Functional characterization of the human α-cardiac actin mutations Y166C and M305L involved in hypertrophic cardiomyopathy

Inherited cardiomyopathies are caused by point mutations in sarcomeric gene products, including α-cardiac muscle actin (ACTC1). We examined the biochemical and cell biological properties of the α-cardiac actin mutations Y166C and M305L identified in hypertrophic cardiomyopathy (HCM). Untagged wild-type (WT) cardiac actin, and the Y166C and M305L mutants were expressed by the baculovirus/Sf9-cell system and affinity purified by immobilized gelsolin G4-6. Their correct folding was verified by a number of assays. The mutant actins also displayed a disturbed intrinsic ATPase activity and an altered polymerization behavior in the presence of tropomyosin, gelsolin, and Arp2/3 complex. Both mutants stimulated the cardiac β-myosin ATPase to only 50?% of WT cardiac F-actin. Copolymers of WT and increasing amounts of the mutant actins led to a reduced stimulation of the myosin ATPase. Transfection of established cell lines revealed incorporation of EGFP- and hemagglutinin (HA)-tagged WT and both mutant actins into cytoplasmic stress fibers. Adenoviral vectors of HA-tagged WT and Y166C actin were successfully used to infect adult and neonatal rat cardiomyocytes (NRCs). The expressed HA-tagged actins were incorporated into the minus-ends of NRC thin filaments, demonstrating the ability to form hybrid thin filaments with endogenous actin. In NRCs, the Y166C mutant led after 72?h to a shortening of the sarcomere length when compared to NRCs infected with WT actin. Thus our data demonstrate that a mutant actin can be integrated into cardiomyocyte thin filaments and by its reduced mode of myosin interaction might be the basis for the initiation of HCM.     

Factors influencing the distribution of 99m-technetium methylene diphosphonate in bone and soft tissues

Summary The influences of dilution, storage and pH on the distribution of 99m-technetium methylene diphosphonate (99m-Tc-MDP) in bone and various soft tissues have been investigated in the rat. The results show a marked departure from normality when large dilution factors and very acidic or basic preparations are used.     

A new class of anthelmintics effective against drug-resistant nematodes

Anthelmintic resistance in human and animal pathogenic helminths has been spreading in prevalence and severity to a point where multidrug resistance against the three major classes of anthelmintics--the benzimidazoles, imidazothiazoles and macrocyclic lactones--has become a global phenomenon in gastrointestinal nematodes of farm animals. Hence, there is an urgent need for an anthelmintic with a new mode of action. Here we report the discovery of the amino-acetonitrile derivatives (AADs) as a new chemical class of synthetic anthelmintics and describe the development of drug candidates that are efficacious against various species of livestock-pathogenic nematodes. These drug candidates seem to have a novel mode of action involving a unique, nematode-specific clade of acetylcholine receptor subunits. The AADs are well tolerated and of low toxicity to mammals, and overcome existing resistances to the currently available anthelmintics.     

Imaging in the era of molecular oncology

New technologies for imaging molecules, particularly optical technologies, are increasingly being used to understand the complexity, diversity and in vivo behaviour of cancers. 'Omic' approaches are providing comprehensive 'snapshots' of biological indicators, or biomarkers, of cancer, but imaging can take this information a step further, showing the activity of these markers in vivo and how their location changes over time. Advances in experimental and clinical imaging are likely to improve how cancer is understood at a systems level and, ultimately, should enable doctors not only to locate tumours but also to assess the activity of the biological processes within these tumours and to provide 'on the spot' treatment.     

Coupling of spin and orbital motion of electrons in carbon nanotubes

Electrons in atoms possess both spin and orbital degrees of freedom. In non-relativistic quantum mechanics, these are independent, resulting in large degeneracies in atomic spectra. However, relativistic effects couple the spin and orbital motion, leading to the well-known fine structure in their spectra. The electronic states in defect-free carbon nanotubes are widely believed to be four-fold degenerate, owing to independent spin and orbital symmetries, and also to possess electron-hole symmetry. Here we report measurements demonstrating that in clean nanotubes the spin and orbital motion of electrons are coupled, thereby breaking all of these symmetries. This spin-orbit coupling is directly observed as a splitting of the four-fold degeneracy of a single electron in ultra-clean quantum dots. The coupling favours parallel alignment of the orbital and spin magnetic moments for electrons and antiparallel alignment for holes. Our measurements are consistent with recent theories that predict the existence of spin-orbit coupling in curved graphene and describe it as a spin-dependent topological phase in nanotubes. Our findings have important implications for spin-based applications in carbon-based systems, entailing new design principles for the realization of quantum bits (qubits) in nanotubes and providing a mechanism for all-electrical control of spins in nanotubes.     

Ecology: a niche for cyanobacteria containing chlorophyll d

The cyanobacterium known as Acaryochloris marina is a unique phototroph that uses chlorophyll d as its principal light-harvesting pigment instead of chlorophyll a, the form commonly found in plants, algae and other cyanobacteria; this means that it depends on far-red light for photosynthesis. Here we demonstrate photosynthetic activity in Acaryochloris-like phototrophs that live underneath minute coral-reef invertebrates (didemnid ascidians) in a shaded niche enriched in near-infrared light. This discovery clarifies how these cyanobacteria are able to thrive as free-living organisms in their natural habitat.