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Experience sculpts brain structure and function. Activity-dependent modulation of the myelinated infrastructure of the nervous system has emerged as a dimension of adaptive change during childhood development and in adulthood. Myelination is a richly dynamic process, with neuronal activity regulating oligodendrocyte precursor cell proliferation, oligodendrogenesis and myelin structural changes in some axonal subtypes and in some regions of the nervous system. This myelin plasticity and consequent changes to conduction velocity and circuit dynamics can powerfully influence neurological functions, including learning and memory. Conversely, disruption of the mechanisms mediating adaptive myelination can contribute to cognitive impairment. The robust effects of neuronal activity on normal oligodendroglial precursor cells, a putative cellular origin for many forms of glioma, indicates that dysregulated or ‘hijacked’ mechanisms of myelin plasticity could similarly promote growth in this devastating group of brain cancers. Indeed, neuronal activity promotes the pathogenesis of many forms of glioma in preclinical models through activity-regulated paracrine factors and direct neuron-to-glioma synapses. This synaptic integration of glioma into neural circuits is central to tumour growth and invasion. Thus, not only do neuron–oligodendroglial interactions modulate neural circuit structure and function in the healthy brain, but neuron–glioma interactions also have important roles in the pathogenesis of glial malignancies.Neuron–oligodendroglial interactions modulate neural circuit structure and function in the healthy brain. In this Review, Taylor and Monje describe the accumulating evidence for how glial malignancies subvert and repurpose these powerful neuron–glial interactions to drive glioma pathophysiology.

The Best American Mystery Stories 2016 is a feast of both literary crime and hard-boiled detection, featuring a seemingly innocent murderer, a drug dealer in love, a drunken prank gone terribly wrong, and plenty of other surprising twists and turns.

This review explains the origin of the LIV-1 family of zinc transporters, paying attention to how this family of nine human proteins was originally discovered. Structural and functional differences between these nine human LIV-1 family members and the five other ZIP transporters are examined. These differences are both related to aspects of the protein sequence, the conservation of important motifs and to the effect this may have on their overall function. The LIV-1 family are dependent on various post-translational modifications, such as phosphorylation and cleavage, which play an important role in their ability to transport zinc. These modifications and their implications are discussed in detail. Some of these proteins have been implicated in cancer which is examined. Furthermore, some additional areas of potential fruitful discovery are discussed and suggested as worthy of examination in the future.

A combined forecast from multiple models is typically more accurate than an individual forecast, but there are few examples of studies of combining in infectious disease forecasting. We investigated the accuracy of different ways of combining interval forecasts of weekly incident and cumulative coronavirus disease-2019 (COVID-19) mortality. We considered weekly interval forecasts, for 1- to 4-week prediction horizons, with out-of-sample periods of approximately 18 months ending on 8 January 2022, for multiple locations in the United States, using data from the COVID-19 Forecast Hub. Our comparison involved simple and more complex combining methods, including methods that involve trimming outliers or performance-based weights. Prediction accuracy was evaluated using interval scores, weighted interval scores, skill scores, ranks, and reliability diagrams. The weighted inverse score and median combining methods performed best for forecasts of incident deaths. Overall, the leading inverse score method was 12% better than the mean benchmark method in forecasting the 95% interval and, considering all interval forecasts, the median was 7% better than the mean. Overall, the median was the most accurate method for forecasts of cumulative deaths. Compared to the mean, the median's accuracy was 65% better in forecasting the 95% interval, and 43% better considering all interval forecasts. For all combining methods except the median, combining forecasts from only compartmental models produced better forecasts than combining forecasts from all models. Combining forecasts can improve the contribution of probabilistic forecasting to health policy decision making during epidemics. The relative performance of combining methods depends on the extent of outliers and the type of models in the combination. The median combination has the advantage of being robust to outlying forecasts. Our results support the Hub's use of the median and we recommend further investigation into the use of weighted methods.

