Freier Wille und Naturgesetze: Überlegungen zum Konsequenzargument

In this paper, we argue that the Consequence Argument relies on empirical premises. In particular, we show how the argument depends upon assumptions about the character of the laws of nature

Phosducin induces a structural change in transducin βγ

AbstractBackground: Phosducin binds tightly to the βγ subunits (Gtβγ) of the heterotrimeric G protein transducin, preventing Gtβγ reassociation with Gtα–GDP and thereby inhibiting the G-protein cycle. Phosducin-like proteins appear to be widely distributed and may play important roles in regulating many heterotrimeric G-protein signaling pathways.Results: The 2.8 å crystal structure of a complex of bovine retinal phosducin with Gtβγ shows how the two domains of phosducin cover one side and the top of the seven-bladed β propeller of Gtβγ. The binding of phosducin induces a distinct structural change in the β propeller of Gtβγ, such that a small cavity opens up between blades 6 and 7. Electron density in this cavity has been assigned to the farnesyl moiety of the γ subunit.Conclusions: βγ subunits of heterotrimeric G proteins can exist in two distinct conformations. In the R (relaxed) state, corresponding to the structure of the free βγ or the structure of βγ in the αβγ heterotrimer, the hydrophobic farnesyl moiety of the γ subunit is exposed, thereby mediating membrane association. In the T (tense) state, as observed in the phosducin–Gtβγ structure, the farnesyl moiety of the γ subunit is effectively buried in the cavity formed between blades 6 and 7 of the β subunit. Binding of phosducin to Gtβγ induces the formation of this cavity, resulting in a switch from the R to the T conformation. This sequesters βγ from the membrane to the cytosol and turns off the signal-transduction cascade. Regulation of this membrane association/dissociation switch of Gtβγ by phosducin may be a general mechanism for attenuation of G protein coupled signal transduction cascades

Are We Free to Make the Laws?

Humeans about laws maintain that laws of nature are nothing over and above the complete distribution of non-modal, categorical properties in spacetime. ‘Humean compatibilists’ argue that if Humeanism about laws is true, then agents in a deterministic world can do otherwise than they are lawfully determined to do because of the distinctive nature of Humean laws. More specifically, they reject a central premise of the Consequence argument by maintaining that deterministic laws of nature are ‘up to us’. In this paper, we present a new argument for Humean compatibilism. We argue that Humeans about laws indeed have resources for defending compatibilism that non-Humeans lack (though not for the reasons typically discussed in the literature). Moreover, we show that utilizing these resources does not lead to objectionable consequences. Humeans about laws should thus embrace Humean compatibilism

NightShift: NMR shift inference by general hybrid model training - a framework for NMR chemical shift prediction

BACKGROUND: NMR chemical shift prediction plays an important role in various applications in computational biology. Among others, structure determination, structure optimization, and the scoring of docking results can profit from efficient and accurate chemical shift estimation from a three-dimensional model. A variety of NMR chemical shift prediction approaches have been presented in the past, but nearly all of these rely on laborious manual data set preparation and the training itself is not automatized, making retraining the model, e.g., if new data is made available, or testing new models a time-consuming manual chore. RESULTS: In this work, we present the framework NightShift (NMR Shift Inference by General Hybrid Model Training), which enables automated data set generation as well as model training and evaluation of protein NMR chemical shift prediction. In addition to this main result – the NightShift framework itself – we describe the resulting, automatically generated, data set and, as a proof-of-concept, a random forest model called Spinster that was built using the pipeline. CONCLUSION: By demonstrating that the performance of the automatically generated predictors is at least en par with the state of the art, we conclude that automated data set and predictor generation is well-suited for the design of NMR chemical shift estimators. The framework can be downloaded from https://bitbucket.org/akdehof/nightshift. It requires the open source Biochemical Algorithms Library (BALL), and is available under the conditions of the GNU Lesser General Public License (LGPL). We additionally offer a browser-based user interface to our NightShift instance employing the Galaxy framework via https://ballaxy.bioinf.uni-sb.de/

