The to date largest comparative study of nine state-of-the-art drug target prediction methods finds that deep learning outperforms all other competitors. The results are based on a benchmark of 1300 assays and half a million compounds.

NMDA receptors promote neuronal survival but also cause cell degeneration and neuron loss. The mechanisms underlying these opposite effects on neuronal fate are unknown. Whole-genome expression profiling revealed that NMDA receptor signaling is decoded at the genomic level through activation of two distinct, largely nonoverlapping gene-expression programs. The location of the NMDA receptor activated specifies the transcriptional response: synaptic NMDA receptors induce a coordinate upregulation of newly identified pro-survival genes and downregulation of pro-death genes. Extrasynaptic NMDA receptors fail to activate this neuroprotective program, but instead induce expression of Clca1, a putative calcium-activated chloride channel that kills neurons. These results help explain the opposing roles of synaptic and extrasynaptic NMDA receptors on neuronal fate. They also demonstrate that the survival function is implemented in neurons through a multicomponent system of functionally related genes, whose coordinate expression is controlled by specific calcium signal initiation sites.

In both academia and the pharmaceutical industry, large-scale assays for drug discovery are expensive and often impractical, particularly for the increasingly important physiologically relevant model systems that require primary cells, organoids, whole organisms, or expensive or rare reagents. We hypothesized that data from a single high-throughput imaging assay can be repurposed to predict the biological activity of compounds in other assays, even those targeting alternate pathways or biological processes. Indeed, quantitative information extracted from a three-channel microscopy-based screen for glucocorticoid receptor translocation was able to predict assay-specific biological activity in two ongoing drug discovery projects. In these projects, repurposing increased hit rates by 50- to 250-fold over that of the initial project assays while increasing the chemical structure diversity of the hits. Our results suggest that data from high-content screens are a rich source of information that can be used to predict and replace customized biological assays.

Self-assembled bilayer membranes have a remarkable inclination to form closed shells or vesicles. This bilayer-vesicle transition has been shown experimentally and by various kinds of computer simulation techniques. Here we study this transition using coarse-grained molecular dynamics. The advantage of this simulation technique is that it allows for a detailed analysis of the transition, such as changes of the internal energy. Generally it is assumed that the bilayer-vesicle transition is driven by minimization of the edge energy. However, our simulations, which include solvent particles, show an increase in the potential energy of the system during the transition, implicating that the transition is not energy but entropy driven.

BackgroundRecent studies designed to identify the mechanism by which retinal horizontal cells communicate with cones have implicated two processes. According to one account, horizontal cell hyperpolarization induces an increase in pH within the synaptic cleft that activates the calcium current (Ca2+-current) in cones, enhancing transmitter release. An alternative account suggests that horizontal cell hyperpolarization increases the Ca2+-current to promote transmitter release through a hemichannel-mediated ephaptic mechanism.Methodology/Principal FindingsTo distinguish between these mechanisms, we interfered with the pH regulating systems in the retina and studied the effects on the feedback responses of cones and horizontal cells. We found that the pH buffers HEPES and Tris partially inhibit feedback responses in cones and horizontal cells and lead to intracellular acidification of neurons. Application of 25 mM acetate, which does not change the extracellular pH buffer capacity, does lead to both intracellular acidification and inhibition of feedback. Because intracellular acidification is known to inhibit hemichannels, the key experiment used to test the pH hypothesis, i.e. increasing the extracellular pH buffer capacity, does not discriminate between a pH-based feedback system and a hemichannel-mediated feedback system. To test the pH hypothesis in a manner independent of artificial pH-buffer systems, we studied the effect of interfering with the endogenous pH buffer, the bicarbonate/carbonic anhydrase system. Inhibition of carbonic anhydrase allowed for large changes in pH in the synaptic cleft of bipolar cell terminals and cone terminals, but the predicted enhancement of the cone feedback responses, according to the pH-hypothesis, was not observed. These experiments thus failed to support a proton mediated feedback mechanism. The alternative hypothesis, the hemichannel-mediated ephaptic feedback mechanism, was therefore studied experimentally, and its feasibility was buttressed by means of a quantitative computer model of the cone/horizontal cell synapse.ConclusionWe conclude that the data presented in this paper offers further support for physiologically relevant ephaptic interactions in the retina.