Chris Jones, Jacques Grill and colleagues report the identification of recurrent activating mutations in ACVR1 in diffuse intrinsic pontine gliomas. Diffuse intrinsic pontine gliomas (DIPGs) are highly infiltrative malignant glial neoplasms of the ventral pons that, due to their location within the brain, are unsuitable for surgical resection and consequently have a universally dismal clinical outcome. The median survival time is 9–12 months, with neither chemotherapeutic nor targeted agents showing substantial survival benefit in clinical trials in children with these tumors 1 . We report the identification of recurrent activating mutations in the ACVR1 gene, which encodes a type I activin receptor serine/threonine kinase, in 21% of DIPG samples. Strikingly, these somatic mutations (encoding p.Arg206His, p.Arg258Gly, p.Gly328Glu, p.Gly328Val, p.Gly328Trp and p.Gly356Asp substitutions) have not been reported previously in cancer but are identical to mutations found in the germ line of individuals with the congenital childhood developmental disorder fibrodysplasia ossificans progressiva (FOP) 2 and have been shown to constitutively activate the BMP–TGF-β signaling pathway. These mutations represent new targets for therapeutic intervention in this otherwise incurable disease.

Background Low-volume high-intensity interval training (HIT) appears to be an efficient and practical way to develop physical fitness. Objective Our objective was to estimate meta-analysed mean effects of HIT on aerobic power (maximum oxygen consumption [ V O 2max ] in an incremental test) and sprint fitness (peak and mean power in a 30-s Wingate test). Data Sources Five databases (PubMed, MEDLINE, Scopus, BIOSIS and Web of Science) were searched for original research articles published up to January 2014. Search terms included ‘high intensity’, ‘HIT’, ‘sprint’, ‘fitness’ and ‘ V O 2max ’. Study Selection Inclusion criteria were fitness assessed pre- and post-training; training period ≥2 weeks; repetition duration 30–60 s; work/rest ratio <1.0; exercise intensity described as maximal or near maximal; adult subjects aged >18 years. Data Extraction The final data set consisted of 55 estimates from 32 trials for V O 2max , 23 estimates from 16 trials for peak sprint power, and 19 estimates from 12 trials for mean sprint power. Effects on fitness were analysed as percentages via log transformation. Standard errors calculated from exact p values (where reported) or imputed from errors of measurement provided appropriate weightings. Fixed effects in the meta-regression model included type of study (controlled, uncontrolled), subject characteristics (sex, training status, baseline fitness) and training parameters (number of training sessions, repetition duration, work/rest ratio). Probabilistic magnitude-based inferences for meta-analysed effects were based on standardized thresholds for small, moderate and large changes (0.2, 0.6 and 1.2, respectively) derived from between-subject standard deviations (SDs) for baseline fitness. Results A mean low-volume HIT protocol (13 training sessions, 0.16 work/rest ratio) in a controlled trial produced a likely moderate improvement in the V O 2max of active non-athletic males (6.2 %; 90 % confidence limits ±3.1 %), when compared with control. There were possibly moderate improvements in the V O 2max of sedentary males (10.0 %; ±5.1 %) and active non-athletic females (3.6 %; ±4.3 %) and a likely small increase for sedentary females (7.3 %; ±4.8 %). The effect on the V O 2max of athletic males was unclear (2.7 %; ±4.6 %). A possibly moderate additional increase was likely for subjects with a 10 mL·kg −1 ·min −1 lower baseline V O 2max (3.8 %; ±2.5 %), whereas the modifying effects of sex and difference in exercise dose were unclear. The comparison of HIT with traditional endurance training was unclear (−1.6 %; ±4.3 %). Unexplained variation between studies was 2.0 % (SD). Meta-analysed effects of HIT on Wingate peak and mean power were unclear. Conclusions Low-volume HIT produces moderate improvements in the aerobic power of active non-athletic and sedentary subjects. More studies are needed to resolve the unclear modifying effects of sex and HIT dose on aerobic power and the unclear effects on sprint fitness.

