In recent years sufficient new information has accumulated to change current views of which mechanisms of corrosion are operating in water-cooled reactors. The total number of publications is now so ...enormous that it is impossible for a short review to be completely comprehensive. This review concentrates on those studies that have resulted in changed views of the importance of various mechanisms. There seems to be insufficient evidence to support an hypothesis that increased corrosion rates in reactor result directly from displacement damage to the oxide by fast neutron bombardment. Replacing this hypothesis are the observations that redistribution of Fe from second phase particles (SPPs) into the Zr matrix by fast neutron recoil reduces the corrosion resistance of Zircaloy type alloys both in-reactor and in laboratory tests. There is little support for the idea that an irradiation induced phase change from monoclinic to tetragonal (or cubic) zirconia is important in-reactor, since such transformed zirconias are unstable in ∼300 °C water and revert to the monoclinic phase; as do chemically stabilised zirconias. New alloys with improved corrosion resistance in PWRs are generally low in Fe (and Sn), or have Fe in the form of more radiation resistant SPPs than those in the Zircaloys. Similarly, the hypothesis that nodular corrosion in BWRs was directly related to an effect of irradiation produced radical species in the water is unsupported. However, local dissolution of the oxide film by radiation produced species such as H
2O
2 may be occurring, and the close mechanistic relationship between nodular corrosion and ‘shadow corrosion’ is very evident. Thus, galvanic potentials between large SPPs (or clusters of SPPs) and the Zr matrix, aided by greatly increased electronic conduction of zirconia in irradiated systems appears to offer an hypothesis that provides a rationale for the observed effects of SPP sizes and numbers. Irradiation induced redistribution of Fe from the SPPs into the Zr matrix eliminates nodular corrosion susceptibility in Zircaloys.
Programmable RNA editing enables reversible recoding of RNA information for research and disease treatment. Previously, we developed a programmable adenosine-to-inosine (A-to-I) RNA editing approach ...by fusing catalytically inactivate RNA-targeting CRISPR-Cas13 (dCas13) with the adenine deaminase domain of ADAR2. Here, we report a cytidine-to-uridine (C-to-U) RNA editor, referred to as RNA Editing for Specific C-to-U Exchange (RESCUE), by directly evolving ADAR2 into a cytidine deaminase. RESCUE doubles the number of mutations targetable by RNA editing and enables modulation of phosphosignaling-relevant residues. We apply RESCUE to drive β-catenin activation and cellular growth. Furthermore, RESCUE retains A-to-I editing activity, enabling multiplexed C-to-U and A-to-I editing through the use of tailored guide RNAs.
Background
The present interdisciplinary consensus review proposes clinical considerations and recommendations for anaesthetic practice in patients undergoing gastrointestinal surgery with an ...Enhanced Recovery after Surgery (ERAS) programme.
Methods
Studies were selected with particular attention being paid to meta‐analyses, randomized controlled trials and large prospective cohort studies. For each item of the perioperative treatment pathway, available English‐language literature was examined and reviewed. The group reached a consensus recommendation after critical appraisal of the literature.
Results
This consensus statement demonstrates that anaesthesiologists control several preoperative, intraoperative and postoperative ERAS elements. Further research is needed to verify the strength of these recommendations.
Conclusions
Based on the evidence available for each element of perioperative care pathways, the Enhanced Recovery After Surgery (ERAS ®) Society presents a comprehensive consensus review, clinical considerations and recommendations for anaesthesia care in patients undergoing gastrointestinal surgery within an ERAS programme. This unified protocol facilitates involvement of anaesthesiologists in the implementation of the ERAS programmes and allows for comparison between centres and it eventually might facilitate the design of multi‐institutional prospective and adequately powered randomized trials.
RNA editing with CRISPR-Cas13 Cox, David B. T.; Gootenberg, Jonathan S.; Abudayyeh, Omar O. ...
Science (American Association for the Advancement of Science),
11/2017, Letnik:
358, Številka:
6366
Journal Article
Recenzirano
Odprti dostop
Nucleic acid editing holds promise for treating genetic disease, particularly at the RNA level, where disease-relevant sequences can be rescued to yield functional protein products. Type VI ...CRISPR-Cas systems contain the programmable single-effector RNA-guided ribonuclease Cas13. We profiled type VI systems in order to engineer a Cas13 ortholog capable of robust knockdown and demonstrated RNA editing by using catalytically inactive Cas13 (dCas13) to direct adenosine-to-inosine deaminase activity by ADAR2 (adenosine deaminase acting on RNA type 2) to transcripts in mammalian cells. This system, referred to as RNA Editing for Programmable A to I Replacement (REPAIR), which has no strict sequence constraints, can be used to edit full-length transcripts containing pathogenic mutations. We further engineered this system to create a high-specificity variant and minimized the system to facilitate viral delivery. REPAIR presents a promising RNA-editing platform with broad applicability for research, therapeutics, and biotechnology.
The clustered regularly interspaced short palindromic repeat (CRISPR)-CRISPR-associated genes (Cas) adaptive immune system defends microbes against foreign genetic elements via DNA or RNA-DNA ...interference. We characterize the class 2 type VI CRISPR-Cas effector C2c2 and demonstrate its RNA-guided ribonuclease function. C2c2 from the bacterium Leptotrichia shahii provides interference against RNA phage. In vitro biochemical analysis shows that C2c2 is guided by a single CRISPR RNA and can be programmed to cleave single-stranded RNA targets carrying complementary protospacers. In bacteria, C2c2 can be programmed to knock down specific mRNAs. Cleavage is mediated by catalytic residues in the two conserved Higher Eukaryotes and Prokaryotes Nucleotide-binding (HEPN) domains, mutations of which generate catalytically inactive RNA-binding proteins. These results broaden our understanding of CRISPR-Cas systems and suggest that C2c2 can be used to develop new RNA-targeting tools.
