Effect of Combined Systemic and Local Morpholino Treatment on the Spinal Muscular Atrophy Δ7 Mouse Model Phenotype

BACKGROUND: Spinal muscular atrophy (SMA) is a fatal motor neuron disease of childhood that is caused by mutations in the SMN1 gene. Currently, no effective treatment is available. One possible therapeutic approach is the use of antisense oligos (ASOs) to redirect the splicing of the paralogous gene SMN2, thus increasing functional SMN protein production. Various ASOs with different chemical properties are suitable for these applications, including a morpholino oligomer (MO) variant with a particularly excellent safety and efficacy profile. OBJECTIVE: We investigated a 25-nt MO sequence targeting the negative intronic splicing silencer (ISS-N1) 10 to 34 region. METHODS: We administered a 25-nt MO sequence against the ISS-N1 region of SMN2 (HSMN2Ex7D[-10-34]) in the SMAΔ7 mouse model and evaluated the effect and neuropathologic phenotype. We tested different concentrations (from 2 to 24 nM) and delivery protocols (intracerebroventricular injection, systemic injection, or both). We evaluated the treatment efficacy regarding SMN levels, survival, neuromuscular phenotype, and neuropathologic features. RESULTS: We found that a 25-nt MO sequence against the ISS-N1 region of SMN2 (HSMN2Ex7D[-10-34]) exhibited superior efficacy in transgenic SMAΔ7 mice compared with previously described sequences. In our experiments, the combination of local and systemic administration of MO (bare or conjugated to octaguanidine) was the most effective approach for increasing full-length SMN expression, leading to robust improvement in neuropathologic features and survival. Moreover, we found that several small nuclear RNAs were deregulated in SMA mice and that their levels were restored by MO treatment. CONCLUSION: These results indicate that MO-mediated SMA therapy is efficacious and can result in phenotypic rescue, providing important insights for further development of ASO-based therapeutic strategies in SMA patients.

Towards a new model of care: integrating mental health, substance use, and somatic care

Although research and clinical interventions for patients with dual disorders have been described since as early as the 1980s, the day-to-day treatment of these patients remains problematic and challenging in many countries. Throughout this book, many approaches and possible pathways have been outlined. Based upon these experiences, some key points can be extracted in order to guide to future developments. (1) New diagnostic approaches are warranted when dealing with patients who have multiple problems, given the limitations of the current categorical systems. (2) Greater emphasis should be placed on secondary prevention and early intervention for children and adolescents at an increased risk of later-life dual disorders. (3) Mental, addiction, and somatic care systems can be integrated, adopting a patient-focused approach to care delivery. (4) Recovery should be taken into consideration when defining treatment intervention and outcome goals. (5) It is important to reduce societal risk factors, such as poverty and early childhood adversity. (6) More resources are needed to provide adequate mental health care in the various countries. The development of European guidance initiatives would provide benefits in many of these areas, making it possible to ensure a more harmonized standard of care for patients with dual disorders.

Detecting single-target changes in multiple object tracking: The case of peripheral vision

In sports games, it is often necessary to perceive a large number of moving objects (e.g., the ball and players). In this context, the role of peripheral vision for processing motion information in the periphery is often discussed especially when motor responses are required. In an attempt to test the capability of using peripheral vision in those sports-games situations, a Multiple-Object-Tracking task that requires to track a certain number of targets amidst distractors, was chosen to determine the sensitivity of detecting target changes with peripheral vision only. Participants’ primary task was to recall four targets (out of 10 rectangular stimuli) after six seconds of quasi-random motion. As a second task, a button had to be pressed if a target change occurred (Exp 1: stop vs. form change to a diamond for 0.5 s; Exp 2: stop vs. slowdown for 0.5 s). Eccentricities of changes (5-10° vs. 15-20°) were manipulated, decision accuracy (recall and button press correct), motor response time and saccadic reaction time (change onset to saccade onset) were calculated and eye-movements were recorded. Results show that participants indeed used peripheral vision to detect changes, because either no or very late saccades to the changed target were executed in correct trials. Moreover, a saccade was more often executed when eccentricities were small. Response accuracies were higher and response times were lower in the stop conditions of both experiments while larger eccentricities led to higher response times in all conditions. Summing up, it could be shown that monitoring targets and detecting changes can be processed by peripheral vision only and that a monitoring strategy on the basis of peripheral vision may be the optimal one as saccades may be afflicted with certain costs. Further research is planned to address the question whether this functionality is also evident in sports tasks.

VIRTOPSY--scientific documentation, reconstruction and animation in forensic: individual and real 3D data based geo-metric approach including optical body/object surface and radiological CT/MRI scanning.

