Regulation of mRNA translation by a photoriboswitch.

Optogenetic tools have revolutionized the study of receptor-mediated processes, but such tools are lacking for RNA-controlled systems. In particular, light-activated regulatory RNAs are needed for spatiotemporal control of gene expression. To fill this gap, we used in vitro selection to isolate a novel riboswitch that selectively binds the trans isoform of a stiff-stilbene (amino-tSS)-a rapidly and reversibly photoisomerizing small molecule. Structural probing revealed that the RNA binds amino-tSS about 100-times stronger than the cis photoisoform (amino-cSS). In vitro and in vivo functional analysis showed that the riboswitch, termed Werewolf-1 (Were-1), inhibits translation of a downstream open reading frame when bound to amino-tSS. Photoisomerization of the ligand with a sub-millisecond pulse of light induced the protein expression. In contrast, amino-cSS supported protein expression, which was inhibited upon photoisomerization to amino-tSS. Reversible photoregulation of gene expression using a genetically encoded RNA will likely facilitate high-resolution spatiotemporal analysis of complex RNA processes

Scientific Integrity in the Forensic Sciences: Consumerism, Conflicts of Interest, and Transparency

The goal of this paper is to discuss scientific integrity, consumerism, conflicts of interest, and transparency within the context of forensic science. Forensic scientists play crucial roles within the legal system and are constantly under various pressures when performing analytical work, generating reports based on their analyses, or testifying to the content of these reports. Maintaining the scientific integrity of these actions is paramount to supporting a functional legal system and the practice of good science. Our goal is to discuss the importance of scientific integrity as well as the factors it may compromise, so that forensic practitioners may be better equipped to recognize and avoid conflicts of interest when they arise. In this discussion we define terms, concepts, and professional relationships as well as present three case studies to contextualize these ideas

Computational analysis of transport in three-dimensional heterogeneous materials: An OpenFOAM®-based simulation framework

Porous and heterogeneous materials are found in many applications from composites, membranes, chemical reactors, and other engineered materials to biological matter and natural subsurface structures. In this work we propose an integrated approach to generate, study and upscale transport equations in random and periodic porous structures. The geometry generation is based on random algorithms or ballistic deposition. In particular, a new algorithm is proposed to generate random packings of ellipsoids with random orientation and tunable porosity and connectivity. The porous structure is then meshed using locally refined Cartesian-based or unstructured strategies. Transport equations are thus solved in a finite-volume formulation with quasi-periodic boundary conditions to simplify the upscaling problem by solving simple closure problems consistent with the classical theory of homogenisation for linear advection–diffusion–reaction operators. Existing simulation codes are extended with novel developments and integrated to produce a fully open-source simulation pipeline. A showcase of a few interesting three-dimensional applications of these computational approaches is then presented. Firstly, convergence properties and the transport and dispersion properties of a periodic arrangement of spheres are studied. Then, heat transfer problems are considered in a pipe with layers of deposited particles of different heights, and in heterogeneous anisotropic materials

Choosing the optimal dose in sublingual immunotherapy: Rationale for the 300 index of reactivity dose

Sublingual immunotherapy (SLIT) is an effective and well-tolerated method of treating allergic respiratory diseases associated with seasonal and perennial allergens. In contrast to the subcutaneous route, SLIT requires a much greater amount of antigen to achieve a clinical effect. Many studies have shown that SLIT involves a dose-response relationship, and therefore it is important to use a proven clinically effective dose from the onset of treatment, because low doses are ineffective and very high doses may increase the risk of side effects. A well-defined standardization of allergen content is also crucial to ensure consistent quality, potency and appropriate immunomodulatory action of the SLIT product. Several methods of measuring antigenicity are used by manufacturers of SLIT products, including the index of reactivity (IR), standardized quality tablet unit, and bioequivalent allergy unit. A large body of evidence has established the 300 IR dose of SLIT as offering optimal efficacy and tolerability for allergic rhinitis due to grass and birch pollen and HDM, and HDM-induced moderate, persistent allergic asthma. The 300 IR dose also offers consistency of dosing across a variety of different allergens, and is associated with higher rates of adherence and patient satisfaction. Studies in patients with grass pollen allergies showed that the 300 IR dose has a rapid onset of action, is effective in both adults and children in the short term and, when administered pre-coseasonally in the long term, and maintains the clinical benefit, even after cessation of treatment. In patients with HDM-associated AR and/or asthma, the 300 IR dose also demonstrated significant improvements in symptoms and quality of life, and significantly decreased use of symptomatic medication. The 300 IR dose is well tolerated, with adverse events generally being of mild or moderate severity, declining in frequency and severity over time and in the subsequent courses. We discuss herein the most important factors that affect the selection of the optimal dose of SLIT with natural allergens, and review the rationale and evidence supporting the use of the 300 IR dose

