ALBERT

Description: A long-standing pathomechanistic model proposes that the polyglutamine (polyQ)-length-dependent toxicity threshold observed in all polyQ diseases is triggered by a conformational change within the monomer that occurs only above a certain polyQ length. If true, this yet undefined and elusive mutant-specific toxic conformation would constitute a direct therapeutic target. Three anti-polyQ antibodies—MW1, 1C2 and 3B5H10—have been extensively used to probe the conformation of polyQ. The crystal structure of the MW1 epitope reveals a linear, non-pathogenic polyQ. In contrast, although the detailed structure of its epitope is unknown, the 3B5H10 antibody is widely advertised and used as a conformational antibody that recognizes the toxic conformation of expanded polyQ. We solved the crystal structure of the 1C2 antigen-binding domain (1C2-Fab) and performed a direct comparison between the 1C2, MW1 and 3B5H10 structures. The MW1 and 1C2 antibodies have similar sequences and structures, consistent with their binding to short polyQ and their polyQ length-discrimination properties. Unexpectedly, the 3B5H10 antibody also shares striking features with MW1 and 1C2, which prompted us to revisit its binding properties. We show that the 3B5H10 epitope is actually a short, non-pathogenic polyQ. All three antibodies MW1, 1C2 and 3B5H10 interact similarly with polyQ of various lengths, and bind small polyQ epitopes in similar linear and extended conformations. Together with studies published during the recent years, our work argues against the hypothesis that a mutant-specific conformation in monomeric polyQ molecules is the toxic entity responsible for polyQ diseases.

Description: An approach for the control and understanding of supported molecular catalysts is demonstrated with the design and synthesis of open and closed variants of a grafted Lewis acid active site, consisting of Al(III)-calix[4]arene complexes on the surface of silica. The calixarene acts as a molecular template that enforces open and...

Description: Variational data assimilation systems for numerical weather prediction rely on a transformation of model variables to a set of control variables that are assumed to be uncorrelated. Most implementations of this transformation are based on the assumption that the balanced part of the flow can be represented by the vorticity. However, this assumption is likely to break down in dynamical regimes characterized by low Burger number. It has recently been proposed that a variable transformation based on potential vorticity should lead to control variables that are uncorrelated over a wider range of regimes. In this paper we test the assumption that a transform based on vorticity and one based on potential vorticity produce an uncorrelated set of control variables. Using a shallow-water model we calculate the correlations between the transformed variables in the different methods. We show that the control variables resulting from a vorticity-based transformation may retain large correlations in some dynamical regimes, whereas a potential vorticity-based transformation successfully produces a set of uncorrelated control variables. Calculations of spatial correlations show that the benefit of the potential vorticity transformation is linked to its ability to capture more accurately the balanced component of the flow. Copyright © 2011 Royal Meteorological Society and British Crown Copyright, the Met Office

Description: Elongation factor P (EF-P) is a conserved ribosome-binding protein that structurally mimics tRNA to enable the synthesis of peptides containing motifs that otherwise would induce translational stalling, including polyproline. In many bacteria, EF-P function requires post-translational modification with ( R )-β-lysine by the lysyl-tRNA synthetase paralog PoxA. To investigate how recognition of EF-P by PoxA evolved from tRNA recognition by aminoacyl-tRNA synthetases, we compared the roles of EF-P/PoxA polar contacts with analogous interactions in a closely related tRNA/synthetase complex. PoxA was found to recognize EF-P solely via identity elements in the acceptor loop, the domain of the protein that interacts with the ribosome peptidyl transferase center and mimics the 3'-acceptor stem of tRNA. Although the EF-P acceptor loop residues required for PoxA recognition are highly conserved, their conservation was found to be independent of the phylogenetic distribution of PoxA. This suggests EF-P first evolved tRNA mimicry to optimize interactions with the ribosome, with PoxA-catalyzed aminoacylation evolving later as a secondary mechanism to further improve ribosome binding and translation control.