Until today, most of the documentation of forensic relevant medical findings is limited to traditional 2D photography, 2D conventional radiographs, sketches and verbal description. There are still some limitations of the classic documentation in forensic science especially if a 3D documentation is necessary. The goal of this paper is to demonstrate new 3D real data based geo-metric technology approaches. This paper present approaches to a 3D geo-metric documentation of injuries on the body surface and internal injuries in the living and deceased cases. Using modern imaging methods such as photogrammetry, optical surface and radiological CT/MRI scanning in combination it could be demonstrated that a real, full 3D data based individual documentation of the body surface and internal structures is possible in a non-invasive and non-destructive manner. Using the data merging/fusing and animation possibilities, it is possible to answer reconstructive questions of the dynamic development of patterned injuries (morphologic imprints) and to evaluate the possibility, that they are matchable or linkable to suspected injury-causing instruments. For the first time, to our knowledge, the method of optical and radiological 3D scanning was used to document the forensic relevant injuries of human body in combination with vehicle damages. By this complementary documentation approach, individual forensic real data based analysis and animation were possible linking body injuries to vehicle deformations or damages. These data allow conclusions to be drawn for automobile accident research, optimization of vehicle safety (pedestrian and passenger) and for further development of crash dummies. Real 3D data based documentation opens a new horizon for scientific reconstruction and animation by bringing added value and a real quality improvement in forensic science.

Context Aware e-Learning Objects and their Types from the Perspective of the Object-Oriented Paradigm

The contribution of this article demonstrates how to identify context-aware types of e-Learning objects (eLOs) derived from the subject domains. This perspective is taken from an engineering point of view and is applied during requirements elicitation and analysis relating to present work in constructing an object-oriented (OO), dynamic, and adaptive model to build and deliver packaged e-Learning courses. Consequently, three preliminary subject domains are presented and, as a result, three primitive types of eLOs are posited. These types educed from the subject domains are of structural, conceptual, and granular nature. Structural objects are responsible for the course itself, conceptual objects incorporate adaptive and logical interoperability, while granular objects congregate granular assets. Their differences, interrelationships, and responsibilities are discussed. A major design challenge relates to adaptive behaviour. Future research addresses refinement on the subject domains and adaptive hypermedia systems.

CHARACTERIZATION AND TREATMENT OF A NOVEL MOUSE MODEL OF TSC-ASSOCIATED AUTISM

Tuberous sclerosis complex (TSC) is a dominant tumor suppressor disorder caused by mutations in either TSC1 or TSC2. The proteins of these genes form a complex to inhibit the mammalian target of rapamycin complex 1 (mTORC1), which controls protein translation and cell growth. TSC causes substantial neuropathology, often leading to autism spectrum disorders (ASDs) in up to 60% of patients. The anatomic and neurophysiologic links between these two disorders are not well understood. However, both disorders share cerebellar abnormalities. Therefore, we have characterized a novel mouse model in which the Tsc2 gene was selectively deleted from cerebellar Purkinje cells (Tsc2f/-;Cre). These mice exhibit progressive Purkinje cell degeneration. Since loss of Purkinje cells is a well-reported postmortem finding in patients with ASD, we conducted a series of behavior tests to assess if Tsc2f/-;Cre mice displayed autistic-like deficits. Using the three chambered social choice assay, we found that Tsc2f/-;Cre mice showed behavioral deficits, exhibiting no preference between a stranger mouse and an inanimate object, or between a novel and a familiar mouse. Tsc2f/-;Cre mice also demonstrated increased repetitive behavior as assessed with marble burying activity. Altogether, these results demonstrate that loss of Tsc2 in Purkinje cells in a haploinsufficient background lead to behavioral deficits that are characteristic of human autism. Therefore, Purkinje cells loss and/or dysfunction may be an important link between TSC and ASD. Additionally, we have examined some of the cellular mechanisms resulting from mutations in Tsc2 leading to Purkinje cell death. Loss of Tsc2 led to upregulation of mTORC1 and increased cell size. As a consequence of increased protein synthesis, several cellular stress pathways were upregulated. Principally, these included altered calcium signaling, oxidative stress, and ER stress. Likely as a consequence of ER stress, there was also upregulation of ubiquitin and autophagy. Excitingly, treatment with an mTORC1 inhibitor, rapamycin attenuated mTORC1 activity and prevented Purkinje cell death by reducing of calcium signaling, the ER stress response, and ubiquitin. Remarkably, rapamycin treatment also reversed the social behavior deficits, thus providing a promising potential therapy for TSC-associated ASD.

De los registros a los objetos : Semántica y comportamiento de los documentos: el desafío de la Web 3.0

Se presenta un panorama y los interrogantes fundamentales de la etapa de la Web 3.0. Se analizan las características actuales de los sistemas bibliográficos estructurados con el modelo entidad-relación. Se definen los niveles conceptual, lógico y físico en los sistemas informáticos; consecuentemente se presentan las características de los FRBR y se obervan las relaciones entre obra y documento en el modelo conceptual FRBR. Se describen los FRBRoo como una interpretación con una lógica de objetos de los mismos requerimientos funcionales. Finalmente se plantean las tendencias a futuro, tales como pasar de las modelizaciones de entidad-relación a la de objetos, la explicitación con anotación semántica consistente, el mapeo de bases bibliográficas existentes y el desarrollo de ontologías para que los sistemas documentales se integren en la Web Semática

