Interaction of hemojuvelin with neogenin results in iron accumulation in human embryonic kidney 293 cells

Type 2 hereditary hemochromatosis (HH) or juvenile hemochromatosis is an early onset, genetically heterogeneous, autosomal recessive disorder of iron overload. Type 2A HH is caused by mutations in the recently cloned hemojuvelin gene (HJV; also called HFE2) (Papanikolaou, G., Samuels, M. E., Ludwig, E. H., MacDonald, M. L., Franchini, P. L., Dube, M. P., Andres, L., MacFarlane, J., Sakellaropoulos, N., Politou, M., Nemeth, E., Thompson, J., Risler, J. K., Zaborowska, C., Babakaiff, R., Radomski, C. C., Pape, T. D., Davidas, O., Christakis, J., Brissot, P., Lockitch, G., Ganz, T., Hayden, M. R., and Goldberg, Y. P. (2004) Nat. Genet. 36, 77–82), whereas Type 2B HH is caused by mutations in hepcidin. HJV is highly expressed in both skeletal muscle and liver. Mutations in HJV are implicated in the majority of diagnosed juvenile hemochromatosis patients. In this study, we stably transfected HJV cDNA into human embryonic kidney 293 cells and characterized the processing of HJV and its effect on iron homeostasis. Our results indicate that HJV is a glycosylphosphatidylinositol-linked protein and undergoes a partial autocatalytic cleavage during its intracellular processing. HJV co-immunoprecipitated with neogenin, a receptor involved in a variety of cellular signaling processes. It did not interact with the closely related receptor DCC (deleted in Colon Cancer). In addition, the HJV G320V mutant implicated in Type 2A HH did not co-immunoprecipitate with neogenin. Immunoblot analysis of ferritin levels and transferrin-55Fe accumulation studies indicated that the HJV-induced increase in intracellular iron levels in human embryonic kidney 293 cells is dependent on the presence of neogenin in the cells, thus linking these two proteins to intracellular iron homeostasis

Comparison of the Interactions of Transferrin Receptor and Transferrin Receptor 2 with Transferrin and the Hereditary Hemochromatosis Protein HFE

The transferrin receptor (TfR) interacts with two proteins important for iron metabolism, transferrin (Tf) and HFE, the protein mutated in hereditary hemochromatosis. A second receptor for Tf, TfR2, was recently identified and found to be functional for iron uptake in transfected cells (Kawabata, H., Germain, R. S., Vuong, P. T., Nakamaki, T., Said, J. W., and Koeffler, H. P. (2000) J. Biol. Chem. 275, 16618-16625). TfR2 has a pattern of expression and regulation that is distinct from TfR, and mutations in TfR2 have been recognized as the cause of a non-HFE linked form of hemochromatosis (Camaschella, C., Roetto, A., Cali, A., De Gobbi, M., Garozzo, G., Carella, M., Majorano, N., Totaro, A., and Gasparini, P. (2000) Nat. Genet. 25, 14-15). To investigate the relationship between TfR, TfR2, Tf, and HFE, we performed a series of binding experiments using soluble forms of these proteins. We find no detectable binding between TfR2 and HFE by co-immunoprecipitation or using a surface plasmon resonance-based assay. The affinity of TfR2 for iron-loaded Tf was determined to be 27 nM, 25-fold lower than the affinity of TfR for Tf. These results imply that HFE regulates Tf-mediated iron uptake only from the classical TfR and that TfR2 does not compete for HFE binding in cells expressing both forms of TfR

The quality control theory of aging

The quality control (QC) theory of aging is based on the concept that aging is the result of a reduction in QC of cellular systems designed to maintain lifelong homeostasis. Four QC systems associated with aging are 1) inadequate protein processing in a distressed endoplasmic reticulum (ER); 2) histone deacetylase (HDAC) processing of genomic histones and gene silencing; 3) suppressed AMPK nutrient sensing with inefficient energy utilization and excessive fat accumulation; and 4) beta-adrenergic receptor (BAR) signaling and environmental and emotional stress. Reprogramming these systems to maintain efficiency and prevent aging would be a rational strategy for increased lifespan and improved health. The QC theory can be tested with a pharmacological approach using three well-known and safe, FDA-approved drugs: 1) phenyl butyric acid, a chemical chaperone that enhances ER function and is also an HDAC inhibitor, 2) metformin, which activates AMPK and is used to treat type 2 diabetes, and 3) propranolol, a beta blocker which inhibits BAR signaling and is used to treat hypertension and anxiety. A critical aspect of the QC theory, then, is that aging is associated with multiple cellular systems that can be targeted with drug combinations more effectively than with single drugs. But more importantly, these drug combinations will effectively prevent, delay, or reverse chronic diseases of aging that impose such a tremendous health burden on our society

