Non-abelian D=11 Supermembrane

We obtain a U(M) action for supermembranes with central charges in the Light Cone Gauge (LCG). The theory realizes all of the symmetries and constraints of the supermembrane together with the invariance under a U(M) gauge group with M arbitrary. The worldvolume action has (LCG) N=8 supersymmetry and it corresponds to M parallel supermembranes minimally immersed on the target M9xT2 (MIM2). In order to ensure the invariance under the symmetries and to close the corresponding algebra, a star-product determined by the central charge condition is introduced. It is constructed with a nonconstant symplectic two-form where curvature terms are also present. The theory is in the strongly coupled gauge-gravity regime. At low energies, the theory enters in a decoupling limit and it is described by an ordinary N=8 SYM in the IR phase for any number of M2-branes.Comment: Contribution to the Proceedings of the Dubna International SQS'09 Workshop ("Supersymmetries and Quantum Symmetries-2009", July 29 - August 3, 2009. 12pg, Late

Evaluation of game templates to support programming activities in schools

Game creation challenges in schools potentially provide engaging, goal-oriented, and interactive experiences in classes; thereby supporting the transfer of knowledge for learning in a fun and pedagogic manner. A key element of the ongoing European project No One Left Behind (NOLB) is to integrate a game-making teaching framework (GMTF) into the educational app Pocket Code. Pocket Code allows learners to create programs in a visual Lego®-style way to facilitate learning how to code at secondary high schools. The concept of the NOLB GMTF is based on principles of the Universal Design for Learning (UDL) model. Its focus lies on three pillars of learning: the what, how, and why. Thereby, the NOLB GMTF is a common set of concepts, practices, pedagogy, and methods. This framework provides a coherent approach to learning and teaching by integrating leisure oriented gaming methods into multi-discipline curricula. One output of this framework is the integration of game-based methods via game templates that refer to didactical scenarios that include a refined set of genres, assets, rules, challenges, and strategies. These templates allows: 1) teachers to start with a well-structured program, and 2) pupils to add content and adjust the code to integrate their own ideas. During the project game genres such as adventure, action, and quiz, as well as rewards or victory point mechanisms, have been embedded into different subjects, e.g., science, mathematics, and arts. The insights gained during the class hours were used to generate 13 game templates, which are integrated in Create@School (a new version of the Pocket Code app which targets schools). To test the efficiency of these templates, user experience (UX) tests were conducted during classes to compare games created by pupils who used templates and those who started to create a game from scratch. Preliminary results showed that these templates allow learners to focus on subject-relevant problem solving activities rather than on understanding the functionality of the app. This directly leads to more time to express their creativity in different levels and more time for extra tasks

Generation of versatile ss-dsDNA hybrid substrates for single-molecule analysis.

Here, we describe a rapid and versatile protocol to generate gapped DNA substrates for single-molecule (SM) analysis using optical tweezers via site-specific Cas9 nicking and force-induced melting. We provide examples of single-stranded (ss) DNA gaps of different length and position. We outline protocols to visualize these substrates by replication protein A-enhanced Green Fluorescent Protein (RPA-eGFP) and SYTOX Orange staining using commercially available optical tweezers (C-TRAP). Finally, we demonstrate the utility of these substrates for SM analysis of bidirectional growth of RAD-51-ssDNA filaments. For complete details on the use and execution of this protocol, please refer to Belan et al. (2021)

Formal Analysis of Linear Control Systems using Theorem Proving

Control systems are an integral part of almost every engineering and physical system and thus their accurate analysis is of utmost importance. Traditionally, control systems are analyzed using paper-and-pencil proof and computer simulation methods, however, both of these methods cannot provide accurate analysis due to their inherent limitations. Model checking has been widely used to analyze control systems but the continuous nature of their environment and physical components cannot be truly captured by a state-transition system in this technique. To overcome these limitations, we propose to use higher-order-logic theorem proving for analyzing linear control systems based on a formalized theory of the Laplace transform method. For this purpose, we have formalized the foundations of linear control system analysis in higher-order logic so that a linear control system can be readily modeled and analyzed. The paper presents a new formalization of the Laplace transform and the formal verification of its properties that are frequently used in the transfer function based analysis to judge the frequency response, gain margin and phase margin, and stability of a linear control system. We also formalize the active realizations of various controllers, like Proportional-Integral-Derivative (PID), Proportional-Integral (PI), Proportional-Derivative (PD), and various active and passive compensators, like lead, lag and lag-lead. For illustration, we present a formal analysis of an unmanned free-swimming submersible vehicle using the HOL Light theorem prover.Comment: International Conference on Formal Engineering Method

