Pathogenic Mechanisms underlying the Early Epileptic Encephalopathy CDKL5 Disorder

Cyclin-dependent kinase-like 5 (CDKL5) is an X-linked gene associated with early infantile epileptic encephalopathy, atypical Rett Syndrome, and autism spectrum disorders. Patients with CDKL5 mutations display a heterogeneous array of clinical symptoms, the most prominent of which include early-onset epileptic seizures, intellectual disability, marked hypotonia, and autistic features. Despite the strong genetic linkage between CDKL5 mutations and neurodevelopmental disorders, the biological function of CDKL5 and its pathogenic mechanisms remain largely uncharacterized. Consequently, treatments for CDKL5 disorder have been largely ineffective and limited to symptom management. This study aims to dissect the molecular and cellular basis of CDKL5 disorder using novel mouse models and to identify signaling pathways that can be targeted for therapeutic development. To determine the genetic causality of CDKL5 disorder, we generated the first Cdkl5 knockout (KO) mouse and found that mice lacking CDKL5 mimic key symptoms of CDKL5 disorder, including impaired motor control, poor learning and memory, and autistic-like behaviors. KO mice also show deficits in neural circuit communication and alterations in many signal transduction pathways, but do not develop spontaneous seizures. Previous studies using in vitro cell cultures and shRNA-mediated knockdown have implicated CDKL5 in dendritic morphogenesis and the phosphorylation of MeCP2, mutations of which cause Rett Syndrome, but the results of these studies are contentious. Therefore, to understand the in vivo function of CDKL5 and to investigate how loss of CDKL5 contributes to epileptic and autistic features, we have generated Cdkl5 conditional KO mice. Notably, our studies show that selective deletion of Cdkl5 from forebrain GABAergic neurons (Dlx-cKO) recapitulates autistic-like phenotypes, whereas selective removal of Cdkl5 from forebrain glutamatergic neurons (Nex-cKO) results in the development of spontaneous seizures. The separation of distinct aspects of CDKL5 disorder-related phenotypes in the two complementary conditional KO lines suggests that the epileptic and autistic phenotypes of CDKL5 disorder are mediated by distinct neural circuits and that loss of CDKL5 in specific cell types may differentially disrupt signaling pathways and impair neuronal function

Wallops Island natural rain data analysis

ScTI has performed a detailed analysis of four optical rain gauge ORG-105 sensors tested by Wallops Island on 8 May 1992. The four ORG's tested were S/N 2236, 2237, 2239, and 2241. Shown is a 30 minute time series of the individual ORG's, the ORG average, and the weighing gauge. The sensors tracked well with rainrates (RR) up to 45 mm/hr for the period. Also shown is a plot of accumulated rainfall over the same period. It can be seen that even though the ORG's tracked well, some ORG's tended to read higher and some read lower during the event

3D VISUALIZATION OF GENETIC MUTATIONS IN PANCREATIC INTRAEPITHELIAL NEOPLASIA

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest forms of cancer in the United States and is often diagnosed in advanced stages with poor prognosis. A new workflow called CODA that uses machine learning to reconstruct pancreas pathology, from precursor lesions to PDAC, has been established to study PDAC in humans in three-dimensions. Although the genetic mutations that drive PDAC are known, there exists little information regarding 3D spatial distribution of these mutations. Once defined in 3D, these mutations would need to be visualized in a clear and organized way. The application of genetic sequencing to 3D-constructed precursor lesions in the human pancreas afforded a novel opportunity to develop tools to visualize complex genetic changes in three dimensions. Each lesion was subdivided for deeper resolution of lesion heterogeneity. The visualization developed took a 3D scatter plot approach. Genetic mutations were represented by mapped objected spaced equally throughout the precursor lesions. Each genetic mutation was assigned a color. Object size was used to represent prevalence of each genetic mutation in 4 distinct 3D precursor lesions in each gene sequencing region. Four visualization outputs were created, including still images, turntable videos, an interactive platform, and a promotional image. The interactive platform includes a 3D interactive model that a user can rotate and scale, togglable genetic mutation representations, and a switch between “prevalence” and “no prevalence” modes. Modeling was done using 4D® and ZBrush®. Unity was used for lighting, materials, and creation of the 3D interactive platform. This thesis project experimented with ways in which data commonly visualized in a 2D manner could be visualized in a 3D space. The visualization represents a first step in understanding tumorigenesis in three dimensions and its contributing factors as related to tumor microenvironments in human

Key Users and Box Office Analysis in an Interest Based Virtual Community

In recent years, with the growth of the Internet technology, the users of virtual community not only play the role of the information receiver but also a very important one to provide information. However, there is large amount of information aggregated daily and therefore information overloading has become a very serious problem. Under this situation, how to find information efficiently is also a very important issue. In this paper, we believe users in a virtual community may affect each other, especially those with high influence who have been called as Key Users. Therefore, we observe the biggest virtual community of movies on the Internet which is named IMDb (The Internet Movie Database). An architecture also has been proposed that combines Social Networks Analysis and the features of IMDb to discover those users who have high influence in the virtual community. We collected 17 months (January 2010 to May 2011) from IMDb including 17 366 users and 243 074 reviews. By applying the method we proposed, there are about 22 key users and 111 reviews were discovered. We also use the box office of the movies to justify our results

Local tunneling spectroscopy as signatures of the Fulde-Ferrell-Larkin-Ovchinnikov state in s- and d-wave Superconductors

The Fulde-Ferrell-Larkin-Ovchinnikov (FFLO) states for two-dimensional s- and d-wave superconductors (s- and d-SC) are self-consistently studied under an in-plane magnetic field. While the stripe solution of the order parameter (OP) is found to have lower free energy in s-SC, a square lattice solution appears to be energetically more favorable in the case of d-SC. At certain symmetric sites, we find that the features in the local density of states (LDOS) can be ascribed to two types of bound states. We also show that the LDOS maps for d-SC exhibit bias-energy-dependent checkerboard patterns. These characteristics can serve as signatures of the FFLO states.Comment: 5 pages, 5 figures Type and grammaratic errors corrected. Last figure replaced by colored one. To appear in PR

Fault-Tolerant Electro-Responsive Surfaces for Dynamic Micropattern Molds and Tunable Optics.

Electrically deformable surfaces based on dielectric elastomers have recently demonstrated controllable microscale roughness, ease of operation, fast response, and possibilities for programmable control. Potential applications include marine anti-biofouling, dynamic pattern generation, and voltage-controlled smart windows. Most of these systems, however, exhibit limited durability due to irreversible dielectric breakdown. Lowering device voltage to avoid this issue is hindered by an inadequate understanding of the electrically-induced wrinkling deformation as a function of the deformable elastic film thickness. Here we report responsive surfaces that overcome these shortcomings: we achieve fault-tolerant behavior based on the ability to self-insulate breakdown faults, and we enhance fundamental understanding of the system by quantifying the critical field necessary to induce wrinkles in films of different thickness and comparing to analytical models. We also observe new capabilities of these responsive surfaces, such as field amplification near local breakdown sites, which enable actuation and wrinkle pattern formation at lower applied voltages. We demonstrate the wide applicability of our responsive, fault-tolerant films by using our system for adjustable transparency films, tunable diffraction gratings, and a dynamic surface template/factory from which various static micropatterns can be molded on demand