Arginine methylation of yeast mRNA-binding protein Npl3 directly affects its function, nuclear export, and intranuclear protein interactions

Arginine methylation can affect both nucleocytoplasmic transport and protein-protein interactions of RNA-binding proteins. These effects are seen in cells that lack the yeast hnRNP methyltransferase (HMT1), raising the question of whether effects on specific proteins are direct or indirect. The presence of multiple arginines in individual methylated proteins also raises the question of whether overall methylation or methylation of a subset of arginines affects protein function. We have used the yeast mRNA-binding protein Npl3 to address these questions in vivo. Matrix-assisted laser desorption/ionization Fourier transform mass spectrometry was used to identify 17 methylated arginines in Npl3 purified from yeast: whereas 10 Arg-Gly-Gly (RGG) tripeptides were exclusively dimethylated, variable levels off methylation were found for 5 RGG and 2 RG motif arginines. We constructed a set of Npl3 proteins in which subsets of the RGG arginines were mutated to lysine. Expression of these mutant proteins as the sole form of Npl3 specifically affected growth of a strain that requires Hmtl. Although decreased growth generally correlated with increased numbers of Arg-to-Lys mutations, lysine substitutions in the N terminus of the RGG domain showed more severe effects. Npl3 with all 15 RGG arginines mutated to lysine exited the nucleus independent of Hmtl, indicating a direct effect of methylation on Npl3 transport. These mutations also resulted in a decreased, methylation-independent interaction of Npl3 with transcription elongation factor Tho2 and inhibited Npl3 self-association. These results support a model in which arginine methylation facilitates Npl3 export directly by weakening contacts with nuclear proteins. © 2005 by The American Society for Biochemistry and Molecular Biology, Inc

Markov analysis of stochastic resonance in a periodically driven integrate-fire neuron

We model the dynamics of the leaky integrate-fire neuron under periodic stimulation as a Markov process with respect to the stimulus phase. This avoids the unrealistic assumption of a stimulus reset after each spike made in earlier work and thus solves the long-standing reset problem. The neuron exhibits stochastic resonance, both with respect to input noise intensity and stimulus frequency. The latter resonance arises by matching the stimulus frequency to the refractory time of the neuron. The Markov approach can be generalized to other periodically driven stochastic processes containing a reset mechanism.Comment: 23 pages, 10 figure

Characterization of the manganese sites in manganese redox enzymes: Catalase and superoxide dismutase.

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/30701/1/0000346.pd

A higher-resolution version of the Max Planck Institute Earth System Model (MPI-ESM1.2-HR)

The MPI‐ESM1.2 is the latest version of the Max Planck Institute Earth System Model and is the baseline for the Coupled Model Intercomparison Project Phase 6 and current seasonal and decadal climate predictions. This paper evaluates a coupled higher‐resolution version (MPI‐ESM1.2‐HR) in comparison with its lower‐resolved version (MPI‐ESM1.2‐LR). We focus on basic oceanic and atmospheric mean states and selected modes of variability, the El Niño/Southern Oscillation and the North Atlantic Oscillation. The increase in atmospheric resolution in MPI‐ESM1.2‐HR reduces the biases of upper‐level zonal wind and atmospheric jet stream position in the northern extratropics. This results in a decrease of the storm track bias over the northern North Atlantic, for both winter and summer season. The blocking frequency over the European region is improved in summer, and North Atlantic Oscillation and related storm track variations improve in winter. Stable Atlantic meridional overturning circulations are found with magnitudes of ~16 Sv for MPI‐ESM1.2‐HR and ~20 Sv for MPI‐ESM1.2‐LR at 26°N. A strong sea surface temperature bias of ~5°C along with a too zonal North Atlantic current is present in both versions. The sea surface temperature bias in the eastern tropical Atlantic is reduced by ~1°C due to higher‐resolved orography in MPI‐ESM‐HR, and the region of the cold‐tongue bias is reduced in the tropical Pacific. MPI‐ESM1.2‐HR has a well‐balanced radiation budget and its climate sensitivity is explicitly tuned to 3 K. Although the obtained reductions in long‐standing biases are modest, the improvements in atmospheric dynamics make this model well suited for prediction and impact studies

