Hfsp Journal最新文献

Being one of the world's neglected diseases, Chagas has neither a vaccine nor a satisfactory therapy. Inoculation of murine models with the ganglioside GM1 has shown a strikingly nonlinear effect, leading to a strong decrease in parasite load at low doses but reverting to a load increase at high doses. Cardiocyte destruction concomitant with the disease is also significantly reduced by a moderate application of GM1. A mathematical model for the interaction between the parasite and the immune system is shown to explain these effects and is used to predict an optimal dosage that maximizes parasite removal with minimal cardiocyte destruction.

There has been considerable recent interest in deciphering the adaptive properties underlying the structure and function of metabolic networks. Various features of metabolic networks such as the global topology, distribution of fluxes, and mutational robustness, have been proposed to have adaptive significance and hence reflect design principles. However, whether evolutionary processes alternative to direct selection on the trait under investigation also play a role is often ignored and the selection pressures maintaining a given metabolic trait often remain speculative. Some systems-level traits might simply arise as by-products of selection on other traits or even through random genetic drift. Here, we ask which systems-level aspects of metabolism are likely to have adaptive utility and which could be better explained as by-products of other evolutionary forces. We conclude that the global topological characteristics of metabolic networks and their mutational robustness are unlikely to be directly shaped by natural selection. Conversely, models of optimal design revealed that various aspects of individual pathways and the behavior of the whole network show signs of adaptations, even though the exact selective forces often remain elusive. Comparative and experimental approaches, which so far have been relatively rarely employed, could help to distinguish between alternative adaptive scenarios.

IN BOTH THE VOICE AND MUSICAL WIND INSTRUMENTS, A VALVE (VOCAL FOLDS, LIPS, OR REED) LIES BETWEEN AN UPSTREAM AND DOWNSTREAM DUCT: trachea and vocal tract for the voice; vocal tract and bore for the instrument. Examining the structural similarities and functional differences gives insight into their operation and the duct-valve interactions. In speech and singing, vocal tract resonances usually determine the spectral envelope and usually have a smaller influence on the operating frequency. The resonances are important not only for the phonemic information they produce, but also because of their contribution to voice timbre, loudness, and efficiency. The role of the tract resonances is usually different in brass and some woodwind instruments, where they modify and to some extent compete or collaborate with resonances of the instrument to control the vibration of a reed or the player's lips, andor the spectrum of air flow into the instrument. We give a brief overview of oscillator mechanisms and vocal tract acoustics. We discuss recent and current research on how the acoustical resonances of the vocal tract are involved in singing and the playing of musical wind instruments. Finally, we compare techniques used in determining tract resonances and suggest some future developments.

Molecular motors are cellular nanomachines that convert the energy from nucleotide binding, hydrolysis, and product release into mechanical work. Because molecular motors contribute to fundamental processes in all living organisms, including genome replication, gene transcription, protein synthesis, organelle transport, and cell division, understanding how the chemical (ATP utilization) and mechanical (motility) cycles are linked is of fundamental importance. A recent study reports the direct visualization of simultaneous nucleotide binding and mechanical displacement of a single myosin 5a molecule, a processive molecular motor protein that takes successive approximately 36-nm steps along actin filaments of the cytoskeleton. This new work demonstrates an exciting advance in single-molecule enzymology and advances our understanding of the link between chemical catalysis and mechanical work in molecular motors, particularly those that operate under internal and external loads.

Microbiology was revolutionized in the 1990's by the discovery that many different bacterial species coordinate their behavior when they form a group. In fact, bacteria are now considered multicellular organisms capable of communicating and changing behavior in relation to their cell-density; since 1994 this has been called quorum sensing. This group behavior ensures survival and propagation of the community in many natural environments. Bacterial intercellular communication is mediated by different chemical signals that are synthesized by bacteria which are then either secreted or diffused in the external environment. Bacteria are then able to detect the type and concentration of the signal resulting in regulation of gene expression and, consequently, a synchronized response by the community. The predominant signalling molecules produced by Gram-negative bacteria are N-acyl derivatives of homoserine lactone (AHLs) which have been shown to be produced by over seventy bacterial species. In this essay we discuss the importance of quorum sensing via AHLs and highlight current and future trends in this important field of research.

