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Chromosomal rearrangements are key events in the pathogenesis of a range of disorders. Here the authors utilize a zinc finger nuclease translocation reporter to identify PARP3 as a regulator of these events at sites enriched for G quadruplex DNA.

Recent insights into the receptors expressed by sensory neurons are providing the beginnings of a biological basis for designing therapies to block nociceptive information before it reaches the spinal cord. This approach could potentially avoid some of the side effects in the central nervous system caused by currently available analgesics. (pages 821–826)

Davis et al. extend their previous efforts to use inhibitor-kinase interactions to understand kinase inhibitor selectivity by profiling the binding of 72 kinase inhibitors to 442 human kinase catalytic domains. The data reveal group-specific differences in selectivity and suggest the feasibility of developing reasonably specific inhibitors for most kinases.

A genome-wide association study in 293,723 individuals identifies 74 genetic variants associated with educational attainment, which, although only explaining a small proportion of the variation in educational attainment, highlights candidate genes and pathways for further study.

Boutary et al. describe siRNA based therapy conjugated with squalene nanoparticles as an efficient approach to normalize PMP22 protein levels, restore locomotor activity, electrophysiological parameters and function of myelin sheath in CMT1A mouse models. These findings could be useful to develop therapeutic strategies for inherited peripheral neuropathies.

Chemokines were discovered as cytokines that have chemotactic properties. They are receiving renewed attention, this time from neuroscientists, owing to the possibility that they might act as neurotransmitters or neuromodulators. In a provocative Opinion article, Rostène and colleages review the evidence for this possibility.

In a post-approval study including more than 17,000 patients on the safety of pulsed field ablation, a new method for treatment of atrial fibrillation, the procedure was found to have a low rate of adverse events but was associated with some unexpected rare complications that will need further study.

The authors defined a roadmap for investigating the genetic covariance between structural or functional brain phenotypes and risk for psychiatric disorders. Their proof-of-concept study using the largest available common variant data sets for schizophrenia and volumes of several (mainly subcortical) brain structures did not find evidence of genetic overlap.

Using two-photon calcium imaging, the authors found that although tonotopy was present in mouse auditory cortex at a coarse scale, it was fractured on a fine scale. Intensity tuning appeared to have no topography at all, but subthreshold responses revealed that there was some clustering of neurons with similar response properties.

In this study, the authors show that, in newborn cortical neurons, the TrkB and TrkC receptors are transactivated by the EGF receptor, rather than by their traditional ligands, BDNF and NT-3. This transactivation appears to be involved in the migration of these neurons from the ventricular zone to the cortical plate.

The dynamic localization of PLK1 to kinetochores is required for faithful chromosome segregation. Peter, Sumara and colleagues demonstrate that a KHL22-containing E3 ligase mediates degradation-independent removal of PLK1 from kinetochores to ensure satisfaction of the spindle assembly checkpoint and proper mitotic progression.

The basis of regulation of proliferation of pluripotent embryonic stem cells has been unclear. It is found that endogenous GABA receptor signalling controls proliferation of embryonic stem cells and other tissue-specific stem cell types via a mechanism that involves cell cycle proteins previously associated with cellular DNA damage responses.

Here, the authors combinein vivopatch-clamp recordings and optogenetics to show that balanced dendritic excitation and inhibition provides a sensitive ‘push-pull’ mechanism that generates the bidirectional modulation of Purkinje cell SSp output necessary for normal locomotor behaviour.

Xu et al. show that satellite-measured urbanicity (living in a densely populated area) is correlated with brain volume, cortical surface area and brain network connectivity in a sample of 3,867 people from China and Europe.

The patch-clamp technique enables probing of the gating behavior of individual ion channel proteins, but unambiguous analysis of single-channel datasets is challenging. Here, the authors present a deep learning approach for extracting Markov models from single-channel recordings.

Large genome-wide meta-analysis of clinically diagnosed late-onset Alzheimer’s disease (LOAD) from 94,437 individuals identifies new LOAD risk loci and implicates Aβ formation, tau protein binding, immune response and lipid metabolism.

Advances in the understanding of the genetic and environmental causes of schizophrenia, and their relationship to aberrant patterns of neurodevelopment, have led to growing interest in the possibility that 'disease-modifying' strategies could alter the course to — and of — this debilitating disorder, rather than just alleviating its symptoms. This article provides a broad-based consideration of the challenges and opportunities inherent in such efforts.

This study identifies distinct classes of neurons in the fly brain, which respond to external cooling, warming, or both, and contribute to behavioural response; the results illustrate how higher brain centres extract a stimulus’ quality, intensity and timing from a simple temperature map at the periphery.

To adaptively navigate their environments organisms need to predict and cancel out the sensory consequences of their actions. Here the authors show that granule cells within the cerebellum-like structure of weakly electric fish have delayed responses that closely match the timing of self-generated sensory inputs. This enables corollary discharges to be transformed into negative images that are well-tuned to the animal's own behavior.

TGFα and VEGF-B produced by microglia regulate astrocyte function in the experimental autoimmune encephalomyelitis model of multiple sclerosis.

Johannes Lemke, Holger Lerche and colleagues report the identification of de novo mutations in the potassium channel gene KCNA2 in patients with epileptic encephalopathies. The authors confirm in vitro that two mutations cause dominant loss of channel function, whereas the other two mutations induce gain-of-function effects, leading to permanently open channels.

The approval of therapies for progressive multiple sclerosis has heightened the need for thorough assessment of disease progression and treatment response. This Review provides a comprehensive summary of available and emerging techniques, including advanced imaging, fluid biomarkers and patient-reported outcomes, highlighting their combined use for the accurate assessment of disease.

Fonzo et al. found that brain activity during a form of emotional regulation predicted how well individuals with depression would respond to a common antidepressant. Brain function assays may herald a new era of precision medicine in psychiatry.

Julie Williams, Michael Owen and colleagues report staged follow-up and meta-analyses of genome-wide association studies for Alzheimer's disease from the GERAD+ consortium. They identify common variants at ABCA7 and MS4A6A/MS4A4E associated with Alzheimer's disease and support for several additional susceptibility loci.

In the thalamic reticular nucleus there are two neuron types that are segregated into central and edge zones and receive inputs from different thalamocortical nuclei, creating subcircuits with distinct dynamics.