Summary

We investigate the ability of a focused helium ion beam to selectively modify and mill materials. The sub nanometer probe size of the helium ion microscope used provides lateral control not previously available for helium ion irradiation experiments. At high incidence angles the helium ions were found to remove surface material from a silicon lamella leaving the subsurface structure intact for further analysis. Surface roughness and contaminants were both reduced by the irradiation process. Fabrication is also realized with a high level of patterning acuity. Implantation of helium beneath the surface of the sample is visualized in cross section allowing direct observation of the extended effects of high dose irradiation. The effect of the irradiation on the crystal structure of the material is presented. Applications of the sample modification process are presented and further prospects discussed.

Skeletal muscle Akt activity stimulates muscle growth and imparts resistance to obesity, glucose intolerance and fatty liver disease. We recently found that ursolic acid increases skeletal muscle Akt activity and stimulates muscle growth in non-obese mice. Here, we tested the hypothesis that ursolic acid might increase skeletal muscle Akt activity in a mouse model of diet-induced obesity. We studied mice that consumed a high fat diet lacking or containing ursolic acid. In skeletal muscle, ursolic acid increased Akt activity, as well as downstream mRNAs that promote glucose utilization (hexokinase-II), blood vessel recruitment (Vegfa) and autocrine/paracrine IGF-I signaling (Igf1). As a result, ursolic acid increased skeletal muscle mass, fast and slow muscle fiber size, grip strength and exercise capacity. Interestingly, ursolic acid also increased brown fat, a tissue that shares developmental origins with skeletal muscle. Consistent with increased skeletal muscle and brown fat, ursolic acid increased energy expenditure, leading to reduced obesity, improved glucose tolerance and decreased hepatic steatosis. These data support a model in which ursolic acid reduces obesity, glucose intolerance and fatty liver disease by increasing skeletal muscle and brown fat, and suggest ursolic acid as a potential therapeutic approach for obesity and obesity-related illness.

SUMMARY

Skeletal muscle atrophy is a common and debilitating condition that lacks a pharmacologic therapy. To develop a potential therapy, we identified 63 mRNAs that were regulated by fasting in both human and mouse muscle, and 29 mRNAs that were regulated by both fasting and spinal cord injury in human muscle. We used these two unbiased mRNA expression signatures of muscle atrophy to query the Connectivity Map, which singled out ursolic acid as a compound whose signature was opposite to those of atrophy-inducing stresses. A natural compound enriched in apples, ursolic acid reduced muscle atrophy and stimulated muscle hypertrophy in mice. It did so by enhancing skeletal muscle insulin/IGF-I signaling, and inhibiting atrophy-associated skeletal muscle mRNA expression. Importantly, ursolic acid’s effects on muscle were accompanied by reductions in adiposity, fasting blood glucose and plasma cholesterol and triglycerides. These findings identify a potential therapy for muscle atrophy and perhaps other metabolic diseases.

Interactions between blood platelets and nanoparticles have both pharmacological and toxicological significance and may lead to platelet activation and aggregation. Platelet aggregation is usually studied using light aggregometer that neither mimics the conditions found in human microvasculature nor detects microaggregates. A new method for the measurement of platelet microaggregation under flow conditions using a commercially available quartz crystal microbalance with dissipation (QCM-D) has recently been developed. The aim of the current study was to investigate if QCM-D could be used for the measurement of nanoparticle-platelet interactions. Silica, polystyrene, and gold nanoparticles were tested. The interactions were also studied using light aggregometry and flow cytometry, which measured surface abundance of platelet receptors. Platelet activation was imaged using phase contrast and scanning helium ion microscopy. QCM-D was able to measure nanoparticle-induced platelet microaggregation for all nanoparticles tested at concentrations that were undetectable by light aggregometry and flow cytometry. Microaggregates were measured by changes in frequency and dissipation, and the presence of platelets on the sensor surface was confirmed and imaged by phase contrast and scanning helium ion microscopy.

This article describes recent events in the governance of standard-setting for 2 areas of US health policy — states' decisions about which prescription drugs to cover under Medicaid and other public programs and making health an aspect of foreign policy — and whether these events offer lessons for policy making. In prescription drug coverage, methodologic advances in research that evaluates health services and the politics of restraining the rate of growth in health expenditures enabled policy makers in most states to establish new public processes for assessing and applying evidence about the effectiveness of competing drugs. Their counterparts in foreign policy, in contrast, made few changes in existing processes for choosing which interventions to support. The history of governance in each area of policy making for health explains the selection of standards to evaluate evidence about interventions and whether and how to use this evidence to guide policy.