Children's trust and the development of prosocial behavior

This study examined the role of children’s trust beliefs and trustworthiness in the development of prosocial behavior using data from four waves of a longitudinal study in a large, ethnically diverse sample of children in Switzerland (mean age = 8.11 years at Time 1, N = 1,028). Prosocial behavior directed towards peers was measured at all assessment points by teacher reports. Children’s trust beliefs and their trustworthiness with peers were assessed and calculated by a social relations analysis at the first assessment point using children’s reports of the extent to which classmates kept promises. In addition, teacher reports of children’s trustworthiness were assessed at all four assessment points. Latent growth curve modeling yielded a decrease in prosocial behavior over time. Peer- and teacher-reported trustworthiness predicted higher initial levels of prosocial behavior, and peer-reported trustworthiness predicted less steep decreases in prosocial behavior over time. Autoregressive cross-lagged analysis also revealed bidirectional longitudinal associations between teacher-reported trustworthiness and prosocial behavior. We discuss the implications of the findings for research on the role of trust in the development of children’s prosocial behavior

Autosomal dominant hereditary spastic paraplegia: Novel mutations in the REEP1 gene (SPG31)

<p>Abstract</p> <p>Background</p> <p>Mutations in the <it>SPG4 </it>gene (spastin) and in the <it>SPG3A </it>gene (atlastin) account for the majority of 'pure' autosomal dominant form of hereditary spastic paraplegia (HSP). Recently, mutations in the <it>REEP1 </it>gene were identified to cause autosomal dominant HSP type SPG31. The purpose of this study was to determine the prevalence of <it>REEP1 </it>mutations in a cohort of 162 unrelated Caucasian index patients with 'pure' HSP and a positive family history (at least two persons per family presented symptoms).</p> <p>Methods</p> <p>162 patients were screened for mutations by, both, DHPLC and direct sequencing.</p> <p>Results</p> <p>Ten mutations were identified in the <it>REEP1 </it>gene, these included eight novel mutations comprising small insertions/deletions causing frame shifts and subsequently premature stop codons, one nonsense mutation and one splice site mutation as well as two missense mutations. Both missense mutations and the splice site mutation were not identified in 170 control subjects.</p> <p>Conclusion</p> <p>In our HSP cohort we found pathogenic mutations in 4.3% of cases with autosomal dominant inheritance. Our results confirm the previously observed mutation range of 3% to 6.5%, respectively, and they widen the spectrum of <it>REEP1 </it>mutations.</p

Learning intrinsic excitability in medium spiny neurons

We present an unsupervised, local activation-dependent learning rule for intrinsic plasticity (IP) which affects the composition of ion channel conductances for single neurons in a use-dependent way. We use a single-compartment conductance-based model for medium spiny striatal neurons in order to show the effects of parametrization of individual ion channels on the neuronal activation function. We show that parameter changes within the physiological ranges are sufficient to create an ensemble of neurons with significantly different activation functions. We emphasize that the effects of intrinsic neuronal variability on spiking behavior require a distributed mode of synaptic input and can be eliminated by strongly correlated input. We show how variability and adaptivity in ion channel conductances can be utilized to store patterns without an additional contribution by synaptic plasticity (SP). The adaptation of the spike response may result in either "positive" or "negative" pattern learning. However, read-out of stored information depends on a distributed pattern of synaptic activity to let intrinsic variability determine spike response. We briefly discuss the implications of this conditional memory on learning and addiction.Comment: 20 pages, 8 figure

Imaging Mass Spectrometry: Hype or Hope?

Imaging mass spectrometry is currently receiving a significant amount of attention in the mass spectrometric community. It offers the potential of direct examination of biomolecular patterns from cells and tissue. This makes it a seemingly ideal tool for biomedical diagnostics and molecular histology. It is able to generate beautiful molecular images from a large variety of surfaces, ranging from cancer tissue sections to polished cross sections from old-master paintings. What are the parameters that define and control the implications, challenges, opportunities, and (im)possibilities associated with the application of imaging MS to biomedical tissue studies. Is this just another technological hype or does it really offer the hope to gain new insights in molecular processes in living tissue? In this critical insight this question is addressed through the discussion of a number of aspects of MS imaging technology and sample preparation that strongly determine the outcome of imaging MS experiments