Theory of terahertz electric oscillations by supercooled superconductors

We predict that below T_c a regime of negative differential conductivity (NDC) can be reached. The superconductor should be supercooled to T<T_c in the normal phase under DC voltage. In such a nonequilibrium situation the NDC of the superconductor is created by the excess conductivity of the fluctuation Cooper pairs. We propose NDC of supercooled superconductors to be used as an active medium for generation of electric oscillations. Such generators can be used in the superconducting electronics as a new type THz source of radiation. Oscillations can be modulated by the change of the bias voltage, electrostatic doping by a gate electrode when the superconductor is the channel of a field effect transistor, or by light. When small amplitude oscillations are stabilized near the critical temperature T_c the generator can be used as a bolometer. The essential for the applications NDC is predicted by the solution of the Boltzmann kinetic equation for the metastable in the normal phase Cooper pairs. Boltzmann equation for fluctuation Cooper pairs is a result of state-of-the-art application of the microscopic theory of superconductivity. Our theoretical conclusions are based on some approximations like time dependent Ginzburg-Landau theory, but nevertheless can reliably predict appearance of NDC. The maximal frequency at which superconductors can operate as generators is determined by the critical temperature \hbar omega_max ~ k_B T_c. For high-T_c superconductors this maximal frequency falls well inside the terahertz range. Technical conditions to avoid nucleation of the superconducting phase are briefly discussed. We suggest that nanostructured high-T_c superconductors patterned in a single chip can give the best technical performance of the proposed oscillator.Comment: 7 page

Energy Information Augmented Community-Based Energy Reduction

More than one-half of all U.S. states have instituted energy efficiency mandates requiring utilities to reduce energy use. To achieve these goals, utilities have been permitted rate structures to help them incentivize energy reduction projects. This strategy is proving to be only modestly successful in stemming energy consumption growth. By the same token, community energy reduction programs have achieved moderate to very significant energy reduction. The research described here offers an important tool to strengthen the community energy reduction efforts—by providing such efforts energy information tailored to the energy use patterns of each building occupant. The information provided most importantly helps each individual energy customer understand their potential for energy savings and what reduction measures are most important to them. This information can be leveraged by the leading community organization to prompt greater action in its community. A number of case studies of this model are shown. Early results are promising

1975 commercial grape spray schedule

"MP 263, 2/75/1.5M"PRE-BLOOM SPRAYS -- BLOOM SPRAYS -- POST-BLOOM SPRAYS -- SUMMER SPRAYSBy W.R. Enns and W.S. Craig (Department of Entomology), A.E. Gaus (Department of Horticulture) and P.W. Steiner, H.W. Shaffer, and E.W. Palm (Department of Plant Pathology

Environmental influences on familial discordance of phenotype in people with homocystinuria: a case report

<p>Abstract</p> <p>Introduction</p> <p>Non-heritable factors may have an influence on the clinical expression of monogenic inherited metabolic diseases.</p> <p>Case presentation</p> <p>This is a case report of a man whose mother had been diagnosed late in childhood with pyridoxine responsive homocystinuria with lens dislocation and neurodevelopmental delay. These severe complications were not observed in her son who was pyridoxine unresponsive but who had been treated appropriately since early infancy.</p> <p>Conclusion</p> <p>The phenotype of people with homocystinuria can be discordant within a family, with variability in metabolic and clinical expression depending upon both the genotype and therapeutic interventions. Offspring of people with homocystinuria should be screened in early infancy and, if positive, treated appropriately whether they have pyridoxine responsive or unresponsive disease.</p

Microsimulation Modeling for Health Decision Sciences Using R: A Tutorial

Microsimulation models are becoming increasingly common in the field of decision modeling for health. Because microsimulation models are computationally more demanding than traditional Markov cohort models, the use of computer programming languages in their development has become more common. R is a programming language that has gained recognition within the field of decision modeling. It has the capacity to perform microsimulation models more efficiently than software commonly used for decision modeling, incorporate statistical analyses within decision models, and produce more transparent models and reproducible results. However, no clear guidance for the implementation of microsimulation models in R exists. In this tutorial, we provide a step-by-step guide to build microsimulation models in R and illustrate the use of this guide on a simple, but transferable, hypothetical decision problem. We guide the reader through the necessary steps and provide generic R code that is flexible and can be adapted for other models. We also show how this code can be extended to address more complex model structures and provide an efficient microsimulation approach that relies on vectorization solutions

Perfectionism and self-conscious emotions in British and Japanese students: Predicting pride and embarrassment after success and failure

Regarding self-conscious emotions, studies have shown that different forms of perfectionism show different relationships with pride, shame, and embarrassment depending on success and failure. What is unknown is whether these relationships also show cultural variations. Therefore, we conducted a study investigating how self-oriented and socially prescribed perfectionism predicted pride and embarrassment after success and failure comparing 363 British and 352 Japanese students. Students were asked to respond to a set of scenarios where they imagined achieving either perfect (success) or flawed results (failure). In both British and Japanese students, self-oriented perfectionism positively predicted pride after success and embarrassment after failure whereas socially prescribed perfectionism predicted embarrassment after success and failure. Moreover, in Japanese students, socially prescribed perfectionism positively predicted pride after success and self-oriented perfectionism negatively predicted pride after failure. The findings have implications for our understanding of perfectionism indicating that the perfectionism–pride relationship not only varies between perfectionism dimensions, but may also show cultural variations