Patent: Methods of Treating FGF21-Associated Disorders

The invention relates to the identification of new polypeptide and protein variants of fibroblast growth factor 21 (FGF21) that have improved pharmaceutical properties. Also disclosed are methods for treating FGF21-associated disorders, includ ing metabolic conditions

Patent: Dual Function Proteins for Treating Metabolic Disorders

The present invention relates to new proteins comprising fibroblast growth factor 2 1 (FGF21 ) and other metabolic regulators known to improve metabolic profiles in subjects to whom they are administered

ESMValTool (v1.0) – a community diagnostic and performance metrics tool for routine evaluation of Earth system models in CMIP

A community diagnostics and performance metrics tool for the evaluation of Earth system models (ESMs) has been developed that allows for routine comparison of single or multiple models, either against predecessor versions or against observations. The priority of the effort so far has been to target specific scientific themes focusing on selected essential climate variables (ECVs), a range of known systematic biases common to ESMs, such as coupled tropical climate variability, monsoons, Southern Ocean processes, continental dry biases, and soil hydrology–climate interactions, as well as atmospheric CO2 budgets, tropospheric and stratospheric ozone, and tropospheric aerosols. The tool is being developed in such a way that additional analyses can easily be added. A set of standard namelists for each scientific topic reproduces specific sets of diagnostics or performance metrics that have demonstrated their importance in ESM evaluation in the peer-reviewed literature. The Earth System Model Evaluation Tool (ESMValTool) is a community effort open to both users and developers encouraging open exchange of diagnostic source code and evaluation results from the Coupled Model Intercomparison Project (CMIP) ensemble. This will facilitate and improve ESM evaluation beyond the state-of-the-art and aims at supporting such activities within CMIP and at individual modelling centres. Ultimately, we envisage running the ESMValTool alongside the Earth System Grid Federation (ESGF) as part of a more routine evaluation of CMIP model simulations while utilizing observations available in standard formats (obs4MIPs) or provided by the user

Rapid dissection and model-based optimization of inducible enhancers in human cells using a massively parallel reporter assay

Learning to read and write the transcriptional regulatory code is of central importance to progress in genetic analysis and engineering. Here we describe a massively parallel reporter assay (MPRA) that facilitates the systematic dissection of transcriptional regulatory elements. In MPRA, microarray-synthesized DNA regulatory elements and unique sequence tags are cloned into plasmids to generate a library of reporter constructs. These constructs are transfected into cells and tag expression is assayed by high-throughput sequencing. We apply MPRA to compare >27,000 variants of two inducible enhancers in human cells: a synthetic cAMP-regulated enhancer and the virus-inducible interferon-β enhancer. We first show that the resulting data define accurate maps of functional transcription factor binding sites in both enhancers at single-nucleotide resolution. We then use the data to train quantitative sequence-activity models (QSAMs) of the two enhancers. We show that QSAMs from two cellular states can be combined to design enhancer variants that optimize potentially conflicting objectives, such as maximizing induced activity while minimizing basal activity.National Human Genome Research Institute (U.S.) (grant R01HG004037)National Science Foundation (U.S.) ((NSF) grant PHY-0957573)National Science Foundation (U.S.) (NSF grant PHY-1022140)Broad Institut

Altered spin state equilibrium in the T309V mutant of cytochrome P450 2D6: a spectroscopic and computational study

Cytochrome P450 2D6 (CYP2D6) is one of the most important cytochromes P450 in humans. Resonance Raman data from the T309V mutant of CYP2D6 show that the substitution of the conserved I-helix threonine situated in the enzyme’s active site perturbs the heme spin equilibrium in favor of the six-coordinated low-spin species. A mechanistic hypothesis is introduced to explain the experimental observations, and its compatibility with the available structural and spectroscopic data is tested using quantum-mechanical density functional theory calculations on active-site models for both the CYP2D6 wild type and the T309V mutant