Methods to Discover and Evaluate Proteasome Small Molecule Stimulators

Protein accumulation has been identified as a characteristic of many degenerative conditions, such as neurodegenerative diseases and aging. In most cases, these conditions also present with diminished protein degradation. The ubiquitin-proteasome system (UPS) is responsible for the degradation of the majority of proteins in cells; however, the activity of the proteasome is reduced in these disease states, contributing to the accumulation of toxic protein. It has been hypothesized that proteasome activity, both ubiquitin-dependent and -independent, can be chemically stimulated to reduce the load of protein in diseased cells. Several methods exist to identify and characterize stimulators of proteasome activity. In this review, we detail the ways in which protease activity can be enhanced and analyze the biochemical and cellular methods of identifying stimulators of both the ubiquitin-dependent and -independent proteasome activities

The joint US/UK 1990 epoch world magnetic model

A detailed summary of the data used, analyses performed, modeling techniques employed, and results obtained in the course of the 1990 Epoch World Magnetic Modeling effort are given. Also, use and limitations of the GEOMAG algorithm are presented. Charts and tables related to the 1990 World Magnetic Model (WMM-90) for the Earth's main field and secular variation in Mercator and polar stereographic projections are presented along with useful tables of several magnetic field components and their secular variation on a 5-degree worldwide grid

Economic influences on child growth status, from the Children's Healthy Living Program in the US-affiliated Pacific region

Mean obesity level of the 2 - 8-year-old children in the region was 14.4%, 14.1% were overweight, 2.7% were underweight, 1.4% were stunted, and 6.8% were stunted at birth. Acanthosis nigricans prevalence was 5%, an indicator of pre-diabetes. Sixty-one percent of the children were Native Hawaiian or Pacific Islander and 20% were of more than one race. Food insecurity was common. It was especially high in the Federated States of Micronesia and the Republic of the Marshall Islands at over 70%. Twenty-five percent of households in the region earned less than $10,000 per year. World Bank-defined upper middle-income jurisdictions had relatively high levels of both undernutrition and obesity. Jurisdiction income level was the most important factor influencing growth status in multivariate models. Policies and strategies for jurisdiction economic development and improvement of child growth status should protect local food systems and active living during economic transition. The terms of the renegotiated compact of free association with the United States, especially in the upper middle-income countries (Palau and the Republic of the Marshall Islands) that are experiencing a dual burden of undernutrition and overnutrition, are expected to play a key role in the future health of residents of these jurisdictions

Assessing Cognitive Distraction Using Event Related Potentials

This report examines the utility of using Event-Related Brain Potentials (ERPs) to evaluate cognitive distraction in the context of driving an automobile. Across two studies, ERPs (both P300 latency and P300 amplitude) were found to be effective in quantifying the cognitive workload experienced by drivers when they interact with in-vehicle voice-command systems

Cost analysis of noninvasive blood-based microRNA testing versus CT scans for follow-up in patients with testicular germ-cell tumors

BACKGROUND: Our group has developed a noninvasive blood-based microRNA (miRNA) test for improving diagnosis, disease monitoring, and relapse detection in malignant testicular germ-cell tumors (TGCTs). Performance analysis suggests the test is likely to have comparable sensitivity and specificity in detecting TGCT as computed tomography (CT), thus reducing the need for serial CT scans for follow-up monitoring, with associated reductions in cumulative radiation burden and second cancer risk. To facilitate clinical adoption, we undertook a cost analysis to identify the budget impact of replacing CT scans with miRNA testing within health care systems. METHODS: The TGCT aftercare pathway was mapped out using National Comprehensive Cancer Network guidelines. A Markov model was built to simulate the impact of the miRNA test on TGCT aftercare costs. Incidence, treatment probabilities, relapse rate, and death rate data were collected from published studies to populate the model. RESULTS: Applying our model to the US health care system, the miRNA test has the potential to save up to $69 million per year in aftercare expenses related to TGCT treatment, with exact savings depending on the adoption rate and test price. CONCLUSION: This analysis demonstrates the potential positive budget impact of adopting miRNA testing in place of CT scans in the clinical management of TGCTs

Randomised Trial of Chloroquine/Sulphadoxine-Pyrimethamine in Gambian Children with Malaria: Impact against Multidrug-Resistant P. falciparum