De los registros a los objetos : Semántica y comportamiento de los documentos: el desafío de la Web 3.0

Se presenta un panorama y los interrogantes fundamentales de la etapa de la Web 3.0. Se analizan las características actuales de los sistemas bibliográficos estructurados con el modelo entidad-relación. Se definen los niveles conceptual, lógico y físico en los sistemas informáticos; consecuentemente se presentan las características de los FRBR y se obervan las relaciones entre obra y documento en el modelo conceptual FRBR. Se describen los FRBRoo como una interpretación con una lógica de objetos de los mismos requerimientos funcionales. Finalmente se plantean las tendencias a futuro, tales como pasar de las modelizaciones de entidad-relación a la de objetos, la explicitación con anotación semántica consistente, el mapeo de bases bibliográficas existentes y el desarrollo de ontologías para que los sistemas documentales se integren en la Web Semática

De los registros a los objetos : Semántica y comportamiento de los documentos: el desafío de la Web 3.0

Se presenta un panorama y los interrogantes fundamentales de la etapa de la Web 3.0. Se analizan las características actuales de los sistemas bibliográficos estructurados con el modelo entidad-relación. Se definen los niveles conceptual, lógico y físico en los sistemas informáticos; consecuentemente se presentan las características de los FRBR y se obervan las relaciones entre obra y documento en el modelo conceptual FRBR. Se describen los FRBRoo como una interpretación con una lógica de objetos de los mismos requerimientos funcionales. Finalmente se plantean las tendencias a futuro, tales como pasar de las modelizaciones de entidad-relación a la de objetos, la explicitación con anotación semántica consistente, el mapeo de bases bibliográficas existentes y el desarrollo de ontologías para que los sistemas documentales se integren en la Web Semática

Benthic cover map of Heron Reef derived from a high-spatial-resolution multi-spectral satellite image using object based image analysis

Providing accurate maps of coral reefs where the spatial scale and labels of the mapped features correspond to map units appropriate for examining biological and geomorphic structures and processes is a major challenge for remote sensing. The objective of this work is to assess the accuracy and relevance of the process used to derive geomorphic zone and benthic community zone maps for three western Pacific coral reefs produced from multi-scale, object-based image analysis (OBIA) of high-spatial-resolution multi-spectral images, guided by field survey data. Three Quickbird-2 multi-spectral data sets from reefs in Australia, Palau and Fiji and georeferenced field photographs were used in a multi-scale segmentation and object-based image classification to map geomorphic zones and benthic community zones. A per-pixel approach was also tested for mapping benthic community zones. Validation of the maps and comparison to past approaches indicated the multi-scale OBIA process enabled field data, operator field experience and a conceptual hierarchical model of the coral reef environment to be linked to provide output maps at geomorphic zone and benthic community scales on coral reefs. The OBIA mapping accuracies were comparable with previously published work using other methods; however, the classes mapped were matched to a predetermined set of features on the reef.

Object Kinetic Monte Carlo calculations of irradiated Fe-Cr dilute alloys: The effect of the interaction radius between substitutional Cr and self-interstitial Fe

ObjectKineticMonteCarlo models allow for the study of the evolution of the damage created by irradiation to time scales that are comparable to those achieved experimentally. Therefore, the essential ObjectKineticMonteCarlo parameters can be validated through comparison with experiments. However, this validation is not trivial since a large number of parameters is necessary, including migration energies of point defects and their clusters, binding energies of point defects in clusters, as well as the interactionradii. This is particularly cumbersome when describing an alloy, such as the Fe–Cr system, which is of interest for fusion energy applications. In this work we describe an ObjectKineticMonteCarlo model for Fe–Cr alloys in the dilute limit. The parameters used in the model come either from density functional theory calculations or from empirical interatomic potentials. This model is used to reproduce isochronal resistivity recovery experiments of electron irradiateddiluteFe–Cr alloys performed by Abe and Kuramoto. The comparison between the calculated results and the experiments reveal that an important parameter is the capture radius between substitutionalCr and self-interstitialFe atoms. A parametric study is presented on the effect of the capture radius on the simulated recovery curves.

Moving Object Detection for Real-Time High-Quality Lightweight Applications on Smart Cameras

Here, a novel and efficient strategy for moving object detection by non-parametric modeling on smart cameras is presented. Whereas the background is modeled using only color information, the foreground model combines color and spatial information. The application of a particle filter allows the update of the spatial information and provides a priori information about the areas to analyze in the following images, enabling an important reduction in the computational requirements and improving the segmentation results

Study of the II Network as the Compound Slot Equivalent Circuit Model

A combination of Method of Moments (MoM) and compound slot Equivalent Circuit Model for linear array design is presented in this document. From the S Matrix of the single element, the more suitable network for its characterization is analyzed and selected. Then according to the radiation requirements of the desired array, the elements are designed and then properly connected by means of Forward Matching Procedure (FMP), which takes into account impedance matters in order to keep the input matched at the designing frequency. Comparison between HFSS simulations and MoM-FMP results are also presented. First part of this work was introduced in (1)(2) but a summary is included here to make the understanding easier.