The dimensions of the protein import channels in the outer and inner mitochondrial membranes

Most mitochondrial proteins are imported into mitochondria through transmembrane channels composed largely, and perhaps exclusively, of proteins. We have determined the effective internal diameter of the protein import channel in the mitochondrial outer membrane to be between 20 Å and 26 Å during translocation. The diameter of the import channel in the inner membrane is smaller than the diameter of the outer membrane import channel. These results were obtained by measuring the effect of rigid steric bulk introduced into precursor proteins on import.

Delayed symptom onset and increased life expectancy in Sandhoff disease mice treated with N-butyldeoxynojirimycin

Sandhoff disease is a neurodegenerative disorder resulting from the autosomal recessive inheritance of mutations in the HEXB gene, which encodes the β-subunit of β-hexosaminidase. GM2 ganglioside fails to be degraded and accumulates within lysosomes in cells of the periphery and the central nervous system (CNS). There are currently no therapies for the glycosphingolipid lysosomal storage diseases that involve CNS pathology, including the GM2 gangliosidoses. One strategy for treating this and related diseases is substrate deprivation. This would utilize an inhibitor of glycosphingolipid biosynthesis to balance synthesis with the impaired rate of catabolism, thus preventing storage. One such inhibitor is N-butyldeoxynojirimycin, which currently is in clinical trials for the potential treatment of type 1 Gaucher disease, a related disease that involves glycosphingolipid storage in peripheral tissues, but not in the CNS. In this study, we have evaluated whether this drug also could be applied to the treatment of diseases with CNS storage and pathology. We therefore have treated a mouse model of Sandhoff disease with the inhibitor N-butyldeoxynojirimycin. The treated mice have delayed symptom onset, reduced storage in the brain and peripheral tissues, and increased life expectancy. Substrate deprivation therefore offers a potentially general therapy for this family of lysosomal storage diseases, including those with CNS disease.

Novel polymers: Molecular to nanoscale order in three dimensions

The assembly of polymer chains in solution is a powerful method that is leading to the preparation of interesting and unique macromolecular-based synthetic nanostructures. Specific control over the intramolecular and intermolecular physical interactions dictates either the folding of single chains or the aggregation and ordering of multiple chains. This control is provided through the selective placement of functional groups along the polymer backbone and the relative strengths of their attractive and repulsive interactions.

Mapping the universe in three dimensions

The determination of the three-dimensional layout of galaxies is critical to our understanding of the evolution of galaxies and the structures in which they lie, to our determination of the fundamental parameters of cosmology, and to our understanding of both the past and future histories of the universe at large. The mapping of the large scale structure in the universe via the determination of galaxy red shifts (Doppler shifts) is a rapidly growing industry thanks to technological developments in detectors and spectrometers at radio and optical wavelengths. First-order application of the red shift-distance relation (Hubble’s law) allows the analysis of the large-scale distribution of galaxies on scales of hundreds of megaparsecs. Locally, the large-scale structure is very complex but the overall topology is not yet clear. Comparison of the observed red shifts with ones expected on the basis of other distance estimates allows mapping of the gravitational field and the underlying total density distribution. The next decade holds great promise for our understanding of the character of large-scale structure and its origin.

Novel phenomena in dilute electron systems in two dimensions

For the past two decades, all two-dimensional systems of electrons were believed to be insulating in the limit of zero temperature. Recent experiments provide evidence for an unexpected transition to a conducting phase at very low electron densities. The nature of this phase is not understood and is currently the focus of intense theoretical and experimental attention.

Corneal collagen fibril structure in three dimensions: Structural insights into fibril assembly, mechanical properties, and tissue organization

The ability of the cornea to transmit light while being mechanically resilient is directly attributable to the formation of an extracellular matrix containing orthogonal sheets of collagen fibrils. The detailed structure of the fibrils and how this structure underpins the mechanical properties and organization of the cornea is understood poorly. In this study, we used automated electron tomography to study the three-dimensional organization of molecules in corneal collagen fibrils. The reconstructions show that the collagen molecules in the 36-nm diameter collagen fibrils are organized into microfibrils (≈4-nm diameter) that are tilted by ≈15° to the fibril long axis in a right-handed helix. An unexpected finding was that the microfibrils exhibit a constant-tilt angle independent of radial position within the fibril. This feature suggests that microfibrils in concentric layers are not always parallel to each other and cannot retain the same neighbors between layers. Analysis of the lateral structure shows that the microfibrils exhibit regions of order and disorder within the 67-nm axial repeat of collagen fibrils. Furthermore, the microfibrils are ordered at three specific regions of the axial repeat of collagen fibrils that correspond to the N- and C-telopeptides and the d-band of the gap zone. The reconstructions also show macromolecules binding to the fibril surface at sites that correspond precisely to where the microfibrils are most orderly.