OBJECTIVES: In the Gambia, the combination of chloroquine (CQ) and sulphadoxine-pyrimethamine (SP) has replaced CQ monotherapy for treatment of malaria caused by Plasmodium falciparum. We measured the efficacy of the combination CQ/SP, and the prevalence of parasites carrying alleles associated with resistance to CQ or SP. DESIGN: We conducted a single-blind, randomised, controlled trial to compare the efficacy of CQ/SP to that of SP or CQ alone. SETTING: The study took place in the town of Farafenni and surrounding villages in the Gambia. PARTICIPANTS: Participants were children aged 12 mo to 10 y presenting as outpatients with uncomplicated P. falciparum malaria. INTERVENTIONS: 500 children were randomised to receive CQ, SP, or CQ/SP as supervised treatment and actively followed over 28 d. OUTCOME MEASURES: Primary outcome was parasitaemia at any time during follow-up. Secondary outcomes were PCR-confirmed recrudescent infections among treatment failures, and clinical failure requiring rescue medication by day 28. Pretreatment parasite isolates from 161 patients were tested for the presence of resistance-associated genetic markers. RESULTS: The prevalence of parasitological failure by day 28 for the CQ group was 60.3%, compared to 17.6% for SP (odds ratio [OR], 0.106; 95% confidence interval [CI], 0.057–0.194; p < 0.001) and 13.9% for CQ/SP (OR versus CQ, 0.140; 95% CI, 0.078–0.250; p < 0.001). There was no difference between the SP and CQ/SP groups (OR, 1.324; 95% CI, 0.705–2.50). The projected prevalence of PCR-corrected treatment failure was 30.2, 6.06, and 3.94% in the CQ, SP, and CQ/SP groups, respectively. The pfdhfr-triple mutant and pfdhps-437G mutation were common, with prevalences of 67.4 and 51.2%, respectively. Pretreatment carriage of pfdhps-437G and of multidrug-resistant parasite genotypes was associated with treatment failure in the SP group, but not in the CQ or CQ/SP groups. CONCLUSIONS: The combination of CQ/SP was an efficacious treatment for uncomplicated malaria in Gambian children in this study, but the frequent occurrence of multidrug-resistant parasites suggests that this observed efficacy is not sustainable

AMPK is essential for energy homeostasis regulation and glucose sensing by POMC and AgRP neurons

Hypothalamic AMP-activated protein kinase (AMPK) has been suggested to act as a key sensing mechanism, responding to hormones and nutrients in the regulation of energy homeostasis. However, the precise neuronal populations and cellular mechanisms involved are unclear. The effects of long-term manipulation of hypothalamic AMPK on energy balance are also unknown. To directly address such issues, we generated POMC alpha 2KO and AgRP alpha 2KO mice lacking AMPK alpha 2 in proopiomelanocortin- (POMC-) and agouti-related protein-expressing (AgRP-expressing) neurons, key regulators of energy homeostasis. POMC alpha 2KO mice developed obesity due to reduced energy expenditure and dysregulated food intake but remained sensitive to leptin. in contrast, AgRPa2KO mice developed an age-dependent lean phenotype with increased sensitivity to a melanocortin agonist. Electrophysiological studies in AMPK alpha 2-deficient POMC or AgRP neurons revealed normal leptin or insulin action but absent responses to alterations in extracellular glucose levels, showing that glucose-sensing signaling mechanisms in these neurons are distinct from those pathways utilized by leptin or insulin. Taken together with the divergent phenotypes of POMC alpha 2KO and AgRP alpha 2KO mice, our findings suggest that while AMPK plays a key role in hypothalamic function, it does not act as a general sensor and integrator of energy homeostasis in the mediobasal hypothalamus

Attitudes and Performance: An Analysis of Russian Workers

This paper investigates the relationship between locus of control and performance among Russian employees, using survey data collected at 28 workplaces in 2002 in Taganrog and at 47 workplaces in 2003 in Ekaterinburg. We develop a measure that allows us to categorize the Russian employees participating in our survey as exhibiting an internal or external locus of control. We then assess the extent to which there are significant differences between “internals” and “externals” in work-related attitudes that may affect performance. In particular, we focus on (1) attitudes about outcomes associated with hard work, (2) level of job satisfaction, (3) expectation of receiving a desired reward, and (4) loyalty to and involvement with one’s organization. In each case we identify where gender and generational differences emerge. Our main objective is to determine whether Russian employees who exhibit an internal locus of control perform better than employees with an external locus of control. Our performance measures include earnings, expected promotions, and assessments of the quantity and quality of work in comparison to others at the same organization doing a similar job. Controlling for a variety of worker characteristics, we find that (1) individuals who exhibit an internal locus of control perform better, but this result is not always statistically significant; (2) even among “internals,” women earn significantly less than men and have a much lower expectation of promotion; (3) even among “internals,” experience with unemployment has a negative influence on performance.http://deepblue.lib.umich.edu/bitstream/2027.42/40144/3/wp758.pd