations on the classification, diagnosis and management of FI in adult patients. CONCLUSION These multidisciplinary European guidelines provide an up-to-date comprehensive evidence-based framework with recommendations on the diagnosis and management of adult patients who suffer from FI

Extracellular nanovesicles for packaging of CRISPR-Cas9 protein and sgRNA to induce therapeutic exon skipping

Prolonged expression of the CRISPR-Cas9 nuclease and gRNA from viral vectors may cause off-target mutagenesis and immunogenicity. Thus, a transient delivery system is needed for therapeutic genome editing applications. Here, we develop an extracellular nanovesicle-based ribonucleoprotein delivery system named NanoMEDIC by utilizing two distinct homing mechanisms. Chemical induced dimerization recruits Cas9 protein into extracellular nanovesicles, and then a viral RNA packaging signal and two self-cleaving riboswitches tether and release sgRNA into nanovesicles. We demonstrate efficient genome editing in various hard-to-transfect cell types, including human induced pluripotent stem (iPS) cells, neurons, and myoblasts. NanoMEDIC also achieves over 90% exon skipping efficiencies in skeletal muscle cells derived from Duchenne muscular dystrophy (DMD) patient iPS cells. Finally, single intramuscular injection of NanoMEDIC induces permanent genomic exon skipping in a luciferase reporter mouse and in mdx mice, indicating its utility for in vivo genome editing therapy of DMD and beyond

Phosphorylation of Syntaxin‐1a by casein kinase 2α (CK2α) regulates presynaptic vesicle exocytosis from the reserve pool

The t-soluble NSF-attachment protein receptor protein Syntaxin-1a (Stx-1a) is abundantly expressed at pre-synaptic terminals where it plays a critical role in the exocytosis of neurotransmitter-containing synaptic vesicles. Stx-1a is phosphorylated by Casein kinase 2α (CK2α) at Ser14, which has been proposed to regulate the interaction of Stx-1a and Munc-18 to control of synaptic vesicle priming. However, the role of CK2α in synaptic vesicle dynamics remains unclear. Here, we show that CK2α over-expression reduces evoked synaptic vesicle release. Furthermore, shRNA-mediated knockdown of CK2α in primary hippocampal neurons strongly enhanced vesicle exocytosis from the reserve pool, with no effect on the readily releasable pool of primed vesicles. In neurons in which endogenous Stx-1a was knocked down and replaced with a CK2α phosphorylation-deficient mutant, Stx-1a(D17A), vesicle exocytosis was also increased. These results reveal a previously unsuspected role of CK2α phosphorylation in specifically regulating the reserve synaptic vesicle pool, without changing the kinetics of release from the readily releasable pool

Validation of the vertical profiles of HCl over the wide range of the stratosphere to the lower thermosphere measured by SMILES

Hydrogen chloride (HCl) is the most abundant (more than 95 %) among inorganic chlorine compounds Cly in the stratosphere. The HCl molecule has been observed to obtain long-term quantitative estimations of total budget of the stratospheric anthropogenic chlorine compounds. In this study, we provided HCl vertical profiles at altitudes of 16–100 km using the superconducting submillimeter-wave limb-emission sounder (SMILES) from space. We used the SMILES Level-2 research product version 3.0.0. The period of the SMILES HCl observation was from October 12, 2009 to April 21, 2010, and the latitude coverage was 40S–65N. The average HCl vertical profile showed an increase with altitude up to the stratopause (~ 45 km), approximately constant values between the stratopause and the upper mesosphere (~ 80 km), and a decrease from the mesopause to the lower thermosphere (~ 100 km). This behavior was observed in the all latitude regions, and reproduced by the SD-WACCM model. We compared the SMILES HCl vertical profiles in the stratosphere and lower mesosphere with HCl profiles from MLS on the Aura satellite, as well as from ACE-FTS on SCISAT and from TELIS (balloon-borne). The TELIS observations were performed using the superconductive limb emission technique, as used by SMILES. The globally averaged vertical HCl profiles of SMILES well agreed with those of MLS and ACE-FTS within 0.25 and 0.2 ppbv between 20 and 40 km, respectively. The SMILES HCl concentration was smaller than those of MLS and ACE/FTS as the altitude increased from 40 km, and the difference was approximately 0.4–0.5 ppbv at 50–60 km. The difference between SMILES and TELIS HCl observations was about 0.3 ppbv in the polar winter region between 20 and 34 km, except near 26 km. SMILES HCl error sources that may cause discrepancies with the other observations are investigated by a theoretical error analysis. We calculated errors caused by the uncertainties of spectroscopic parameters, instrument functions, and atmospheric temperature profiles. The jacobian for the temperature explains the negative bias of the SMILES HCl concentration at 50–60 km. The HCl vertical profile from the middle troposphere to the lower thermosphere is reported for the first time from SMILES observations; the data quality is quantified by comparisons with other measurements and via theoretical error analysis

Calpain Cleavage Prediction Using Multiple Kernel Learning

Calpain, an intracellular -dependent cysteine protease, is known to play a role in a wide range of metabolic pathways through limited proteolysis of its substrates. However, only a limited number of these substrates are currently known, with the exact mechanism of substrate recognition and cleavage by calpain still largely unknown. While previous research has successfully applied standard machine-learning algorithms to accurately predict substrate cleavage by other similar types of proteases, their approach does not extend well to calpain, possibly due to its particular mode of proteolytic action and limited amount of experimental data. Through the use of Multiple Kernel Learning, a recent extension to the classic Support Vector Machine framework, we were able to train complex models based on rich, heterogeneous feature sets, leading to significantly improved prediction quality (6% over highest AUC score produced by state-of-the-art methods). In addition to producing a stronger machine-learning model for the prediction of calpain cleavage, we were able to highlight the importance and role of each feature of substrate sequences in defining specificity: primary sequence, secondary structure and solvent accessibility. Most notably, we showed there existed significant specificity differences across calpain sub-types, despite previous assumption to the contrary. Prediction accuracy was further successfully validated using, as an unbiased test set, mutated sequences of calpastatin (endogenous inhibitor of calpain) modified to no longer block calpain's proteolytic action. An online implementation of our prediction tool is available at http://calpain.org

Global Oral Health Policies and Guidelines: Using Silver Diamine Fluoride for Caries Control

Silver diamine fluoride (SDF) was developed in Japan in the 1960s. It is a clear solution containing silver and fluoride ions. Because of its anti-bacterial and remineralizing effect, silver diamine fluoride has been used in managing dental caries for decades worldwide. This paper aims to summarize and discuss the global policies, guidelines, and relevant information on utilizing SDF for caries management. SDF can be used for treating dental caries in most countries. However, it is not permitted to be used in mainland China. Several manufacturers, mainly in Australia, Brazil, India, Japan, and the United States, produce SDF at different concentrations that are commercially available around the world. The prices differ between contents and brands. Different government organizations and dental associations have developed guidelines for clinical use of SDF. Dental professionals can refer to the specific guidelines in their own countries or territories. Training for using SDF is part of undergraduate and/or postgraduate curriculums in almost all countries. However, real utilization of SDF of dentists, especially in the private sector, remains unclear in most places because little research has been conducted. There are at least two ongoing regional-wide large-scale oral health programs, using SDF as one of the components to manage dental caries in young children (one in Hong Kong and one in Mongolia). Because SDF treatment does not require caries removal, and it is simple, non-invasive, and inexpensive, SDF is a valuable strategy for caries management in young children, elderly people, and patients with special needs. In addition, to reduce the risk of bacteria or virus transmission in dental settings, using SDF as a non-aerosol producing procedure should be emphasized under the COVID-19 outbreak.</p