Author: Stephen V. David

The use of state-of-the-art techniques to study neuronal activity during a navigational task involving sound stimuli broadens our understanding of how neuronal populations produce complex behaviours.

Authors: Rodrigo Dienstmann & Josep Tabernero

Progress is being made in the use of personalized approaches to create both in vitro and in vivo tumour models that could be used to aid cancer drug-treatment decisions and increase our understanding of how tumours respond to therapy.

Authors: Bruce E. Kemp & Jonathan S. Oakhill

The molecule fructose-1,6-bisphosphate, which is produced during glucose metabolism, has been shown to mediate cellular sensing of glucose deprivation through an unexpected mechanism.

Authors: Azusa Inoue, Lan Jiang, Falong Lu, Tsukasa Suzuki & Yi Zhang

Authors: Robert T. Manguso, Hans W. Pope, Margaret D. Zimmer, Flavian D. Brown, Kathleen B. Yates, Brian C. Miller, Natalie B. Collins, Kevin Bi, Martin W. LaFleur, Vikram R. Juneja, Sarah A. Weiss, Jennifer Lo, David E. Fisher, Diana Miao, Eliezer Van Allen, David E. Root, Arlene H. Sharpe, John G. Doench & W. Nicholas Haining

Authors: Matthew G. Betts, Christopher Wolf, William J. Ripple, Ben Phalan, Kimberley A. Millers, Adam Duarte, Stuart H. M. Butchart & Taal Levi

Global biodiversity loss is a critical environmental crisis, yet the lack of spatial data on biodiversity threats has hindered conservation strategies. Theory predicts that abrupt biodiversity declines are most likely to occur when habitat availability is reduced to very low levels in the landscape (10–30%). Alternatively, recent evidence indicates that biodiversity is best conserved by minimizing human intrusion into intact and relatively unfragmented landscapes. Here we use recently available forest loss data to test deforestation effects on International Union for Conservation of Nature Red List categories of extinction risk for 19,432 vertebrate species worldwide. As expected, deforestation substantially increased the odds of a species being listed as threatened, undergoing recent upgrading to a higher threat category and exhibiting declining populations. More importantly, we show that these risks were disproportionately high in relatively intact landscapes; even minimal deforestation has had severe consequences for vertebrate biodiversity. We found little support for the alternative hypothesis that forest loss is most detrimental in already fragmented landscapes. Spatial analysis revealed high-risk hot spots in Borneo, the central Amazon and the Congo Basin. In these regions, our model predicts that 121–219 species will become threatened under current rates of forest loss over the next 30 years. Given that only 17.9% of these high-risk areas are formally protected and only 8.9% have strict protection, new large-scale conservation efforts to protect intact forests are necessary to slow deforestation rates and to avert a new wave of global extinctions.

Authors: Changkeun Lee, Jiangtao Guo, Weizhong Zeng, Sunghoon Kim, Ji She, Chunlei Cang, Dejian Ren & Youxing Jiang

TMEM175 is a lysosomal K+ channel that is important for maintaining the membrane potential and pH stability in lysosomes. It contains two homologous copies of a six-transmembrane-helix (6-TM) domain, which has no sequence homology to the canonical tetrameric K+ channels and lacks the TVGYG selectivity filter motif found in these channels. The prokaryotic TMEM175 channel, which is present in a subset of bacteria and archaea, contains only a single 6-TM domain and functions as a tetramer. Here, we present the crystal structure of a prokaryotic TMEM175 channel from Chamaesiphon minutus, CmTMEM175, the architecture of which represents a completely different fold from that of canonical K+ channels. All six transmembrane helices of CmTMEM175 are tightly packed within each subunit without undergoing domain swapping. The highly conserved TM1 helix acts as the pore-lining inner helix, creating an hourglass-shaped ion permeation pathway in the channel tetramer. Three layers of hydrophobic residues on the carboxy-terminal half of the TM1 helices form a bottleneck along the ion conduction pathway and serve as the selectivity filter of the channel. Mutagenesis analysis suggests that the first layer of the highly conserved isoleucine residues in the filter is primarily responsible for channel selectivity. Thus, the structure of CmTMEM175 represents a novel architecture of a tetrameric cation channel whose ion selectivity mechanism appears to be distinct from that of the classical K+ channel family.