Intervention fidelity refers to the degree to which an experimental manipulation has been implemented as intended, but simple, robust methods for quantifying fidelity have not been well documented. Therefore, we aim to illustrate a rigorous quantitative evaluation of intervention fidelity, using data collected during a high-intensity interval training intervention. Single-group measurement study. Seventeen adolescents (mean age ± standard deviation [SD] 14.0 ± 0.3 years) attended a 10-week high-intensity interval training intervention, comprising two exercise sessions per week. Sessions consisted of 4-7 45-s maximal effort repetitions, interspersed with 90-s rest. We collected heart rate data at 5-s intervals and recorded the peak heart rate for each repetition. The high-intensity exercise criterion was ≥ 90% of individual maximal heart rate. For each participant, we calculated the proportion of total exercise repetitions exceeding this threshold. A linear mixed model was applied to properly separate the variability in peak heart rate between- and within-subjects. Results are presented both as intention to treat (including missed sessions) and per protocol (only participants with 100% attendance; n=8). For intention to treat, the median (interquartile range) proportion of repetitions meeting the high-intensity criterion was 58% (42% to 68%). The mean peak heart rate was 85% of maximal, with a between-subject SD of 7.8 (95% confidence interval 5.4 to 11.3) percentage points and a within-subject SD of 15.1 (14.6 to 15.6) percentage points. For the per protocol analysis, the median proportion of high-intensity repetitions was 68% (47% to 86%). The mean peak heart rate was 91% of maximal, with between- and within-subject SDs of 3.1 (-1.3 to 4.6) and 3.4 (3.2 to 3.6) percentage points, respectively. Synthesising information on exercise session attendance and compliance (exercise intensity) quantifies the intervention dose and informs evaluations of treatment fidelity.

High-grade gliomas are lethal brain cancers whose progression is robustly regulated by neuronal activity. Activity-regulated release of growth factors promotes glioma growth, but this alone is insufficient to explain the effect that neuronal activity exerts on glioma progression. Here we show that neuron and glioma interactions include electrochemical communication through bona fide AMPA receptor-dependent neuron–glioma synapses. Neuronal activity also evokes non-synaptic activity-dependent potassium currents that are amplified by gap junction-mediated tumour interconnections, forming an electrically coupled network. Depolarization of glioma membranes assessed by in vivo optogenetics promotes proliferation, whereas pharmacologically or genetically blocking electrochemical signalling inhibits the growth of glioma xenografts and extends mouse survival. Emphasizing the positive feedback mechanisms by which gliomas increase neuronal excitability and thus activity-regulated glioma growth, human intraoperative electrocorticography demonstrates increased cortical excitability in the glioma-infiltrated brain. Together, these findings indicate that synaptic and electrical integration into neural circuits promotes glioma progression. Neurons form synapses onto glioma cells, and depolarization of glioma membranes promotes glioma growth in vivo, whereas blocking electrochemical signalling blocks tumour growth.

The role of the nervous system in the regulation of cancer is increasingly appreciated. In gliomas, neuronal activity drives tumour progression through paracrine signalling factors such as neuroligin-3 and brain-derived neurotrophic factor 1 – 3 (BDNF), and also through electrophysiologically functional neuron-to-glioma synapses mediated by AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors 4 , 5 . The consequent glioma cell membrane depolarization drives tumour proliferation 4 , 6 . In the healthy brain, activity-regulated secretion of BDNF promotes adaptive plasticity of synaptic connectivity 7 , 8 and strength 9 – 15 . Here we show that malignant synapses exhibit similar plasticity regulated by BDNF. Signalling through the receptor tropomyosin-related kinase B 16 (TrkB) to CAMKII, BDNF promotes AMPA receptor trafficking to the glioma cell membrane, resulting in increased amplitude of glutamate-evoked currents in the malignant cells. Linking plasticity of glioma synaptic strength to tumour growth, graded optogenetic control of glioma membrane potential demonstrates that greater depolarizing current amplitude promotes increased glioma proliferation. This potentiation of malignant synaptic strength shares mechanistic features with synaptic plasticity 17 – 22 that contributes to memory and learning in the healthy brain 23 – 26 . BDNF–TrkB signalling also regulates the number of neuron-to-glioma synapses. Abrogation of activity-regulated BDNF secretion from the brain microenvironment or loss of glioma TrkB expression robustly inhibits tumour progression. Blocking TrkB genetically or pharmacologically abrogates these effects of BDNF on glioma synapses and substantially prolongs survival in xenograft models of paediatric glioblastoma and diffuse intrinsic pontine glioma. Together, these findings indicate that BDNF–TrkB signalling promotes malignant synaptic plasticity and augments tumour progression. In glioma, malignant synapses hijack mechanisms of synaptic plasticity to increase glutamate-dependent currents in tumour cells and the formation of neuron–glioma synapses, thereby promoting tumour proliferation and progression.