Phenotypic characteristics of the p.Asn215Ser (p.N215S) GLA mutation in male and female patients with Fabry disease: A multicenter Fabry Registry study.

BackgroundThe p.Asn215Ser or p.N215S GLA variant has been associated with late-onset cardiac variant of Fabry disease.MethodsTo expand on the scarce phenotype data, we analyzed natural history data from 125 p.N215S patients (66 females, 59 males) enrolled in the Fabry Registry (NCT00196742) and compared it with data from 401 patients (237 females, 164 males) harboring mutations associated with classic Fabry disease. We evaluated interventricular septum thickness (IVST), left ventricular posterior wall thickness (LVPWT), estimated glomerular filtration rate and severe clinical events.ResultsIn p.N215S males, mildly abnormal mean IVST and LVPWT values were observed in patients aged 25-34 years, and values gradually increased with advancing age. Mean values were similar to those of classic males. In p.N215S females, these abnormalities occurred primarily in patients aged 55-64 years. Severe clinical events in p.N215S patients were mainly cardiac (males 31%, females 8%) while renal and cerebrovascular events were rare. Renal impairment occurred in 17% of p.N215S males (mostly in patients aged 65-74 years), and rarely in females (3%).Conclusionp.N215S is a disease-causing mutation with severe clinical manifestations found primarily in the heart. Cardiac involvement may become as severe as in classic Fabry patients, especially in males

Teaching tolerance

Babies born with Pompe disease require life-long treatment with enzyme-replacement therapy (ERT). Despite the human origin of the therapy, recombinant human lysosomal acid α glucosidase (GAA, rhGAA), ERT unfortunately leads to the development of high titers of anti-rhGAA antibody, decreased effectiveness of ERT, and a fatal outcome for a significant number of children who have Pompe disease. The severity of disease, anti-drug antibody (ADA) development, and the consequences thereof are directly related to the degree of the enzyme deficiency. Babies born with a complete deficiency GAA are said to have cross-reactive immunologic material (CRIM)–negative Pompe disease and are highly likely to develop GAA ADA. Less frequently, GAA ADA develop in CRIM-positive individuals. Currently, GAA-ADA sero-positive babies are treated with a combination of immunosuppressive drugs to induce immunological tolerance to ERT, but the long-term effect of these regimens is unknown. Alternative approaches that might redirect the immune response toward antigen-specific tolerance without immunosuppressive agents are needed. Methods leading to the induction of antigen-specific regulatory T cells (Tregs), using peptides such as Tregitopes (T regulatory cell epitopes) are under consideration for the future treatment of CRIM-negative Pompe disease. Tregitopes are natural T cell epitopes derived from immunoglobulin G (IgG) that cause the expansion and activation of regulatory T cells (Treg). Teaching the immune system to tolerate GAA by co-delivering GAA with Tregitope peptides might dramatically improve the lives of CRIM-negative babies and could be applied to other enzyme replacement therapies to which ADA have been induced

Human Acid Sphingomyelinase Structures Provide Insight to Molecular Basis of Niemann-Pick Disease

Acid sphingomyelinase (ASM) hydrolyzes sphingomyelin to ceramide and phosphocholine, essential components of myelin in neurons. Genetic alterations in ASM lead to ASM deficiency (ASMD) and have been linked to Niemann–Pick disease types A and B. Olipudase alfa, a recombinant form of human ASM, is being developed as enzyme replacement therapy to treat the non-neurological manifestations of ASMD. Here we present the human ASM holoenzyme and product bound structures encompassing all of the functional domains. The catalytic domain has a metallophosphatase fold, and two zinc ions and one reaction product phosphocholine are identified in a histidine-rich active site. The structures reveal the underlying catalytic mechanism, in which two zinc ions activate a water molecule for nucleophilic attack of the phosphodiester bond. Docking of sphingomyelin provides a model that allows insight into the selectivity of the enzyme and how the ASM domains collaborate to complete hydrolysis. Mapping of known mutations provides a basic understanding on correlations between enzyme dysfunction and phenotypes observed in ASMD patients

CaMKII binds both substrates and activators at the active site [preprint]

Ca2+/calmodulin dependent protein kinase II (CaMKII) is a signaling protein that is required for long-term memory formation. Ca2+/CaM activates CaMKII by binding to its regulatory segment, thereby freeing the substrate binding site. Despite having a large variety of interaction partners, the specificity of CaMKII interactions have not been structurally well-characterized. One exceptional feature of this kinase is that interaction with specific binding partners persistently activates CaMKII. To address the molecular details of this, we solved X-ray crystal structures of the CaMKII kinase domain bound to four different binding partners that modulate CaMKII activity in different ways. We show that all four partners bind in the same manner across the substrate binding site. We generated a sequence alignment based on our structural observations, which revealed conserved interactions. Using biochemistry and molecular dynamics simulations, we propose a mechanistic model that persistent CaMKII activity is facilitated by high affinity binding partners, which compete with the regulatory segment to allow substrate phosphorylation

The cross-currency hedging performance of implied versus statistical forecasting models

