The Fix: A Global Warming Policy Practitioner's Handbook

In the last few years there has been a substantial restating of the global warming 'problem.' According to Bruce Stram, these new conclusions have quite different policy implications than those currently driving the global policy debate. In this paper, Stram outlines a plan that could be turned into concrete, practical, and inexpensive steps, which are intended to put us on a path to resolving the global warming problem. The global warming problem, if it is that, cannot be very usefully addressed with substantial greenhouse gas emissions reduction now. However, other, more strategic, actions to prepare for possible future reductions should be taken now. The initial action suggested here is to develop a formal international program of energy research and development that is 'permanently' funded by a small tax (on carbon) to support energy R&D on a multilateral basis.Environment, Other Topics

A Kinship-Based Modification of the Armitage Trend Test to Address Hidden Population Structure and Small Differential Genotyping Errors

BACKGROUND/AIMS: We propose a modification of the well-known Armitage trend test to address the problems associated with hidden population structure and hidden relatedness in genome-wide case-control association studies. METHODS: The new test adopts beneficial traits from three existing testing strategies: the principal components, mixed model, and genomic control while avoiding some of their disadvantageous characteristics, such as the tendency of the principal components method to over-correct in certain situations or the failure of the genomic control approach to reorder the adjusted tests based on their degree of alignment with the underlying hidden structure. The new procedure is based on Gauss-Markov estimators derived from a straightforward linear model with an imposed variance structure proportional to an empirical relatedness matrix. Lastly, conceptual and analytical similarities to and distinctions from other approaches are emphasized throughout. RESULTS: Our simulations show that the power performance of the proposed test is quite promising compared to the considered competing strategies. The power gains are especially large when small differential differences between cases and controls are present; a likely scenario when public controls are used in multiple studies. CONCLUSION: The proposed modified approach attains high power more consistently than that of the existing commonly implemented tests. Its performance improvement is most apparent when small but detectable systematic differences between cases and controls exist

Posttranslational Modifications in Mitochondria: Protein Signaling in the Powerhouse

There is an intimate interplay between cellular metabolism and the pathophysiology of disease. Mitochondria are essential to maintaining and regulating metabolic function of cells and organs. Mitochondrial dysfunction is implicated in diverse diseases, such as cardiovascular disease, diabetes and metabolic syndrome, neurodegeneration, cancer and aging. Multiple reversible post-translational protein modifications are located in the mitochondria that are responsive to nutrient availability and redox conditions, and which can act in protein-protein interactions to modify diverse mitochondrial functions. Included in this are physiologic redox signaling via reactive oxygen and nitrogen species, phosphorylation, O-GlcNAcylation, acetylation, and succinylation, among others. With the advent of mass proteomic screening techniques, there has been a vast increase in the array of known mitochondrial post-translational modifications and their protein targets. The functional significance of these processes in disease etiology, and the pathologic response to their disruption, are still under investigation. However, many of these reversible modifications act as regulatory mechanisms in mitochondria and show promise for mitochondrial-targeted therapeutic strategies. This review addresses the current knowledge of post-translational processing and signaling mechanisms in mitochondria, and their implications in health and disease

Methodological Issues in Multistage Genome-Wide Association Studies

Because of the high cost of commercial genotyping chip technologies, many investigations have used a two-stage design for genome-wide association studies, using part of the sample for an initial discovery of ``promising'' SNPs at a less stringent significance level and the remainder in a joint analysis of just these SNPs using custom genotyping. Typical cost savings of about 50% are possible with this design to obtain comparable levels of overall type I error and power by using about half the sample for stage I and carrying about 0.1% of SNPs forward to the second stage, the optimal design depending primarily upon the ratio of costs per genotype for stages I and II. However, with the rapidly declining costs of the commercial panels, the generally low observed ORs of current studies, and many studies aiming to test multiple hypotheses and multiple endpoints, many investigators are abandoning the two-stage design in favor of simply genotyping all available subjects using a standard high-density panel. Concern is sometimes raised about the absence of a ``replication'' panel in this approach, as required by some high-profile journals, but it must be appreciated that the two-stage design is not a discovery/replication design but simply a more efficient design for discovery using a joint analysis of the data from both stages. Once a subset of highly-significant associations has been discovered, a truly independent ``exact replication'' study is needed in a similar population of the same promising SNPs using similar methods.Comment: Published in at http://dx.doi.org/10.1214/09-STS288 the Statistical Science (http://www.imstat.org/sts/) by the Institute of Mathematical Statistics (http://www.imstat.org

Mitochondrial protein acetylation and left ventricular function in a model of hypertrophic cardiomyopathy and heart failure

