Muscular dystrophy meets protein biochemistry, the mother of invention

Muscular dystrophies result from a defect in the linkage between the muscle fiber cytoskeleton and the basement membrane (BM). Congenital muscular dystrophy type MDC1A is caused by mutations in laminin α2 that either reduce its expression or impair its ability to polymerize within the muscle fiber BM. Defects in this BM lead to muscle fiber damage from the force of contraction. In this issue of the JCI, McKee and colleagues use a laminin polymerization–competent, designer chimeric BM protein in vivo to restore function of a polymerization-defective laminin, leading to normalized muscle structure and strength in a mouse model of MDC1A. Delivery of such a protein to patients could ameliorate many aspects of their disease

Hyperglycemia and Endothelial Dysfunction in Atherosclerosis: Lessons from Type 1 Diabetes

A clear relationship between diabetes and cardiovascular disease has been established for decades. Despite this, the mechanisms by which diabetes contributes to plaque formation remain in question. Some of this confusion derives from studies in type 2 diabetics where multiple components of metabolic syndrome show proatherosclerotic effects independent of underlying diabetes. However, the hyperglycemia that defines the diabetic condition independently affects atherogenesis in cell culture systems, animal models, and human patients. Endothelial cell biology plays a central role in atherosclerotic plaque formation regulating vessel permeability, inflammation, and thrombosis. The current paper highlights the mechanisms by which hyperglycemia affects endothelial cell biology to promote plaque formation

Strategies to rescue the consequences of inducible arginase-1 deficiency in mice

Arginase-1 catalyzes the conversion of arginine to ornithine and urea, which is the final step of the urea cycle used to remove excess ammonia from the body. Arginase-1 deficiency leads to hyperargininemia in mice and man with severe lethal consequences in the former and progressive neurological impairment to varying degrees in the latter. In a tamoxifen-induced arginase-1 deficient mouse model, mice succumb to the enzyme deficiency within 2 weeks after inducing the knockout and retain <2 % enzyme in the liver. Standard clinical care regimens for arginase-1 deficiency (low-protein diet, the nitrogen-scavenging drug sodium phenylbutyrate, ornithine supplementation) either failed to extend lifespan (ornithine) or only minimally prolonged lifespan (maximum 8 days with low-protein diet and drug). A conditional, tamoxifen-inducible arginase-1 transgenic mouse strain expressing the enzyme from the Rosa26 locus modestly extended lifespan of neonatal mice, but not that of 4-week old mice, when crossed to the inducible arginase-1 knockout mouse strain. Delivery of an arginase-1/enhanced green fluorescent fusion construct by adeno-associated viral delivery (rh10 serotype with a strong cytomegalovirus-chicken beta-actin hybrid promoter) rescued about 30% of male mice with lifespan prolongation to at least 6 months, extensive hepatic expression and restoration of significant enzyme activity in liver. In contrast, a vector of the AAV8 serotype driven by the thyroxine-binding globulin promoter led to weaker liver expression and did not rescue arginase-1 deficient mice to any great extent. Since the induced arginase-1 deficient mouse model displays a much more severe phenotype when compared to human arginase-1 deficiency, these studies reveal that it may be feasible with gene therapy strategies to correct the various manifestations of the disorder and they provide optimism for future clinical studies

Nine challenges in modelling the emergence of novel pathogens.

Studying the emergence of novel infectious agents involves many processes spanning host species, spatial scales, and scientific disciplines. Mathematical models play an essential role in combining insights from these investigations and drawing robust inferences from field and experimental data. We describe nine challenges in modelling the emergence of novel pathogens, emphasizing the interface between models and data.We acknowledge support from the Research and Policy for Infectious Disease Dynamics (RAPIDD) programme of the Science and Technology Directory, Department of Homeland Security, and Fogarty International Center, National Institutes of Health. JLS was also supported by the National Science Foundation (EF-0928987 and OCE-1335657) and the De Logi Chair in Biological Sciences. SF was supported by a UK Medical Research Council Career Development Award in Biostatistics. SR was supported by: Wellcome Trust Project Award 093488/Z/10/Z; R01 TW008246-01 from Fogarty International Centre; and The Medical Research Council (UK, Project Grant MR/J008761/1). JLNW was also supported by the Alborada Trust and the European Union FP7 project ANTIGONE (contract number 278976).This is the final version of the article. It first appeared from Elsevier via http://dx.doi.org/10.1016/j.epidem.2014.09.00

Nudging als politisches Instrument - gute Absicht oder staatlicher Übergriff?

