Transforming binding affinities from three dimensions to two with application to cadherin clustering

Membrane-bound receptors often form large assemblies resulting from binding to soluble ligands, cell-surface molecules on other cells and extracellular matrix proteins. For example, the association of membrane proteins with proteins on different cells (trans-interactions) can drive the oligomerization of proteins on the same cell (cis-interactions). A central problem in understanding the molecular basis of such phenomena is that equilibrium constants are generally measured in three-dimensional solution and are thus difficult to relate to the two-dimensional environment of a membrane surface. Here we present a theoretical treatment that converts three-dimensional affinities to two dimensions, accounting directly for the structure and dynamics of the membrane-bound molecules. Using a multiscale simulation approach, we apply the theory to explain the formation of ordered, junction-like clusters by classical cadherin adhesion proteins. The approach features atomic-scale molecular dynamics simulations to determine interdomain flexibility, Monte Carlo simulations of multidomain motion and lattice simulations of junction formation. A finding of general relevance is that changes in interdomain motion on trans-binding have a crucial role in driving the lateral, cis-, clustering of adhesion receptors.     

A genetically humanized mouse model for hepatitis C virus infection

Hepatitis C virus (HCV) remains a major medical problem. Antiviral treatment is only partially effective and a vaccine does not exist. Development of more effective therapies has been hampered by the lack of a suitable small animal model. Although xenotransplantation of immunodeficient mice with human hepatocytes has shown promise, these models are subject to important challenges. Building on the previous observation that CD81 and occludin comprise the minimal human factors required to render mouse cells permissive to HCV entry in vitro, we attempted murine humanization via a genetic approach. Here we show that expression of two human genes is sufficient to allow HCV infection of fully immunocompetent inbred mice. We establish a precedent for applying mouse genetics to dissect viral entry and validate the role of scavenger receptor type B class I for HCV uptake. We demonstrate that HCV can be blocked by passive immunization, as well as showing that a recombinant vaccinia virus vector induces humoral immunity and confers partial protection against heterologous challenge. This system recapitulates a portion of the HCV life cycle in an immunocompetent rodent for the first time, opening opportunities for studying viral pathogenesis and immunity and comprising an effective platform for testing HCV entry inhibitors in vivo.     

The earliest evidence for anatomically modern humans in northwestern Europe

The earliest anatomically modern humans in Europe are thought to have appeared around 43,000-42,000 calendar years before present (43-42 kyr cal BP), by association with Aurignacian sites and lithic assemblages assumed to have been made by modern humans rather than by Neanderthals. However, the actual physical evidence for modern humans is extremely rare, and direct dates reach no farther back than about 41-39 kyr cal BP, leaving a gap. Here we show, using stratigraphic, chronological and archaeological data, that a fragment of human maxilla from the Kent's Cavern site, UK, dates to the earlier period. The maxilla (KC4), which was excavated in 1927, was initially diagnosed as Upper Palaeolithic modern human. In 1989, it was directly radiocarbon dated by accelerator mass spectrometry to 36.4-34.7 kyr cal BP. Using a Bayesian analysis of new ultrafiltered bone collagen dates in an ordered stratigraphic sequence at the site, we show that this date is a considerable underestimate. Instead, KC4 dates to 44.2-41.5 kyr cal BP. This makes it older than any other equivalently dated modern human specimen and directly contemporary with the latest European Neanderthals, thus making its taxonomic attribution crucial. We also show that in 13 dental traits KC4 possesses modern human rather than Neanderthal characteristics; three other traits show Neanderthal affinities and a further seven are ambiguous. KC4 therefore represents the oldest known anatomically modern human fossil in northwestern Europe, fills a key gap between the earliest dated Aurignacian remains and the earliest human skeletal remains, and demonstrates the wide and rapid dispersal of early modern humans across Europe more than 40 kyr ago.     

Burrows of the sagebrush vole ( Lemmiscus curtatus ) in southeastern Idaho

Normal 0 false false false EN-US X-NONE X-NONE MicrosoftInternetExplorer4 /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-qformat:yes; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:11.0pt; font-family:"Calibri","sans-serif"; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"Times New Roman"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi;} Burrows of the sagebrush vole ( Lemmiscus curtatus ) were analyzed by injecting them with expanding polyurethane foam. Average mean depth ± 1 SE of four burrows was 12.5 ± 2.6 cm. Tunnels were wider than high and flat on the bottom. Three of four burrows were nearly linear, with an average of five entrances. Burrows usually contained one nest made of Artemisia tridentata bark. No middens or communal nests were found. The burrow structure in sagebrush habitat suggests that sagebrush voles occur singly or in pairs rather than in colonies.     