Indiana University-Purdue University Indianapolis (IUPUI)Rationale: The childhood heart disease of Friedreich’s Ataxia (FRDA) is characterized by hypertrophy and failure. It is caused by loss of frataxin (FXN), a mitochondrial protein involved in energy homeostasis. FRDA model hearts have increased mitochondrial protein acetylation and impaired sirtuin 3 (SIRT3) deacetylase activity. Protein acetylation is an important regulator of cardiac metabolism and SIRT3 is protective in heart disease. The underlying pathophysiology of heart failure in FRDA is unclear. I suspect that increased acetylation in FRDA heart mitochondria damages cardiac energy homeostasis by inhibiting activity of key enzymes involved in heart metabolism. Objective: My project tested the hypothesis that altered acetylation of mitochondrial proteins contributes to the cardiomyopathy of FRDA. Methods: Conditional mouse models of FRDA cardiomyopathy with ablation of FXN (FXN KO) or FXN and SIRT3 (FXN/SIRT3 DKO) in the heart were compared to healthy controls. Hearts were evaluated using echocardiography, cardiac catheterization, histology, protein acetylation and expression. FXN KO mice were treated with NAD+ replacement therapy with nicotinamide riboside (NR), and FXN/SIRT3 DKO mice were treated with FXN protein replacement therapy. Results: Acetylation was temporally progressive and paralleled evolution of heart failure in the FXN KO model. High levels of acetylation were associated with cardiac fibrosis, mitochondrial damage, impaired fat metabolism, and diastolic and systolic dysfunction. Acetylation correlated strongly with worse heart function, and loss of SIRT3 in the FXN KO mouse resulted in significant decrease in ejection fraction and fractional shortening. Treatment of the FXN/SIRT3 DKO with FXN protein therapy reduced acetylation but was not sufficient to fully rescue heart function. Increasing NAD+ with NR-treatment in the FXN KO lead to increased mitochondrial protein acetylation and did not improve cardiac outcome. Conclusion: I found a strong negative correlation between heart function and mitochondrial protein acetylation. My findings also provide evidence that absence of SIRT3 expression in the FXN KO heart exacerbates features of heart failure, and that SIRT3 expression is necessary to rescue the FXN KO heart. These results suggest that SIRT3 inactivation and abnormal acetylation contribute to the pathophysiology of heart disease in FRDA

Interethnic differences in pancreatic cancer incidence and risk factors: The Multiethnic Cohort.

While disparity in pancreatic cancer incidence between blacks and whites has been observed, few studies have examined disparity in other ethnic minorities. We evaluated variations in pancreatic cancer incidence and assessed the extent to which known risk factors account for differences in pancreatic cancer risk among African Americans, Native Hawaiians, Japanese Americans, Latino Americans, and European Americans in the Multiethnic Cohort Study. Risk factor data were obtained from the baseline questionnaire. Cox regression was used to estimate the relative risks (RRs) and 95% confidence intervals (CIs) for pancreatic cancer associated with risk factors and ethnicity. During an average 16.9-year follow-up, 1,532 incident pancreatic cancer cases were identified among 184,559 at-risk participants. Family history of pancreatic cancer (RR 1.97, 95% CI 1.50-2.58), diabetes (RR 1.32, 95% CI 1.14-1.54), body mass index ≥30 kg/m2 (RR 1.25, 95% CI 1.08-1.46), current smoking (<20 pack-years RR 1.43, 95% CI 1.19-1.73; ≥20 pack-years RR 1.76, 95% CI 1.46-2.12), and red meat intake (RR 1.17, 95% CI 1.00-1.36) were associated with pancreatic cancer. After adjustment for these risk factors, Native Hawaiians (RR 1.60, 95% CI 1.30-1.98), Japanese Americans (RR 1.33, 95% CI 1.15-1.54), and African Americans (RR 1.20, 95% CI 1.01-1.42), but not Latino Americans (RR 0.90, 95% CI 0.76-1.07), had a higher risk of pancreatic cancer compared to European Americans. Interethnic differences in pancreatic cancer risk are not fully explained by differences in the distribution of known risk factors. The greater risks in Native Hawaiians and Japanese Americans are new findings and elucidating the causes of these high rates may improve our understanding and prevention of pancreatic cancer

Nanowrinkled Carbon Aerogels Embedded with FeN x Sites as Effective Oxygen Electrodes for Rechargeable Zinc-Air Battery.

Rational design of single-metal atom sites in carbon substrates by a flexible strategy is highly desired for the preparation of high-performance catalysts for metal-air batteries. In this study, biomass hydrogel reactors are utilized as structural templates to prepare carbon aerogels embedded with single iron atoms by controlled pyrolysis. The tortuous and interlaced hydrogel chains lead to the formation of abundant nanowrinkles in the porous carbon aerogels, and single iron atoms are dispersed and stabilized within the defective carbon skeletons. X-ray absorption spectroscopy measurements indicate that the iron centers are mostly involved in the coordination structure of FeN4, with a minor fraction (ca. 1/5) in the form of FeN3C. First-principles calculations show that the FeN x sites in the Stone-Wales configurations induced by the nanowrinkles of the hierarchically porous carbon aerogels show a much lower free energy than the normal counterparts. The resulting iron and nitrogen-codoped carbon aerogels exhibit excellent and reversible oxygen electrocatalytic activity, and can be used as bifunctional cathode catalysts in rechargeable Zn-air batteries, with a performance even better than that based on commercial Pt/C and RuO2 catalysts. Results from this study highlight the significance of structural distortions of the metal sites in carbon matrices in the design and engineering of highly active single-atom catalysts