Mechanistic Studies Of A Novel Ppar-Gamma Mutant That Causes Lipodystrophy And Diabetes

PPAR-gamma is a nuclear receptor that plays a central role in metabolic regulation by regulating extensive gene expression networks in adipose, liver, skeletal muscle and many other tissues. Human PPAR-gamma mutations are rare and cause a monogenetic form of severe type II diabetes with metabolic syndrome, known as familiar partial lypodystrophy. The E157D PPAR-gamma mutant causes atypical lipodystrophy in a large Canadian kindred, presenting with multiple musculoskeletal, neurological and hematological abnormalities in addition to the classic lipodystrophy features of insulin-resistant diabetes, hypertension and dyslipidemia. This mutation is localized to the p-box of PPAR-gamma, a small region that interacts directly with the DNA molecule and is required for DNA binding site specificity. Mechanistic analysis revealed that E157D PPAR-gamma binds PPAR-gamma response elements (PPREs), but is mildly, moderately or severely defective at inducing transcription from most promoters, without dominant negative activity. This suppression of transcriptional activity may be mediated by an increased effect of nuclear receptor corepressors on E157D PPAR-gamma. In addition, the mutant binds atypical PPREs in the regulatory regions of a small set of genes outside of the PPAR-gamma-regulated network, and induces transcription of these genes. The loss of transcriptional activity on PPAR-gamma-regulated promoters leads to the metabolic disease in the E157D PPAR-gamma cohort, while the gain of activity on non- PPAR-gamma target promoters may explain the atypical clinical presentation associated with this mutation. The misregulation of target genes by this DNA-contacting mutant highlights a previously under-appreciated importance of the DNA molecule as an allosteric regulator of the transcriptional activity of nuclear receptors. In summary, this dissertation describes a human PPAR-gamma mutation that works through a novel mechanism to cause atypical lipodystrophy, and provides support for a more integrated view of the nuclear receptor-DNA interaction and transcription activation

Interview with Professor Simon J. Bronner

Interview with Professor Simon J. Bronner (Penn State University)

Dynamic Capabilities in Home Health: IT-Enabled Transformation of Post-Acute Care

Home health care can enable shorter hospital stays, reduce re-hospitalization, and contribute to lowered out-of-hospital morbidity and mortality. However, recent changes in Medicare payments and regulations in the US have challenged home health care providers’ business models. Against this backdrop, we draw on the dynamic capability perspective to examine how one home health care provider responded to this challenge over the period 2000-2009 by combining adaptive organization principles and information technology (IT) to transform its post-acute care delivery. The transformation leveraged the organization’s existing dynamic capabilities; improved nursing practices; engaged physicians, nurses, managers, and patients; and implemented remote patient monitoring and other IT-enabled innovations. Integrating information systems and health services literatures, we identify the processes targeted by the transformation, analyze how the provider built adaptive care delivery capability enabled by IT, and demonstrate how the transformation led to improved clinical and financial outcomes. In addition, we offer new insights into the micro-foundations of dynamic capabilities by distinguishing between capabilities at the transactional and transformational levels, and explaining how different types of IT-enabled capabilities shaped, and were shaped by, the home health care provider’s responses to environmental changes

Gene Therapy Medicinal Products: Non-clinical Safety Studies

Currently, gene therapy medicinal products (GTMPs) are actively developed in many countries, including the Russian Federation. However, the use of GTMPs raises class-specific safety concerns.The aim of the study was to determine the main requirements for non-clinical safety testing of GTMPs, to identify risks associated with these medicinal products, to establish criteria for expert assessments, and to find optimisation opportunities for GTMP non-clinical safety programmes, using Russian and international experience in the assessment of submissions and the registration of medicinal products of this class.The Russian Federation, the Eurasian Economic Union, the European Union, and the United States have created regulatory frameworks governing the lifecycle of GTMPs and continue improving these frameworks. The properties of GTMPs may create unique safety issues, such as insertional mutagenesis, unregulated transgene expression, long-term persistence and off-target spread, vertical germline transmission, and environmental risks. To account for these issues, a comprehensive non-clinical safety programme for GTMPs may require additional special studies along with the standard ones. This review focuses on the main approaches to designing non-cellular GTMP safety studies and evaluating the obtained results. The authors identified improvement opportunities for and problematic aspects of study design, as well as conditions for and limitations of non-clinical data extrapolation and clinical safety profile prediction. The continuous improvement and updating of the regulatory frameworks governing non-clinical studies of GTMPs mean that developers of non-clinical safety programmes for GTMPs should use all their experience, as well as relevant national and international guidelines and recommendations