Description: Using cosmogenic isotopes and solute load analysis, we quantify chemical weathering (solutional erosion) and denudation rates over variable time scales in a tectonically stable, moderate-relief, carbonate terrain (Soreq drainage, Judea Hills, Israel), located in a semihumid Mediterranean climate. Long-term (〉10 4 yr) denudation rates were calculated from 36 Cl concentrations in 51 bedrock and sediment samples. Bedrock samples range in elevation (340–850 m), hillslope gradient (0°–30°), and mean annual precipitation (MAP; 500–630 mm) and vary in soil cover thickness (0–75 cm), Mg/Ca ratio (0.0–1.0 mol), clay mineral contents (0–6 wt%), and mechanical strength (41–58 Schmidt hammer rebound units). Soil p CO 2 values at a single location during the course of 1 yr, range between 0.4 and 9.0 mmol mol –1 . Average long-term denudation rate of exposed bedrock samples is 21 ± 7 mm k.y. –1 . Field observations and 36 Cl measurements indicate that soil pockets undergo cycles in the rate of deepening, and that over 10 5 yr time scale, average denudation rates beneath soil pockets are similar to those of exposed bedrock. Sediment samples yield even higher denudation rates, which are probably anthropogenically induced, but could also indicate that the sediment source is soil pockets. Long-term denudation rates are decoupled from hillslope gradient, elevation, and rock strength. Denudation rates show a positive correlation with present-day MAP values, exhibit a complex relation with rock Mg content, and show a weak correlation with clay content. Annual chemical weathering rates were calculated from modern-day solute load measured in waters of perched springs and the regional carbonate aquifer. Our results indicate that on annual, decadal, and 10 4 yr time scales, chemical weathering and denudation are controlled by carbonate dissolution, while mechanical processes are far less significant. Overlap between the distributions of HCO 3 – concentrations measured in runoff, springs, and the regional aquifer water suggests that chemical weathering focuses at the bedrock surface and therefore is comparable with solutional denudation. This result is in contrast to the features of ancient fluvial and colluvial activity (steep nonconcave hillslopes and stream profiles and knickzones in the streams) preserved in the present landscape. Such features were formed in response to mid-Pleistocene uplift and could have been preserved due to a decrease in stream power following the formation of subsurface drainage and the lowering in abrasive clast supply that followed the stabilization of hillslopes in the drainage. Long-term denudation rates calculated from exposed bedrock samples are higher by factor of 1.4 relative to annual, contemporary chemical weathering rates. Increased precipitation by a similar factor, averaged over the last glacial and present interglacial, can explain this difference.

Description: EF-P is a bacterial tRNA-mimic protein, which accelerates the ribosome-catalyzed polymerization of poly-prolines. In Escherichia coli , EF-P is post-translationally modified on a conserved lysine residue. The post-translational modification is performed in a two-step reaction involving the addition of a β-lysine moiety and the subsequent hydroxylation, catalyzed by PoxA and YfcM, respectively. The β-lysine moiety was previously shown to enhance the rate of poly-proline synthesis, but the role of the hydroxylation is poorly understood. We solved the crystal structure of YfcM and performed functional analyses to determine the hydroxylation mechanism. In addition, YfcM appears to be structurally distinct from any other hydroxylase structures reported so far. The structure of YfcM is similar to that of the ribonuclease YbeY, even though they do not share sequence homology. Furthermore, YfcM has a metal ion-coordinating motif, similar to YbeY. The metal ion-coordinating motif of YfcM resembles a 2-His-1-carboxylate motif, which coordinates an Fe(II) ion and forms the catalytic site of non-heme iron enzymes. Our findings showed that the metal ion-coordinating motif of YfcM plays an essential role in the hydroxylation of the β-lysylated lysine residue of EF-P. Taken together, our results suggested the potential catalytic mechanism of hydroxylation by YfcM.

Description: Basin-scale calcification rates are highly important in assessments of the global oceanic carbon cycle. Traditionally, such estimates were based on rates of sedimentation measured with sediment traps or in deep sea cores. Here we estimated CaCO3 precipitation rates in the surface water of the Red Sea from total alkalinity depletion...

Description: The addition of small amounts of multivalent cations to solutions containing double-stranded DNA leads to inter-DNA attraction and eventual condensation. Surprisingly, the condensation is suppressed in double-stranded RNA, which carries the same negative charge as DNA, but assumes a different double helical form. Here, we combine experiment and atomistic simulations to propose a mechanism that explains the variations in condensation of short (25 base-pairs) nucleic acid (NA) duplexes, from B-like form of homopolymeric DNA, to mixed sequence DNA, to DNA:RNA hybrid, to A-like RNA. Circular dichroism measurements suggest that duplex helical geometry is not the fundamental property that ultimately determines the observed differences in condensation. Instead, these differences are governed by the spatial variation of cobalt hexammine (CoHex) binding to NA. There are two major NA-CoHex binding modes—internal and external—distinguished by the proximity of bound CoHex to the helical axis. We find a significant difference, up to 5-fold, in the fraction of ions bound to the external surfaces of the different NA constructs studied. NA condensation propensity is determined by the fraction of CoHex ions in the external binding mode.