CRISPR/Cas9-induced (CTG⋅CAG)n repeat instability in the myotonic dystrophy type 1 locus: implications for therapeutic genome editing

Myotonic dystrophy type 1 (DM1) is caused by (CTG⋅CAG)n-repeat expansion within the DMPK gene and thought to be mediated by a toxic RNA gain of function. Current attempts to develop therapy for this disease mainly aim at destroying or blocking abnormal properties of mutant DMPK (CUG)n RNA. Here, we explored a DNA-directed strategy and demonstrate that single clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9-cleavage in either its 5′ or 3′ unique flank promotes uncontrollable deletion of large segments from the expanded trinucleotide repeat, rather than formation of short indels usually seen after double-strand break repair. Complete and precise excision of the repeat tract from normal and large expanded DMPK alleles in myoblasts from unaffected individuals, DM1 patients, and a DM1 mouse model could be achieved at high frequency by dual CRISPR/Cas9-cleavage at either side of the (CTG⋅CAG)n sequence. Importantly, removal of the repeat appeared to have no detrimental effects on the expression of genes in the DM1 locus. Moreover, myogenic capacity, nucleocytoplasmic distribution, and abnormal RNP-binding behavior of transcripts from the edited DMPK gene were normalized. Dual sgRNA-guided excision of the (CTG⋅CAG)n tract by CRISPR/Cas9 technology is applicable for developing isogenic cell lines for research and may provide new therapeutic opportunities for patients with DM1

Numerical Design of Microporous Carbon Binder Domains Phase in Composite Cathodes for Lithium-Ion Batteries

Lithium-ion battery (LIB) performance can be significantly affected by the nature of the complex electrode microstructure. The carbon binder domain (CBD) present in almost all LIB electrodes is used to enhance mechanical stability and facilitate electronic conduction, and understanding the CBD phase microstructure and how it affects the complex coupled transport processes is crucial to LIB performance optimization. In this work, the influence of microporosity in the CBD phase has been studied in detail for the first time, enabling insight into the relationships between the CBD microstructure and the battery performance. To investigate the effect of the CBD pore size distributions, a random field method is used to generate in silico a multiple-phase electrode structure, including bimodal pore size distributions seen in practice and microporous CBD with a tunable pore size and variable transport properties. The distribution of macropores and the microporous CBD phase substantially affected simulated battery performance, where battery specific capacity improved as the microporosity of the CBD phase increased

Design and sensitivity of a 6-axis seismometer for gravitational wave observatories

We present the design, control system, and noise analysis of a 6-axis seismometer comprising a mass suspended by a single fused silica fiber. We utilize custom-made, compact Michelson interferometers for the readout of the mass motion relative to the table and successfully overcome the sensitivity of existing commercial seismometers by over an order of magnitude in the angular degrees of freedom. We develop the sensor for gravitational-wave observatories, such as LIGO, Virgo, and KAGRA, to help them observe intermediate-mass black holes, increase their duty cycle, and improve localization of sources. Our control system and its achieved sensitivity makes the sensor suitable for other fundamental physics experiments, such as tests of semiclassical gravity, searches for bosonic dark matter, and studies of the Casimir force

Design and sensitivity of a 6-axis seismometer for gravitational wave observatories

We present the design, control system, and noise analysis of a 6-axis seismometer comprising a mass suspended by a single fused silica fibre. We utilise custom-made, compact Michelson interferometers for the readout of the mass motion relative to the table and successfully overcome the sensitivity of existing commercial seismometers by over an order of magnitude in the angular degrees of freedom. We develop the sensor for gravitational-wave observatories, such as LIGO, Virgo, and KAGRA, to help them observe intermediate-mass black holes, increase their duty cycle, and improve localisation of sources. Our control system and its achieved sensitivity makes the sensor suitable for other fundamental physics experiments, such as tests of semiclassical gravity, searches for bosonic dark matter, and studies of the Casimir force

Active platform stabilization with a 6D seismometer

We demonstrate the control scheme of an active platform with a six degree of freedom (6D) seismometer. The inertial sensor simultaneously measures translational and tilt degrees of freedom of the platform and does not require any additional sensors for the stabilization. We show that a feedforward cancelation scheme can efficiently decouple tilt-to-horizontal coupling of the seismometer in the digital control scheme. We stabilize the platform in the frequency band from 250 mHz up to 10 Hz in the translational (X, Y) degrees of freedom and achieve a suppression factor of 100 around 1 Hz. Further suppression of ground vibrations was limited by the non-linear response of the piezo actuators of the platform and by its limited range (5 lm). In this paper, we discuss the 6D seismometer, its control scheme, and the limitations of the test bed

Roadmap on Li-ion battery manufacturing research

Growth in the Li-ion battery market continues to accelerate, driven primarily by the increasing need for economic energy storage for electric vehicles. Electrode manufacture by slurry casting is the first main step in cell production but much of the manufacturing optimisation is based on trial and error, know-how and individual expertise. Advancing manufacturing science that underpins Li-ion battery electrode production is critical to adding to the electrode manufacturing value chain. Overcoming the current barriers in electrode manufacturing requires advances in materials, manufacturing technology, in-line process metrology and data analytics, and can enable improvements in cell performance, quality, safety and process sustainability. In this roadmap we explore the research opportunities to improve each stage of the electrode manufacturing process, from materials synthesis through to electrode calendering. We highlight the role of new process technology, such as dry processing, and advanced electrode design supported through electrode level, physics-based modelling. Progress in data driven models of electrode manufacturing processes is also considered. We conclude there is a growing need for innovations in process metrology to aid fundamental understanding and to enable feedback control, an opportunity for electrode design to reduce trial and error, and an urgent imperative to improve the sustainability of manufacture

Recovering the Divide: A Review of Strategy and Tactics in Business and Management

With origins in military history, strategy and tactics is a frequently used conceptual couplet in the business and management literature. This paper reviews how strategy and tactics are portrayed, identifying a dominant ‘pragmatic’ account of strategy as an expression of formal, planned ends achieved through the subordinate means of tactics. Pragmatic distinctions give rise to a range of well-known problems, in particular in strategy implementation stages. We suggest that some of these problems may be avoided when the strategy–tactics relationship is conceived differently. We elaborate two alternative distinctions: a sociological framing of tactics as mechanisms of resistance to formal, controlling strategies; and a processual perspective, which sidesteps fixed distinctions between tactics and strategy, giving rise to more fluid interrelations between both modes. Based on a review of the business and management literature, we identify key examples of each trope and conclude by drawing insights for each account on the basis of these wider discussions