This article examines the ability of several models to generate optimal hedge ratios. Statistical models employed include univariate and multivariate generalized autoregressive conditionally heteroscedastic (GARCH) models, and exponentially weighted and simple moving averages. The variances of the hedged portfolios derived using these hedge ratios are compared with those based on market expectations implied by the prices of traded options. One-month and three-month hedging horizons are considered for four currency pairs. Overall, it has been found that an exponentially weighted moving-average model leads to lower portfolio variances than any of the GARCH-based, implied or time-invariant approaches

Equine Amplification and Virulence of Subtype IE Venezuelan Equine Encephalitis Viruses Isolated during the 1993 and 1996 Mexican Epizootics

To assess the role of horses as amplification hosts during the 1993 and 1996 Mexican Venezuelan equine encephalitis (VEE) epizootics, we subcutaneously infected 10 horses by using four different equine isolates. Most horses showed little or no disease and low or nonexistent viremia. Neurologic disease developed in only 1 horse, and brain histopathologic examination showed meningeal lymphocytic infiltration, perivascular cuffing, and focalencephalitis. Three animals showed mild meningoencephalitis without clinical disease. Viral RNA was detected in the brain of several animals 12-14 days after infection. These data suggest that the duration and scope of the recent Mexican epizootics were limited by lack of equine amplification characteristic of previous, more extensive VEE outbreaks. The Mexican epizootics may have resulted from the circulation of a more equine-neurotropic, subtype IE virus strain or from increased transmission to horses due to amplification by other vertebrate hosts or transmission by more competent mosquito vectors

The structure of the caspase recruitment domain of BinCARD reveals that all three cysteines can be oxidized

The caspase recruitment domain (CARD) is present in death-domain superfamily proteins involved in inflammation and apoptosis. BinCARD is named for its ability to interact with Bcl10 and inhibit downstream signalling. Human BinCARD is expressed as two isoforms that encode the same N-terminal CARD region but which differ considerably in their C-termini. Both isoforms are expressed in immune cells, although BinCARD-2 is much more highly expressed. Crystals of the CARD fold common to both had low symmetry (space group P1). Molecular replacement was unsuccessful in this low-symmetry space group and, as the construct contains no methionines, first one and then two residues were engineered to methionine for MAD phasing. The double-methionine variant was produced as a selenomethionine derivative, which was crystallized and the structure was solved using data measured at two wavelengths. The crystal structures of the native and selenomethionine double mutant were refined to high resolution (1.58 and 1.40 Å resolution, respectively), revealing the presence of a cis-peptide bond between Tyr39 and Pro40. Unexpectedly, the native crystal structure revealed that all three cysteines were oxidized. The mitochondrial localization of BinCARD-2 and the susceptibility of its CARD region to redox modification points to the intriguing possibility of a redox-regulatory role

Of embodied emissions and inequality: rethinking energy consumption

This paper situates concepts of energy consumption within the context of growing research on embodied emissions. Using the UK as a case study I unpack the global socio-economic and ecological inequalities inherent in the measurement of greenhouse gas emissions on a territorial basis under the international climate change framework. In so doing, I problematise questions of distribution, allocation and responsibility with regards to the pressing need to reduce global GHG emissions and the consumption that generates them. I challenge the disproportionate emphasis that energy policy places on supply as opposed to demand, as well as its overriding focus on the national scale. Consequently I argue that any low carbon transition, in addition to a technological process, is also a geographical one that will involve the reconfiguration of "current spatial patterns of economic and social activity" (Bridge et al., 2013:331), as well as relationships both within countries and regions and between them

Aircraft Regional-Scale Flux Measurements over Complex Landscapes of Mangroves, Desert, and Marine Ecosystems of Magdalena Bay, Mexico

Natural ecosystems are rarely structurally simple or functionally homogeneous. This is true for the complex coastal region of Magdalena Bay, Baja California Sur, Mexico, where the spatial variability in ecosystem fluxes from the Pacific coastal ocean, eutrophic lagoon, mangroves, and desert were studied. The Sky Arrow 650TCN environmental research aircraft proved to be an effective tool in characterizing land–atmosphere fluxes of energy, CO2, and water vapor across a heterogeneous landscape at the scale of 1 km. The aircraft was capable of discriminating fluxes from all ecosystem types, as well as between nearshore and coastal areas a few kilometers distant. Aircraft-derived average midday CO2 fluxes from the desert showed a slight uptake of −1.32 μmol CO2 m−2 s−1, the coastal ocean also showed an uptake of −3.48 μmol CO2 m−2 s−1, and the lagoon mangroves showed the highest uptake of −8.11 μmol CO2 m−2 s−1. Additional simultaneous measurements of the normalized difference vegetation index (NDVI) allowed simple linear modeling of CO2 flux as a function of NDVI for the mangroves of the Magdalena Bay region. Aircraft approaches can, therefore, be instrumental in determining regional CO2 fluxes and can be pivotal in calculating and verifying ecosystem carbon sequestration regionally when coupled with satellite-derived products and ecosystem models