Risks of Nontraumatic Lower-Extremity Amputations in Patients with Type 1 Diabetes: A population-based cohort study in Sweden

OBJECTIVE—The purpose of this study was to estimate the risks of nontraumatic lower-extremity amputations (LEAs) in patients with type 1 diabetes

Small nerve fiber damage and Langerhans cells in type 1 and type 2 diabetes and LADA measured by corneal confocal microscopy

Purpose: Increased corneal and epidermal Langerhans cells (LCs) have been reported in patients with diabetic neuropathy. The aim of this study was to quantify the density of LCs in relation to corneal nerve morphology and the presence of diabetic neuropathy and to determine if this differed in patients with type 1 diabetes mellitus (T1DM), type 2 diabetes mellitus (T2DM), and latent autoimmune diabetes of adults (LADA). Methods: Patients with T1DM (n = 25), T2DM (n = 36), or LADA (n = 23) and control subjects (n = 23) underwent detailed assessment of peripheral neuropathy and corneal confocal microscopy. Corneal nerve fiber density (CNFD), branch density (CNBD), length (CNFL) and total, immature and mature LC densities were quantified. Results: Lower CNFD (P < 0.001), CNBD (P < 0.0001), and CNFL (P < 0.0001) and higher LC density (P = 0.03) were detected in patients with T1DM, T2DM, and LADA compared to controls. CNBD was inversely correlated with mature (r = -0.5; P = 0.008), immature (r = -0.4; P = 0.02) and total (r = -0.5; P = 0.01) LC density, and CNFL was inversely correlated with immature LC density (r = -0.4; P = 0.03) in patients with T1DM but not in patients with T2DM and LADA. Conclusions: This study shows significant corneal nerve loss and an increase in LC density in patients with T1DM, T2DM, and LADA. Furthermore, increased LC density correlated with corneal nerve loss in patients with T1DM

The effect of Ku on telomere replication time is mediated by telomere length but is independent of histone tail acetylation

Peer reviewedPublisher PD

HELQ is a dual-function DSB repair enzyme modulated by RPA and RAD51

DNA double-stranded breaks (DSBs) are deleterious lesions, and their incorrect repair can drive cancer development1. HELQ is a superfamily 2 helicase with 3′ to 5′ polarity, and its disruption in mice confers germ cells loss, infertility and increased predisposition to ovarian and pituitary tumours2,3,4. At the cellular level, defects in HELQ result in hypersensitivity to cisplatin and mitomycin C, and persistence of RAD51 foci after DNA damage3,5. Notably, HELQ binds to RPA and the RAD51-paralogue BCDX2 complex, but the relevance of these interactions and how HELQ functions in DSB repair remains unclear3,5,6. Here we show that HELQ helicase activity and a previously unappreciated DNA strand annealing function are differentially regulated by RPA and RAD51. Using biochemistry analyses and single-molecule imaging, we establish that RAD51 forms a complex with and strongly stimulates HELQ as it translocates during DNA unwinding. By contrast, RPA inhibits DNA unwinding by HELQ but strongly stimulates DNA strand annealing. Mechanistically, we show that HELQ possesses an intrinsic ability to capture RPA-bound DNA strands and then displace RPA to facilitate annealing of complementary sequences. Finally, we show that HELQ deficiency in cells compromises single-strand annealing and microhomology-mediated end-joining pathways and leads to bias towards long-tract gene conversion tracts during homologous recombination. Thus, our results implicate HELQ in multiple arms of DSB repair through co-factor-dependent modulation of intrinsic translocase and DNA strand annealing activities

Visualization of direct and diffusion-assisted RAD51 nucleation by full-length human BRCA2 protein

Homologous recombination (HR) is essential for error-free repair of DNA double-strand breaks, perturbed replication forks (RFs), and post-replicative single-stranded DNA (ssDNA) gaps. To initiate HR, the recombination mediator and tumor suppressor protein BRCA2 facilitates nucleation of RAD51 on ssDNA prior to stimulation of RAD51 filament growth by RAD51 paralogs. Although ssDNA binding by BRCA2 has been implicated in RAD51 nucleation, the function of double-stranded DNA (dsDNA) binding by BRCA2 remains unclear. Here, we exploit single-molecule (SM) imaging to visualize BRCA2-mediated RAD51 nucleation in real time using purified proteins. We report that BRCA2 nucleates and stabilizes RAD51 on ssDNA either directly or through an unappreciated diffusion-assisted delivery mechanism involving binding to and sliding along dsDNA, which requires the cooperative action of multiple dsDNA-binding modules in BRCA2. Collectively, our work reveals two distinct mechanisms of BRCA2-dependent RAD51 loading onto ssDNA, which we propose are critical for its diverse functions in maintaining genome stability and cancer suppression