Authors: Yu Peng, Man Zhang, Lingjun Zheng, Qian Liang, Hanzeng Li, Jeng-Ting Chen, Hongyan Guo, Sawako Yoshina, Yu-Zen Chen, Xiang Zhao, Xiaoqi Wu, Bin Liu, Shohei Mitani, Jau-Song Yu & Ding Xue

The radiation-induced bystander effect (RIBE) refers to a unique process in which factors released by irradiated cells or tissues exert effects on other parts of the animal not exposed to radiation, causing genomic instability, stress responses and altered apoptosis or cell proliferation. Although RIBEs have important implications for radioprotection, radiation safety and radiotherapy, the molecular identities of RIBE factors and their mechanisms of action remain poorly understood. Here we use Caenorhabditis elegans as a model in which to study RIBEs, and identify the cysteine protease CPR-4, a homologue of human cathepsin B, as the first RIBE factor in nematodes, to our knowledge. CPR-4 is secreted from animals irradiated with ultraviolet or ionizing gamma rays, and is the major factor in the conditioned medium that leads to the inhibition of cell death and increased embryonic lethality in unirradiated animals. Moreover, CPR-4 causes these effects and stress responses at unexposed sites distal to the irradiated tissue. The activity of CPR-4 is regulated by the p53 homologue CEP-1 in response to radiation, and CPR-4 seems to exert RIBEs by acting through the insulin-like growth factor receptor DAF-2. Our study provides crucial insights into RIBEs, and will facilitate the identification of additional RIBE factors and their mechanisms of action.

Authors: Caroline A. Runyan, Eugenio Piasini, Stefano Panzeri & Christopher D. Harvey

The cortex represents information across widely varying timescales. For instance, sensory cortex encodes stimuli that fluctuate over few tens of milliseconds, whereas in association cortex behavioural choices can require the maintenance of information over seconds. However, it remains poorly understood whether diverse timescales result mostly from features intrinsic to individual neurons or from neuronal population activity. This question remains unanswered, because the timescales of coding in populations of neurons have not been studied extensively, and population codes have not been compared systematically across cortical regions. Here we show that population codes can be essential to achieve long coding timescales. Furthermore, we find that the properties of population codes differ between sensory and association cortices. We compared coding for sensory stimuli and behavioural choices in auditory cortex and posterior parietal cortex as mice performed a sound localization task. Auditory stimulus information was stronger in auditory cortex than in posterior parietal cortex, and both regions contained choice information. Although auditory cortex and posterior parietal cortex coded information by tiling in time neurons that were transiently informative for approximately 200 milliseconds, the areas had major differences in functional coupling between neurons, measured as activity correlations that could not be explained by task events. Coupling among posterior parietal cortex neurons was strong and extended over long time lags, whereas coupling among auditory cortex neurons was weak and short-lived. Stronger coupling in posterior parietal cortex led to a population code with long timescales and a representation of choice that remained consistent for approximately 1 second. In contrast, auditory cortex had a code with rapid fluctuations in stimulus and choice information over hundreds of milliseconds. Our results reveal that population codes differ across cortex and that coupling is a variable property of cortical populations that affects the timescale of information coding and the accuracy of behaviour.

Authors: Chen-Song Zhang, Simon A. Hawley, Yue Zong, Mengqi Li, Zhichao Wang, Alexander Gray, Teng Ma, Jiwen Cui, Jin-Wei Feng, Mingjiang Zhu, Yu-Qing Wu, Terytty Yang Li, Zhiyun Ye, Shu-Yong Lin, Huiyong Yin, Hai-Long Piao, D. Grahame Hardie & Sheng-Cai Lin

The major energy source for most cells is glucose, from which ATP is generated via glycolysis and/or oxidative metabolism. Glucose deprivation activates AMP-activated protein kinase (AMPK), but it is unclear whether this activation occurs solely via changes in AMP or ADP, the classical activators of AMPK. Here, we describe an AMP/ADP-independent mechanism that triggers AMPK activation by sensing the absence of fructose-1,6-bisphosphate (FBP), with AMPK being progressively activated as extracellular glucose and intracellular FBP decrease. When unoccupied by FBP, aldolases promote the formation of a lysosomal complex containing at least v-ATPase, ragulator, axin, liver kinase B1 (LKB1) and AMPK, which has previously been shown to be required for AMPK activation. Knockdown of aldolases activates AMPK even in cells with abundant glucose, whereas the catalysis-defective D34S aldolase mutant, which still binds FBP, blocks AMPK activation. Cell-free reconstitution assays show that addition of FBP disrupts the association of axin and LKB1 with v-ATPase and ragulator. Importantly, in some cell types AMP/ATP and ADP/ATP ratios remain unchanged during acute glucose starvation, and intact AMP-binding sites on AMPK are not required for AMPK activation. These results establish that aldolase, as well as being a glycolytic enzyme, is a sensor of glucose availability that regulates AMPK.

