Atrogin-1 and MuRF1 regulate cardiac MyBP-C levels via different mechanisms

Familial hypertrophic cardiomyopathy (FHC) is frequently caused by cardiac myosin-binding protein C (cMyBP-C) gene mutations, which should result in C-terminal truncated mutants. However, truncated mutants were not detected in myocardial tissue of FHC patients and were rapidly degraded by the ubiquitin-proteasome system (UPS) after gene transfer in cardiac myocytes. Since the diversity and specificity of UPS regulation lie in E3 ubiquitin ligases, we investigated whether the muscle-specific E3 ligases atrogin-1 or muscle ring finger protein-1 (MuRF1) mediate degradation of truncated cMyBP-C. Human wild-type (WT) and truncated (M7t, resulting from a human mutation) cMyBP-C species were co-immunoprecipitated with atrogin-1 after adenoviral overexpression in cardiac myocytes, and WT-cMyBP-C was identified as an interaction partner of MuRF1 by yeast two-hybrid screens. Overexpression of atrogin-1 in cardiac myocytes decreased the protein level of M7t-cMyBP-C by 80% and left WT-cMyBP-C level unaffected. This was rescued by proteasome inhibition. In contrast, overexpression of MuRF1 in cardiac myocytes not only reduced the protein level of WT- and M7t-cMyBP-C by > 60%, but also the level of myosin heavy chains (MHCs) by > 40%, which were not rescued by proteasome inhibition. Both exogenous cMyBP-C and endogenous MHC mRNA levels were markedly reduced by MuRF1 overexpression. Similar to cardiac myocytes, MuRF1-overexpressing (TG) mice exhibited 40% lower levels of MHC mRNAs and proteins. Protein levels of cMyBP-C were 29% higher in MuRF1 knockout and 34% lower in TG than in WT, without a corresponding change in mRNA levels. These data suggest that atrogin-1 specifically targets truncated M7t-cMyBP-C, but not WT-cMyBP-C, for proteasomal degradation and that MuRF1 indirectly reduces cMyBP-C levels by regulating the transcription of MHC.

Advances in Imaging of Osteoarthritis and Cartilage

Osteoarthritis (OA) is the most frequent form of arthritis, with major implications for individual and public health care without effective treatment available. The field of joint imaging, and particularly magnetic resonance (MR) imaging, has evolved rapidly owing to technical advances and the application of these to the field of clinical research. Cartilage imaging certainly is at the forefront of these developments. In this review, the different aspects of OA imaging and cartilage assessment, with an emphasis on recent advances, will be presented. The current role of radiography, including advances in the technology for joint space width assessment, will be discussed. The development of various MR imaging techniques capable of facilitating assessment of cartilage morphology and the methods for evaluating the biochemical composition of cartilage will be presented. Advances in quantitative morphologic cartilage assessment and semiquantitative whole-organ assessment will be reviewed. Although MR imaging is the most important modality in imaging of OA and cartilage, others such as ultrasonography play a complementary role that will be discussed briefly.

O processo or??ament??rio e a apura????o de custos de produtos e servi??os no setor p??blico do Brasil

O presente artigo aborda a quest??o da apura????o de custos de servi??os p??blicos a partir da perspectiva do processo or??ament??rio no setor p??blico. Nesse sentido, o objetivo principal do trabalho consiste em explicitar uma sistem??tica de an??lise e apura????o de custos de servi??os p??blicos que seja adaptada ao processo or??ament??rio do setor p??blico brasileiro e, assim, contribuir para a obten????o da efici??ncia alocativa e efici??ncia operacional. A sistem??tica de apura????o de custos aqui proposta ?? totalmente compat??vel com os sistemas gerenciais de informa????o utilizados pelo Governo e tem baixo custo de operacionaliza????o porque n??o implica mudan??as apreci??veis nos sistemas de informa????o em uso e na forma de registro das informa????es na contabilidade p??blica. Por fim, a sistem??tica de apura????o de custos de servi??os p??blicos proposta atende ?? Lei de Responsabilidade Fiscal e a complementa quanto ?? apura????o de custos de servi??os e produtos do setor p??blico.