Применение сегментной спайковой модели нейрона со структурной адаптацией для решения задач классификации

Рассматриваются варианты применения сегментной спайковой модели нейрона с возможностью структурной адаптации для решения задач классификации. Проводится анализ современного состояния спайковых нейронных сетей. Делается вывод о крайне низком количестве работ по исследованию сегментных моделей нейрона. В качестве модели нейрона для данной работы обосновывается выбор сегментной спайковой модели. Приводится краткое описание такой модели, отмечены её основные особенности, позволяющие производить её структурное реконфигурирование. Описывается способ структурной адаптации модели ко входному паттерну импульсов. Приводится общая схема организации сегментных спайковых нейронов в сеть для решения задачи классификации. В качестве кодирования числовой информации в паттерны импульсов выбирается временное кодирование. Приводятся краткие результаты экспериментов по решению задачи классификации на общедоступных наборах данных (Iris, MNIST). Делается вывод о сопоставимости полученных результатов с результатами, полученными классическими методами. Кроме того, приводится подробное пошаговое описание экспериментов по определению состояния телеуправляемого необитаемого подводного аппарата: определение расстояния такого аппарата до дна и определение характера его движения. Показано соответствие полученных результатов реальному состоянию телеуправляемого необитаемого подводного аппарата. Сделан вывод о перспективности применения спайковых сегментных моделей нейрона с возможностью структурной адаптации при решении задач классификации. Рассмотрены дальнейшие перспективные продолжения исследований основанных на сегментных спайковых моделях нейрона

Delivering Diagnostic Quality Video over Mobile Wireless Networks for Telemedicine

In real-time remote diagnosis of emergency medical events, mobility can be enabled by wireless video communications. However, clinical use of this potential advance will depend on definitive and compelling demonstrations of the reliability of diagnostic quality video. Because the medical domain has its own fidelity criteria, it is important to incorporate diagnostic video quality criteria into any video compression system design. To this end, we used flexible algorithms for region-of-interest (ROI) video compression and obtained feedback from medical experts to develop criteria for diagnostically lossless (DL) quality. The design of the system occurred in three steps-measurement of bit rate at which DL quality is achieved through evaluation of videos by medical experts, incorporation of that information into a flexible video encoder through the notion of encoder states, and an encoder state update option based on a built-in quality criterion. Medical experts then evaluated our system for the diagnostic quality of the video, allowing us to verify that it is possible to realize DL quality in the ROI at practical communication data transfer rates, enabling mobile medical assessment over bit-rate limited wireless channels. This work lays the scientific foundation for additional validation through prototyped technology, field testing, and clinical trials

Perspectivas para o desenvolvimento da lei nas condições da economia digital

The authors consider the problems of forming the digital economy from the position of law in the article. They analyze the main trends in the development of individual branches of law. They identify the problems arising in the process of legal regulation of digital policy and the economy of modern states.Los autores consideran los problemas de formar la economía digital desde la posición de la ley en el artículo. Analizan las principales tendencias en el desarrollo de ramas individuales de la ley. Identifican los problemas que surgen en el proceso de regulación legal de la política digital y la economía de los estados modernos.Os autores consideram os problemas de formar a economia digital a partir da posição de lei no artigo. Eles analisam as principais tendências no desenvolvimento de ramos individuais da lei. Eles identificam os problemas que surgem no processo de regulação legal da política digital e da economia dos estados modernos