In the vertebrate retina, horizontal cells generate the inhibitory surround of bipolar cells, an essential step in contrast enhancement. For the last decades, the mechanism involved in this inhibitory synaptic pathway has been a major controversy in retinal research. One hypothesis suggests that connexin hemichannels mediate this negative feedback signal; another suggests that feedback is mediated by protons. Mutant zebrafish were generated that lack connexin 55.5 hemichannels in horizontal cells. Whole cell voltage clamp recordings were made from isolated horizontal cells and cones in flat mount retinas. Light-induced feedback from horizontal cells to cones was reduced in mutants. A reduction of feedback was also found when horizontal cells were pharmacologically hyperpolarized but was absent when they were pharmacologically depolarized. Hemichannel currents in isolated horizontal cells showed a similar behavior. The hyperpolarization-induced hemichannel current was strongly reduced in the mutants while the depolarization-induced hemichannel current was not. Intracellular recordings were made from horizontal cells. Consistent with impaired feedback in the mutant, spectral opponent responses in horizontal cells were diminished in these animals. A behavioral assay revealed a lower contrast-sensitivity, illustrating the role of the horizontal cell to cone feedback pathway in contrast enhancement. Model simulations showed that the observed modifications of feedback can be accounted for by an ephaptic mechanism. A model for feedback, in which the number of connexin hemichannels is reduced to about 40%, fully predicts the specific asymmetric modification of feedback. To our knowledge, this is the first successful genetic interference in the feedback pathway from horizontal cells to cones. It provides direct evidence for an unconventional role of connexin hemichannels in the inhibitory synapse between horizontal cells and cones. This is an important step in resolving a long-standing debate about the unusual form of (ephaptic) synaptic transmission between horizontal cells and cones in the vertebrate retina.

Key points• The GABAergic pathway modulates feedback between retinal horizontal cells (HCs) and cone photoreceptors, but is not mediating negative feedback, as previously hypothesized.• Opening of GABA-gated chloride channels in cone photoreceptors reduces the amplitude of feedback responses generated by HCs.• Activation of a different presynaptic chloride current, the calcium-dependent chloride current, in individual cones has a similar effect on feedback as application of GABA.• Modulation of the strength of feedback from HCs seems to be a general consequence of activation of presynaptic chloride currents in cones.• This puts the functional role of these currents in a new perspective; GABA acts as a slow and global neuromodulator enhancing feedback in the light-and attenuating feedback in the dark-adapted retina, whereas the calcium-dependent chloride current modulates feedback fast and locally to tune the size of feedback to local light conditions. AbstractIn neuronal systems, excitation and inhibition must be well balanced to ensure reliable information transfer. The cone/horizontal cell (HC) interaction in the retina is an example of this. Because natural scenes encompass an enormous intensity range both in temporal and spatial domains, the balance between excitation and inhibition in the outer retina needs to be adaptable. How this is achieved is unknown. Using electrophysiological techniques in the isolated retina of the goldfish, it was found that opening Ca 2+ -dependent Cl − channels in recorded cones reduced the size of feedback responses measured in both cones and HCs. Furthermore, we show that cones express Cl − channels that are gated by GABA released from HCs. Similar to activation of I Cl(Ca) , opening of these GABA-gated Cl − channels reduced the size of light-induced feedback responses both in cones and HCs. Conversely, application of picrotoxin, a blocker of GABA A and GABA C receptors, had the opposite effect. In addition, reducing GABA release from HCs by blocking GABA transporters also led to an increase in the size of feedback. Because the independent manipulation of Ca 2+ -dependent Cl − currents in individual cones yielded results comparable to bath-applied GABA, it was concluded that activation of either Cl − current by itself is sufficient to reduce the size of HC feedback. However, additional effects of GABA on outer retinal processing cannot be excluded. These results can be accounted for by an ephaptic feedback model in which a cone Cl − current shunts the current flow in the synaptic cleft. The Ca 2+ -dependent Cl − current might be essential to set the initial balance between the feedforward and the feedback signals active in the cone HC synapse. It prevents that strong feedback from HCs to cones flood the cone with Ca 2+ . Modulation of the feedback strength by GABA might play a role during light/dark adaptation, adjusting the amount of negative feedback to the signal to noise ratio of the cone output.

In the context of drug discovery, a key problem is the identification of candidate molecules that affect proteins associated with diseases. Inside Janssen Pharmaceutica, the Chemogenomics project aims to derive new candidates from existing experiments through a set of machine learning predictor programs, written in single-node C++. These programs take a long time to run and are inherently parallel, but do not use multiple nodes. We show how we reimplemented the pipeline using Apache Spark, which enabled us to lift the existing programs to a multi-node cluster without making changes to the predictors. We have benchmarked our Spark pipeline against the original, which shows almost linear speedup up to 8 nodes. In addition, our pipeline generates fewer intermediate files while allowing easier checkpointing and monitoring. 2015 15th IEEE/ACM International Symposium on Cluster, Cloud and Grid Computing 978-1-4799-8006-2/15 $31.00