Integrating Heterogeneous Odor Response Data into a Common Response Model: A DoOR to the Complete Olfactome

We have developed a new computational framework for merging odor response data sets from heterogeneous studies, creating a consensus metadatabase, the database of odor responses (DoOR). As a result, we obtained a functional atlas of all available odor responses in Drosophila melanogaster. Both the program and the data set are freely accessible and downloadable on the Internet (http://neuro.uni-konstanz.de/DoOR). The procedure can be adapted to other species, thus creating a family of “olfactomes” in the near future. Drosophila melanogaster was chosen because of all species this one is closest to having the complete olfactome characterized, with the highest number of deorphanized receptors available. The database guarantees long-term stability (by offering time-stamped, downloadable versions), up-to-date accuracy (by including new data sets as soon as they are published), and portability (for other species). We hope that this comprehensive repository of odor response profiles will be useful to the olfactory community and to computational neuroscientists alike

Translating Research on Myoelectric Control into Clinics-Are the Performance Assessment Methods Adequate?

Missing an upper limb dramatically impairs daily-life activities. Significant efforts in overcoming the issues arising from this disability have been made in both academia and industry, although their clinical outcome is still limited. Translation of prosthetic research into clinics has been challenging because of the difficulties in meeting the necessary requirements of the market. In this perspective, we focus on myocontrol algorithms for upper limb prostheses and we emphasize that one relevant factor determining the relatively small clinical impact of these methods is the limit of commonly used laboratory performance metrics. The laboratory conditions, in which the majority of the solutions are being evaluated, fail to sufficiently replicate real-life challenges. We qualitatively substantiate this argument with data from seven transradial amputees. Their ability to control a myoelectric prosthesis was tested by measuring the accuracy of offline EMG signal classification, as a typical laboratory performance metrics, as well as by clinical scores when performing standard tests of daily living. Despite all subjects reached relatively high classification accuracy offline, their clinical scores were largely different and were not strongly predicted by classification accuracy. As argued in previous reports, we reinforce the suggestion to test myocontrol systems using clinical tests on amputees, fully fitted with sockets and prostheses highly resembling the systems they would use in daily living, as evaluation benchmark. Agreement on this level of testing for systems developed in research laboratories would facilitate clinically relevant progresses in this field.<br

Structure-Based Development of Small Molecule PFKFB3 Inhibitors: A Framework for Potential Cancer Therapeutic Agents Targeting the Warburg Effect

Cancer cells adopt glycolysis as the major source of metabolic energy production for fast cell growth. The HIF-1-induced PFKFB3 plays a key role in this adaptation by elevating the concentration of Fru-2,6-BP, the most potent glycolysis stimulator. As this metabolic conversion has been suggested to be a hallmark of cancer, PFKFB3 has emerged as a novel target for cancer chemotherapy. Here, we report that a small molecular inhibitor, N4A, was identified as an initial lead compound for PFKFB3 inhibitor with therapeutic potential. In an attempt to improve its potency, we determined the crystal structure of the PFKFB3•N4A complex to 2.4 Å resolution and, exploiting the resulting molecular information, attained the more potent YN1. When tested on cultured cancer cells, both N4A and YN1 inhibited PFKFB3, suppressing the Fru-2,6-BP level, which in turn suppressed glycolysis and, ultimately, led to cell death. This study validates PFKFB3 as a target for new cancer therapies and provides a framework for future development efforts

Diffusive coupling can discriminate between similar reaction mechanisms in an allosteric enzyme system

<p>Abstract</p> <p>Background</p> <p>A central question for the understanding of biological reaction networks is how a particular dynamic behavior, such as bistability or oscillations, is realized at the molecular level. So far this question has been mainly addressed in well-mixed reaction systems which are conveniently described by ordinary differential equations. However, much less is known about how molecular details of a reaction mechanism can affect the dynamics in diffusively coupled systems because the resulting partial differential equations are much more difficult to analyze.</p> <p>Results</p> <p>Motivated by recent experiments we compare two closely related mechanisms for the product activation of allosteric enzymes with respect to their ability to induce different types of reaction-diffusion waves and stationary Turing patterns. The analysis is facilitated by mapping each model to an associated complex Ginzburg-Landau equation. We show that a sequential activation mechanism, as implemented in the model of Monod, Wyman and Changeux (MWC), can generate inward rotating spiral waves which were recently observed as glycolytic activity waves in yeast extracts. In contrast, in the limiting case of a simple Hill activation, the formation of inward propagating waves is suppressed by a Turing instability. The occurrence of this unusual wave dynamics is not related to the magnitude of the enzyme cooperativity (as it is true for the occurrence of oscillations), but to the sensitivity with respect to changes of the activator concentration. Also, the MWC mechanism generates wave patterns that are more stable against long wave length perturbations.</p> <p>Conclusions</p> <p>This analysis demonstrates that amplitude equations, which describe the spatio-temporal dynamics near an instability, represent a valuable tool to investigate the molecular effects of reaction mechanisms on pattern formation in spatially extended systems. Using this approach we have shown that the occurrence of inward rotating spiral waves in glycolysis can be explained in terms of an MWC, but not with a Hill mechanism for the activation of the allosteric enzyme phosphofructokinase. Our results also highlight the importance of enzyme oligomerization for a possible experimental generation of Turing patterns in biological systems.</p

DoOR.functions v2.0.0

<p>A comprehensive update to data and functions of the DoOR project. Please see the publication for more details: http://dx.doi.org/10.1038/srep21841</p

TGF-β signalling is required for CD4⁺ T cell homeostasis but dispensable for regulatory T cell function

TGF-β is widely held to be critical for the maintenance and function of regulatory T (T(reg)) cells and thus peripheral tolerance. This is highlighted by constitutive ablation of TGF-β receptor (TR) during thymic development in mice, which leads to a lethal autoimmune syndrome. Here we describe that TGF-β-driven peripheral tolerance is not regulated by TGF-β signalling on mature CD4⁺ T cells. Inducible TR2 ablation specifically on CD4⁺ T cells did not result in a lethal autoinflammation. Transfer of these TR2-deficient CD4⁺ T cells to lymphopenic recipients resulted in colitis, but not overt autoimmunity. In contrast, thymic ablation of TR2 in combination with lymphopenia led to lethal multi-organ inflammation. Interestingly, deletion of TR2 on mature CD4⁺ T cells does not result in the collapse of the T(reg) cell population as observed in constitutive models. Instead, a pronounced enlargement of both regulatory and effector memory T cell pools was observed. This expansion is cell-intrinsic and seems to be caused by increased T cell receptor sensitivity independently of common gamma chain-dependent cytokine signals. The expression of Foxp3 and other regulatory T cells markers was not dependent on TGF-β signalling and the TR2-deficient T(reg) cells retained their suppressive function both in vitro and in vivo. In summary, absence of TGF-β signalling on mature CD4⁺ T cells is not responsible for breakdown of peripheral tolerance, but rather controls homeostasis of mature T cells in adult mice