International efforts to increase the quality and efficiency of health care services may be creating financial savings that can be used to improve population health. This article examines evidence that such savings (ie, a quality/efficiency or value dividend) are accruing and how they have been allocated and assesses the prospects for reallocating future savings to improve population health. Savings have resulted mainly from reducing the number of inappropriate or harmful interventions, managing care of people with chronic disease more effectively, and implementing health information technology. Savings to date have accrued to the revenues of public and private collective purchasers of care and large provider organizations, but none seem to have been reallocated to address other determinants of health. Furthermore, improved quality sometimes increases spending.

The tumor necrosis factor receptor (TNFR) superfamily mediates signals critical for regulation of the immune system. One family member, CD40, is important for the efficient activation of antibody-producing B cells and other antigen-presenting cells. The molecules and mechanisms that mediate CD40 signaling are only partially characterized. Proteins known to interact with the cytoplasmic domain of CD40 include members of the TNF receptor-associated factor (TRAF) family, which regulate signaling and serve as links to other signaling molecules. To identify additional proteins important for CD40 signaling, we used a combined stimulation/immunoprecipitation procedure to isolate CD40 signaling complexes from B cells and characterized the associated proteins by mass spectrometry. In addition to known CD40-interacting proteins, we detected SMAC/DIABLO, HTRA2/Omi, and HOIP/RNF31/PAUL/ZIBRA. We found that these previously unknown CD40-interacting partners were recruited in a TRAF2-dependent manner. HOIP is a ubiquitin ligase capable of mediating NF-κB activation through the ubiquitin-dependent activation of IKKγ. We found that a mutant HOIP molecule engineered to lack ubiquitin ligase activity inhibited the CD40-mediated activation of NF-κB. Together, our results demonstrate a powerful approach for the identification of signaling molecules associated with cell surface receptors and indicate an important role for the ubiquitin ligase activity of HOIP in proximal CD40 signaling.

One major obstacle to membrane protein structure determination is the selection of a detergent micelle that mimics the native lipid bilayer. Currently, detergents are selected by exhaustive screening because the effects of protein-detergent interactions on protein structure are poorly understood. In this study, the structure and dynamics of an integral membrane protein in different detergents is investigated by nuclear magnetic resonance (NMR) and electron paramagnetic resonance (EPR) spectroscopy, and small angle X-ray scattering (SAXS). The results suggest that matching of the micelle dimensions to the protein’s hydrophobic surface avoids exchange processes that reduce the completeness of the NMR observations. Based on these dimensions, several mixed micelles were designed that improved the completeness of NMR observations. These findings provide a basis for the rational design of mixed micelles that may advance membrane protein structure determination by NMR.

Complexes containing bonds between heteroatoms such as nitrogen and oxygen and “late” transition metals (i.e., those located on the right side of the transition series) have been implicated as reactive intermediates in numerous important catalytic systems. Despite this, our understanding of such M–X linkages still lags behind that of their M–H and M–C analogues. New synthetic strategies have now made possible the isolation and study of a variety of monomeric late-metal alkoxide, aryloxide, and amide complexes, including parent hydroxide and amide species. The heteroatoms in these materials form surprisingly strong bonds to their metal centers, and their bond energies do not necessarily correlate with the energies of the corresponding H–X bonds. The M–X complexes typically exhibit nucleophilic reactivity, in some cases form strong hydrogen bonds to proton donors, and even deprotonate relatively weak acids. These observations, as well as thermodynamic investigations, suggest that late metal–heteroatom bonds are strongly polarized and possess significant ionic character, properties that play an important role in their interactions with organic compounds.

Objective

Review the limitations in cross-sectoral health outcomes research and suggest a future research agenda.

Data Sources, Study Design, Data Collection

Literature review and workshop discussion.

Principal Findings

The research evidence that would aid public and private policy makers in answering the question the title poses is quite limited.

Conclusions

Much more evidence from diverse disciplines is needed, and key areas are suggested. Criteria for progress by 2010 are proposed.