Authors: Heng Rao, Luciana C. Schmidt, Julien Bonin & Marc Robert

Converting CO2 into fuel or chemical feedstock compounds could in principle reduce fossil fuel consumption and climate-changing CO2 emissions. One strategy aims for electrochemical conversions powered by electricity from renewable sources, but photochemical approaches driven by sunlight are also conceivable. A considerable challenge in both approaches is the development of efficient and selective catalysts, ideally based on cheap and Earth-abundant elements rather than expensive precious metals. Of the molecular photo- and electrocatalysts reported, only a few catalysts are stable and selective for CO2 reduction; moreover, these catalysts produce primarily CO or HCOOH, and catalysts capable of generating even low to moderate yields of highly reduced hydrocarbons remain rare. Here we show that an iron tetraphenylporphyrin complex functionalized with trimethylammonio groups, which is the most efficient and selective molecular electro- catalyst for converting CO2 to CO known, can also catalyse the eight-electron reduction of CO2 to methane upon visible light irradiation at ambient temperature and pressure. We find that the catalytic system, operated in an acetonitrile solution containing a photosensitizer and sacrificial electron donor, operates stably over several days. CO is the main product of the direct CO2 photoreduction reaction, but a two-pot procedure that first reduces CO2 and then reduces CO generates methane with a selectivity of up to 82 per cent and a quantum yield (light-to-product efficiency) of 0.18 per cent. However, we anticipate that the operating principles of our system may aid the development of other molecular catalysts for the production of solar fuels from CO2 under mild conditions.

Author: John O. Dabiri

Hair-like sensors are suspected to aid fish navigation in complex environments. Laboratory experiments and computational simulations reveal how these sensors can detect water flow to direct the swimming responses of fish.

Authors: Tobias Rose & Mark Hübener

A sophisticated analysis in mice of how inputs to neurons from other neurons are distributed across individual cells of the brain's visual cortex provides information about how mammalian vision is processed.

Authors: M. Florencia Iacaruso, Ioana T. Gasler & Sonja B. Hofer

How a sensory stimulus is processed and perceived depends on the surrounding sensory scene. In the visual cortex, contextual signals can be conveyed by an extensive network of intra- and inter-areal excitatory connections that link neurons representing stimulus features separated in visual space. However, the connectional logic of visual contextual inputs remains unknown; it is not clear what information individual neurons receive from different parts of the visual field, nor how this input relates to the visual features that a neuron encodes, defined by its spatial receptive field. Here we determine the organization of excitatory synaptic inputs responding to different locations in the visual scene by mapping spatial receptive fields in dendritic spines of mouse visual cortex neurons using two-photon calcium imaging. We find that neurons receive functionally diverse inputs from extended regions of visual space. Inputs representing similar visual features from the same location in visual space are more likely to cluster on neighbouring spines. Inputs from visual field regions beyond the receptive field of the postsynaptic neuron often synapse on higher-order dendritic branches. These putative long-range inputs are more frequent and more likely to share the preference for oriented edges with the postsynaptic neuron when the receptive field of the input is spatially displaced along the axis of the receptive field orientation of the postsynaptic neuron. Therefore, the connectivity between neurons with displaced receptive fields obeys a specific rule, whereby they connect preferentially when their receptive fields are co-oriented and co-axially aligned. This organization of synaptic connectivity is ideally suited for the amplification of elongated edges, which are enriched in the visual environment, and thus provides a potential substrate for contour integration and object grouping.