New species of Mentzelia (Loasaceae) from Grand County, Utah

A new species, Mentzelia (Section Bartonia ) shultziorum , of the Loasaceae (Mentzelioideae) is described. A close relationship with M. multicaulis (Osterh.) Darl. and M. argillosa Darl. is suggested based on the morphology of the flowers, leaves, and seeds.     

C 3 and C 4 Species Changes Identified by δ 13 C values of soil organic matter in a Colorado prairie

We measured carbon isotope signatures (δ 13 C) from 0-10 cm and 10-20 cm soil depth intervals for grassland soils near Boulder, Colorado. These grasslands included tall-, short-, and mixed-grass prairies that were grazed, ungrazed, or hayed. Soils exhibited δ 13 C signatures consistent with observations that current sites are a mix of C 3 and C 4 species, with C 3 plants more abundant in mixed-grass than in native tall- or shortgrass prairies. The δ 13 C signatures were not significantly different for grassland types; however, management treatments (grazing, no grazing, haying) significantly influenced changes in soil δ 13 C signatures from the 0-10 cm to 10-20 cm soil depth intervals. We observed a correlation ( r = 0.63) between isotopic values of surface soils and percent native species in total vegetation cover. Overall, the community type with the lowest percentage of nonindigenous species cover had the most enriched δ 13 C signature. Sites currently grazed by prairie dogs, cattle, or both herbivores had stronger C 3 signatures, indicating that grazing may have increased C 3 plant productivity in these communities at the expense of C 4 grasses. This finding differs from studies of native shortgrass steppe where grazing has the opposite effect on the relative abundance of these 2 functional groups of plants. This result, along with the correlation between C 3 isotopic values and nonnative vegetation abundance, provides evidence that management practices that maintain dominance of C 4 grasses should be encouraged.     

Movements by small mammals on a radioactive waste disposal area in southeastern Idaho

Average linear movement by populations of Dipodomys ordii, Microtus montanus, Perognathus parvus, and Peromyscus maniculatus   was investigated over a 15-month period by live trapping on a low-level, radioactive waste disposal area in Idaho. No significant differences in movement among habitats were observed seasonally, excepting M. montanus in spring. Average linear movements within habitats ranged from 20 to 70 m for all species, but some patterns varied seasonally and among age classes for individual species. Although predation on contaminated small mammals from the disposal area is a vector of radionuclide transport, local movements by these rodents do not appear to be of sufficient magnitude to contribute significantly to redistribution of radioactive particles.     

CEP41 is mutated in Joubert syndrome and is required for tubulin glutamylation at the cilium

Tubulin glutamylation is a post-translational modification that occurs predominantly in the ciliary axoneme and has been suggested to be important for ciliary function. However, its relationship to disorders of the primary cilium, termed ciliopathies, has not been explored. Here we mapped a new locus for Joubert syndrome (JBTS), which we have designated as JBTS15, and identified causative mutations in CEP41, which encodes a 41-kDa centrosomal protein. We show that CEP41 is localized to the basal body and primary cilia, and regulates ciliary entry of TTLL6, an evolutionarily conserved polyglutamylase enzyme. Depletion of CEP41 causes ciliopathy-related phenotypes in zebrafish and mice and results in glutamylation defects in the ciliary axoneme. Our data identify CEP41 mutations as a cause of JBTS and implicate tubulin post-translational modification in the pathogenesis of human ciliary dysfunction.     

Reconfigurable self-assembly through chiral control of interfacial tension

From determining the optical properties of simple molecular crystals to establishing the preferred handedness in highly complex vertebrates, molecular chirality profoundly influences the structural, mechanical and optical properties of both synthetic and biological matter on macroscopic length scales. In soft materials such as amphiphilic lipids and liquid crystals, the competition between local chiral interactions and global constraints imposed by the geometry of the self-assembled structures leads to frustration and the assembly of unique materials. An example of particular interest is smectic liquid crystals, where the two-dimensional layered geometry cannot support twist and chirality is consequently expelled to the edges in a manner analogous to the expulsion of a magnetic field from superconductors. Here we demonstrate a consequence of this geometric frustration that leads to a new design principle for the assembly of chiral molecules. Using a model system of colloidal membranes, we show that molecular chirality can control the interfacial tension, an important property of multi-component mixtures. This suggests an analogy between chiral twist, which is expelled to the edges of two-dimensional membranes, and amphiphilic surfactants, which are expelled to oil-water interfaces. As with surfactants, chiral control of interfacial tension drives the formation of many polymorphic assemblages such as twisted ribbons with linear and circular topologies, starfish membranes, and double and triple helices. Tuning molecular chirality in situ allows dynamical control of line tension, which powers polymorphic transitions between various chiral structures. These findings outline a general strategy for the assembly of reconfigurable chiral materials that can easily be moved, stretched, attached to one another and transformed between multiple conformational states, thus allowing precise assembly and nanosculpting of highly dynamical and designable materials with complex topologies.