A new, freely available third party MATLAB toolbox for the simulation and reconstruction of photoacoustic wave fields is described. The toolbox, named k-Wave, is designed to make realistic ...photoacoustic modeling simple and fast. The forward simulations are based on a k-space pseudo-spectral time domain solution to coupled first-order acoustic equations for homogeneous or heterogeneous media in one, two, and three dimensions. The simulation functions can additionally be used as a flexible time reversal image reconstruction algorithm for an arbitrarily shaped measurement surface. A one-step image reconstruction algorithm for a planar detector geometry based on the fast Fourier transform (FFT) is also included. The architecture and use of the toolbox are described, and several novel modeling examples are given. First, the use of data interpolation is shown to considerably improve time reversal reconstructions when the measurement surface has only a sparse array of detector points. Second, by comparison with one-step, FFT-based reconstruction, time reversal is shown to be sufficiently general that it can also be used for finite-sized planar measurement surfaces. Last, the optimization of computational speed is demonstrated through parallel execution using a graphics processing unit.
The efficient simulation of wave propagation through lossy media in which the absorption follows a frequency power law has many important applications in biomedical ultrasonics. Previous wave ...equations which use time-domain fractional operators require the storage of the complete pressure field at previous time steps (such operators are convolution based). This makes them unsuitable for many three-dimensional problems of interest. Here, a wave equation that utilizes two lossy derivative operators based on the fractional Laplacian is derived. These operators account separately for the required power law absorption and dispersion and can be efficiently incorporated into Fourier based pseudospectral and k-space methods without the increase in memory required by their time-domain fractional counterparts. A framework for encoding the developed wave equation using three coupled first-order constitutive equations is discussed, and the model is demonstrated through several one-, two-, and three-dimensional simulations.
Recently, there has been an increasing focus on the pursuit of targets considered to be less druggable that offer potential for development of promising new therapeutic agents for the treatment of ...diseases with large unmet medical need, particularly in the areas of oncology and virology. However, conducting drug discovery campaigns in "beyond rule of 5" (bRo5) chemical space presents a significant drug design and development challenge to medicinal chemists to achieve acceptable oral pharmacokinetics. Retrospective analysis of past successes and failures in drug discovery bRo5 may shed light on the key principles that contribute to the oral bioavailability of successful bRo5 compounds and improve the efficiency of drug design for future projects. We present here highlights and case studies of lessons learned from discovery of bRo5 compounds. A simple multiparametric scoring function (AB-MPS) was devised that correlated preclinical PK results with cLogD, number of rotatable bonds, and number of aromatic rings.
Prospective Life Cycle Assessment (pLCA) is useful to evaluate the environmental performance of current and emerging technologies in the future. Yet, as energy systems and industries are rapidly ...shifting towards cleaner means of production, pLCA requires an inventory database that encapsulates the expected changes in technologies and the environment at a given point in time, following specific socio-techno-economic pathways. To this end, this study introduces premise, a tool to streamline the generation of prospective inventory databases for pLCA by integrating scenarios generated by Integrated Assessment Models (IAM). More precisely, premise applies a number of transformations on energy-intensive activities found in the inventory database ecoinvent according to projections provided by the IAM. Unsurprisingly, the study shows that, within a given socio-economic narrative, the climate change mitigation target chosen affects the performance of nearly all activities in the database. This is illustrated by focusing on the effects observed on a few activities, such as systems for direct air capture of CO2, lithium-ion batteries, electricity and clinker production as well as freight transport by road, in relation to the applied sector-based transformation and the chosen climate change mitigation target. This work also discusses the limitations and challenges faced when coupling IAM and LCA databases and what improvements are to be brought in to further facilitate the development of pLCA.
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•Prospective LCA can benefit from projections of models such as IAM.•Premise streamlines the production of LCA databases based on prospective scenarios.•Emissions and energy efficiencies of major industries are aligned with IAM scenarios.•Stricter greenhouse gas targets result in larger transformations in the LCA database.•However, such targets result in increased LCA impacts other than global warming.
Abstract Purpose Requiring parental consent may result in sampling biases that confound scientific conclusions and stifle the representation of children most at risk for adverse outcomes. This study ...aims to investigate whether active parental consent, compared with passive parental consent, creates a bias in response rate, demographic makeup, and adverse outcomes in adolescent samples. Methods A meta-analysis was performed on peer-reviewed articles and unpublished dissertations from 1975 to 2016 in five computerized databases ERIC, PsycINFO, MEDLINE, PubMed and ProQuest. Quantitative studies were retained if they included the following keywords: active consent (or informed consent or parental consent), passive consent (or waiver of consent), risk behavior, adolescen*. Results Fifteen studies were identified with a total number of 104,074 children. Results showed (1) response rates were significantly lower for studies using active consent procedure than those using passive consent procedure (Z = 3.05, p = .002); (2) more females, younger participants, and less African-Americans were included in studies using active consent procedures than studies using passive procedures (Z = −2.73, p = .006; Z = −12.06, p < .00001; Z = 2.19, p = .03, respectively); (3) studies with passive consent procedures showed higher rates of self-reported substance use than studies using active consent procedures (Z = 3.07, p = .002). Conclusions Requiring active parental consent can lead to a systematic bias in the sample where the population under study is misrepresented. Institutional review board committees should collaborate with researchers to find solutions that protect minors without silencing the voice of high-risk youth in the literature.
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