Vergleichende Untersuchung zur frühpostoperativen und onkologischen Ergebnisqualität nach operativer Behandlung von Rektumkarzinomen

Magdeburg, Univ., Medizin. Fakultät, Diss., 2010

Increasing quasiconcave production and utility functions with diminishing returns to scale

In microeconomic analysis functions with diminishing returns to scale (DRS) have frequently been employed. Various properties of increasing quasiconcave aggregator functions with DRS are derived. Furthermore duality in the classical sense as well as of a new type is studied for such aggregator functions in production and consumer theory. In particular representation theorems for direct and indirect aggregator functions are obtained. These involve only small sets of generator functions. The study is carried out in the contemporary framework of abstract convexity and abstract concavity.

Psychosocial interventions for people with both severe mental illness and substance misuse.

Objective: To assess the effects of psychosocial interventions for reduction in substance use in people with a serious mental illness compared with standard care. Conclusion: We included 32 RCTs and found no compelling evidence to support any one psychosocial treatment over another for people to remain in treatment or to reduce substance use or improve mental state in people with serious mental illnesses. Furthermore, methodological difficulties exist which hinder pooling and interpreting results. Further high quality trials are required which address these concerns and improve the evidence in this important area.This resource was contributed by The National Documentation Centre on Drug Use.

Field testing of arsenic in groundwater samples of Bangladesh using a test kit based on lyophilized bioreporter bacteria.

A test kit based on living, lyophilized bacterial bioreporters emitting bioluminescence as a response to arsenite and arsenate was applied during a field campaign in six villages across Bangladesh. Bioreporter field measurements of arsenic in groundwater from tube wells were in satisfying agreement with the results of spectroscopic analyses of the same samples conducted in the lab. The practicability of the bioreporter test in terms of logistics and material requirements, suitability for high sample throughput, and waste disposal was much better than that of two commercial chemical test kits that were included as references. The campaigns furthermore demonstrated large local heterogeneity of arsenic in groundwater, underscoring the use of well switching as an effective remedy to avoid high arsenic exposure.

@neurIST infrastructure for advanced disease management through integration of heterogeneous data, computing, and complex processing services

The increasing volume of data describing humandisease processes and the growing complexity of understanding, managing, and sharing such data presents a huge challenge for clinicians and medical researchers. This paper presents the@neurIST system, which provides an infrastructure for biomedical research while aiding clinical care, by bringing together heterogeneous data and complex processing and computing services. Although @neurIST targets the investigation and treatment of cerebral aneurysms, the system’s architecture is generic enough that it could be adapted to the treatment of other diseases.Innovations in @neurIST include confining the patient data pertaining to aneurysms inside a single environment that offers cliniciansthe tools to analyze and interpret patient data and make use of knowledge-based guidance in planning their treatment. Medicalresearchers gain access to a critical mass of aneurysm related data due to the system’s ability to federate distributed informationsources. A semantically mediated grid infrastructure ensures that both clinicians and researchers are able to seamlessly access andwork on data that is distributed across multiple sites in a secure way in addition to providing computing resources on demand forperforming computationally intensive simulations for treatment planning and research.

Social value orientation as a moral intuition: Decision-making in the dictator game

We studied the decision making process in the Dictator Game and showed that decisions are the result of a two-step process. In a first step, decision makers generate an automatic, intuitive proposal. Given sufficient motivation and cognitive resources, they adjust this in a second, more deliberated phase. In line with the social intuitionist model, we show that one s Social Value Orientation determines intuitive choice tendencies in the first step, and that this effect is mediated by the dictator s perceived interpersonal closeness with the receiver. Self-interested concerns subsequently leadto a reduction of donation size in step 2. Finally, we show that increasing interpersonal closeness can promote pro-social decision-making.