Multiplex Networks: A Framework for Studying Multiprocess Multiscale Connectivity Via Coupled-Network Theory With an Application to River Deltas

Transport of water, nutrients, or energy fluxes in many natural or coupled human natural systems occurs along different pathways that often have a wide range of transport timescales and might exchange fluxes with each other dynamically. Although network approaches have been proposed for studying connectivity and transport properties on single-layer networks, theories considering interacting networks are lacking. We present a general framework for transport on multiscale coupled-connectivity systems, via multilayer networks which conceptualize the system as a set of interacting networks, each arranged in a separate layer, and with interactions across layers acknowledged by interlayer links. We illustrate this framework by examining transport in river deltas as a dynamic interaction of flow within river channels and overland flow on the islands, when controlled by the flooding level. We show the potential of the framework to answer quantitative questions related to the characteristic timescale of response in the system

Allergen immunotherapy in asthma; what is new?

The use and role of allergen immunotherapy (AIT) in asthma is still a matter of debate, and no definite recommendation about this is made in guidelines, both for the subcutaneous and sublingual routes. This is essentially due to the fact that most controlled randomised trials were not specifically designed for asthma, and that objective measures of pulmonary function were only occasionally considered. Nonetheless, in many trials, favourable results in asthma (symptoms, medication usage, bronchial reactivity) were consistently reported. There are also several meta analyses in favour of AIT, although their validity is limited by a relevant methodological heterogeneity. In addition to the crude clinical effect, a disease modifying action of AIT (prevention of asthma onset and long-lasting effects) have been reported. The safety is an important aspect to consider in asthma. Fatalities were rare: In Europe no fatality was reported in the last three decades, as in the United States in the last 4 years. Based on previous surveys, and common sense, uncontrolled asthma is still recognized as the most important risk factor for severe adverse events. On the contrary, there is no evidence that AIT can worsen or induce asthma. According to the available evidence, AIT can be safely used as add-on treatment when asthma is associated with rhinitis (a frequent condition), provided that asthma is adequately controlled by pharmacotherapy. AIT cannot be recommended or suggested as single therapy. When asthma is the unique manifestation of respiratory allergy, its use should be evaluated case by case

Remote Monitoring of Sustained Low-Efficiency Dialysis (SLED) Machines in Intensive Care Unit

The Henry Ford Health System provides patients with a safe, improved system of continuous kidney replacement therapy using a proprietary, 24-hour sustained low-efficiency dialysis (SLED). The SLED system utilizes regional citrate anticoagulation (RCA) in conventional hemodialysis machines that have been configured to provide slow dialytic therapy. Within our hospital complex, SLED-RCA systems are deployed in intensive care units distributed over 4 floors in 2 buildings. This widespread footprint represents a spatial challenge for hemodialysis technicians. Fifteen SLED-RCA machines may be running at one time, and each deployed unit may signal an alarm for multiple reasons. Previously, audible alarms prompted intensive care unit nurses to identify the alarming machine and manually notify technicians by telephone. Technicians would then travel to resolve the alarm. To improve the process of addressing SLED-RCA machine alarms, we developed a remote alert alarm system that wirelessly notifies hemodialysis technicians of specific machine alarms. A quality improvement analysis of nearly 1,000 SLED-RCA alarms over a 1-week period revealed that the average time for alarm correction with a remote alert alarm system was approximately 5 minutes. Reducing alarm resolution time may free technicians and nurses for other critical duties