Die Verhaltensökonomie und ihre praktischen Implikationen geraten immer stärker in den Fokus auch der deutschen Politik. Individuelle Entscheidungen sollen im Sinne eines „libertären Paternalismus“ „sanft“ beeinflusst werden. Die „Nudges“ bestehen in Standardvorgaben, Selbstbindungen und der Informationsbereitstellung. Deren Anwendung setzt allerdings die Klärung einiger Fragen voraus: Wer darf sich anmaßen, für die Wirtschaftssubjekte „kluge“ Entscheidungen zu treffen? Bei welchen Entscheidungen sind Eingriffe einer anderen Instanz begründbar? Mit welchem Zeithorizont und aufgrund welcher Wohlfahrtsüberlegungen wird eine Entscheidung als „richtig“ definiert? Welcher Rationalitätsbegriff steht hinter dem Konzept

Holey Carbon Nanotubes from Controlled Air Oxidation

Defects in various nanomaterials are often desirable to enable enhanced functional group attachments and attain properties that are not available with their intact counterparts. A new paradigm in the defective low-dimensional carbon nanomaterials is to create holes on the graphitic surfaces via partial etching. For example, holey graphene, graphene sheets with through-thickness holes, was synthesized using several different partial etching approaches and found useful for various applications such as field-effect transistors, sensors, energy storage devices, and separation membranes. In these applications, the presence of holes led to unique advantages, such as bandgap widening, chemical functionalization of hole edges, improved through-the-thickness ion transport with lowered tortuosity, and improved accessible surface area. Here, we present a facile method to prepare holey carbon nanotubes via controlled air oxidation. Although no additional catalyst was added, the residual iron nanoparticles from nanotube growth encapsulated in the nanotube cavity significantly contributed to the hole generation through the nanotube walls. The holey carbon nanotube products exhibited enhanced surface area, pore volume, and oxygen-containing functional groups, which led to their much enhanced electrochemical capacitive properties. Synthesis and characterization details of this novel class of holey carbon nanomaterials are presented, and their potential applications are discussed

Tubular CPT1A deletion minimally affects aging and chronic kidney injury

Kidney tubules use fatty acid oxidation (FAO) to support their high energetic requirements. Carnitine palmitoyltransferase 1A (CPT1A) is the rate-limiting enzyme for FAO, and it is necessary to transport long-chain fatty acids into mitochondria. To define the role of tubular CPT1A in aging and injury, we generated mice with tubule-specific deletion of Cpt1a (Cpt1aCKO mice), and the mice were either aged for 2 years or injured by aristolochic acid or unilateral ureteral obstruction. Surprisingly, Cpt1aCKO mice had no significant differences in kidney function or fibrosis compared with wild-type mice after aging or chronic injury. Primary tubule cells from aged Cpt1aCKO mice had a modest decrease in palmitate oxidation but retained the ability to metabolize long-chain fatty acids. Very-long-chain fatty acids, exclusively oxidized by peroxisomes, were reduced in kidneys lacking tubular CPT1A, consistent with increased peroxisomal activity. Single-nuclear RNA-Seq showed significantly increased expression of peroxisomal FAO enzymes in proximal tubules of mice lacking tubular CPT1A. These data suggest that peroxisomal FAO may compensate in the absence of CPT1A, and future genetic studies are needed to confirm the role of peroxisomal β-oxidation when mitochondrial FAO is impaired