By exploring the folding pathways of the B1 domain of protein L with a series of equilibrium and rapid kinetic experiments, we have found its unfolded state to be more complex than suggested by two-state folding models. Using an ultrarapid mixer to initiate protein folding within approximately 2-4 microseconds, we observe folding kinetics by intrinsic tryptophan fluorescence and fluorescence resonance energy transfer. We detect at least two processes faster than 100 mus that would be hidden within the burst phase of a stopped-flow instrument measuring tryptophan fluorescence. Previously reported measurements of slow intramolecular diffusion are commensurate with the slower of the two observed fast phases. These results suggest that a multidimensional energy landscape is necessary to describe the folding of protein L, and that the dynamics of the unfolded state is dominated by multiple small energy barriers.

Amyotropic lateral sclerosis (ALS) is a neurodegenerative disease linked to misfolding and aggregation of the homodimeric enzyme superoxide dismutase (SOD1). In contrast to the precursors of other neurodegenerative diseases, SOD1 is a soluble and simple-to-study protein with immunoglobulin-like structure. Also, there are more than 120 ALS-provoking SOD1 mutations at the disposal for detailed elucidation of the disease-triggering factors at molecular level. In this article, we review recent progress in the characterization of the folding and assembly pathway of the SOD1 dimer and how this is affected by ALS-provoking mutations. Despite the diverse nature of these mutations, the results offer so far a surprising simplicity. The ALS-provoking mutations decrease either protein stability or net repulsive charge: the classical hallmarks for a disease mechanism triggered by association of non-native protein. In addition, the mutant data identifies immature SOD1 monomers as the species from which the cytotoxic pathway emerges, and point at compromised folding cooperativity as a key disease determinant. The relative ease by which these data can be obtained makes SOD1 a promising model for elucidating also the origin of other neurodegenerative diseases where the precursor proteins are structurally more elusive.

Traditionally, folding experiments have been directed at determining equilibrium and relaxation rate constants of proteins that fold with two-state-like kinetics. More recently, the combination of free energy surface approaches inspired by theory with the discovery of proteins that fold in the downhill regime has greatly widened the battlefield for experimentalists. Downhill folding proteins cross very small or no free energy barrier at all so that all relevant partially folded conformations become experimentally accessible. From these combined efforts we now have tools to estimate the height of thermodynamic and kinetic folding barriers. Procedures to measure with atomic resolution the structural heterogeneity of conformational ensembles at varying unfolding degrees are also available. Moreover, determining the dynamic modes driving folding and how they change as folding proceeds is finally at our fingertips. These developments allow us to address via experiment fundamental questions such as the origin of folding cooperativity, the relationship between structure and stability, or how to engineer folding barriers. Moreover, the level of detail attained in this new breed of experiments should provide powerful benchmarks for computer simulations of folding and force-field refinement.

There have been relatively few detailed comprehensive studies of the folding of protein domains (or modules) in the context of their natural covalently linked neighbors. This is despite the fact that a significant proportion of the proteome consists of multidomain proteins. In this review we highlight some key experimental investigations of the folding of multidomain proteins to draw attention to the difficulties that can arise in analyzing such systems. The evidence suggests that interdomain interactions can significantly affect stability, folding, and unfolding rates. However, preliminary studies suggest that folding pathways are unaffected-to this extent domains can be truly considered to be independent folding units. Nonetheless, it is clear that interactions between domains cannot be ignored, in particular when considering the effects of mutations.

Structural data play a central role in understanding biological function at the molecular level. At present, the majority of high-resolution structural data about biological macromolecules and their complexes originates from crystallography. In crystal structure determination, the major hurdle to overcome is the production of crystals of sufficient size and quality. High-flux x-ray beams with diameters of a few micrometers or less help to alleviate this problem as small beams allow the use of small crystals or scanning of large crystals for regions of acceptable diffraction. Using sophisticated x-ray optics and mechanics with submicrometer precision, Riekel et al.[Acta Crystallogr., Sect. D: Biol. Crystallogr., 64, 158-166 (2008)], have recently demonstrated that an x-ray beam of 1 mum can be used to determine the crystal structure of a protein to a resolution of 1.5 A. The smallest volume from which usable diffraction data were collected amounted to 20 mum(3), corresponding to not more than 2x10(8) unit cells. In a diffraction volume of micrometer dimensions, radiation damage is expected to be reduced with respect to large volumes as a significant fraction of the photoelectrons produced by the incident radiation escapes from the diffracting volume before dissipating their energy. The possibility to make use of small andor inhomogeneous crystals in combination with a possible reduction in radiation damage due to size effects has the potential to make many more systems amenable to crystal structure analysis.