Authors: Pablo Oteiza, Iris Odstrcil, George Lauder, Ruben Portugues & Florian Engert

When flying or swimming, animals must adjust their own movement to compensate for displacements induced by the flow of the surrounding air or water. These flow-induced displacements can most easily be detected as visual whole-field motion with respect to the animal’s frame of reference. Despite this, many aquatic animals consistently orient and swim against oncoming flows (a behaviour known as rheotaxis) even in the absence of visual cues. How animals achieve this task, and its underlying sensory basis, is still unknown. Here we show that, in the absence of visual information, larval zebrafish (Danio rerio) perform rheotaxis by using flow velocity gradients as navigational cues. We present behavioural data that support a novel algorithm based on such local velocity gradients that fish use to avoid getting dragged by flowing water. Specifically, we show that fish use their mechanosensory lateral line to first sense the curl (or vorticity) of the local velocity vector field to detect the presence of flow and, second, to measure its temporal change after swim bouts to deduce flow direction. These results reveal an elegant navigational strategy based on the sensing of flow velocity gradients and provide a comprehensive behavioural algorithm, also applicable for robotic design, that generalizes to a wide range of animal behaviours in moving fluids.

Authors: Tian Hua, Kiran Vemuri, Spyros P. Nikas, Robert B. Laprairie, Yiran Wu, Lu Qu, Mengchen Pu, Anisha Korde, Shan Jiang, Jo-Hao Ho, Gye Won Han, Kang Ding, Xuanxuan Li, Haiguang Liu, Michael A. Hanson, Suwen Zhao, Laura M. Bohn, Alexandros Makriyannis, Raymond C. Stevens & Zhi-Jie Liu

The cannabinoid receptor 1 (CB1) is the principal target of the psychoactive constituent of marijuana, the partial agonist Δ9-tetrahydrocannabinol (Δ9-THC). Here we report two agonist-bound crystal structures of human CB1 in complex with a tetrahydrocannabinol (AM11542) and a hexahydrocannabinol (AM841) at 2.80 Å and 2.95 Å resolution, respectively. The two CB1–agonist complexes reveal important conformational changes in the overall structure, relative to the antagonist-bound state, including a 53% reduction in the volume of the ligand-binding pocket and an increase in the surface area of the G-protein-binding region. In addition, a ‘twin toggle switch’ of Phe2003.36 and Trp3566.48 (superscripts denote Ballesteros–Weinstein numbering) is experimentally observed and appears to be essential for receptor activation. The structures reveal important insights into the activation mechanism of CB1 and provide a molecular basis for predicting the binding modes of Δ9-THC, and endogenous and synthetic cannabinoids. The plasticity of the binding pocket of CB1 seems to be a common feature among certain class A G-protein-coupled receptors. These findings should inspire the design of chemically diverse ligands with distinct pharmacological properties.

Authors: Vasanthi S. Viswanathan, Matthew J. Ryan, Harshil D. Dhruv, Shubhroz Gill, Ossia M. Eichhoff, Brinton Seashore-Ludlow, Samuel D. Kaffenberger, John K. Eaton, Kenichi Shimada, Andrew J. Aguirre, Srinivas R. Viswanathan, Shrikanta Chattopadhyay, Pablo Tamayo, Wan Seok Yang, Matthew G. Rees, Sixun Chen, Zarko V. Boskovic, Sarah Javaid, Cherrie Huang, Xiaoyun Wu, Yuen-Yi Tseng, Elisabeth M. Roider, Dong Gao, James M. Cleary, Brian M. Wolpin, Jill P. Mesirov, Daniel A. Haber, Jeffrey A. Engelman, Jesse S. Boehm, Joanne D. Kotz, Cindy S. Hon, Yu Chen, William C. Hahn, Mitchell P. Levesque, John G. Doench, Michael E. Berens, Alykhan F. Shamji, Paul A. Clemons, Brent R. Stockwell & Stuart L. Schreiber

Plasticity of the cell state has been proposed to drive resistance to multiple classes of cancer therapies, thereby limiting their effectiveness. A high-mesenchymal cell state observed in human tumours and cancer cell lines has been associated with resistance to multiple treatment modalities across diverse cancer lineages, but the mechanistic underpinning for this state has remained incompletely understood. Here we molecularly characterize this therapy-resistant high-mesenchymal cell state in human cancer cell lines and organoids and show that it depends on a druggable lipid-peroxidase pathway that protects against ferroptosis, a non-apoptotic form of cell death induced by the build-up of toxic lipid peroxides. We show that this cell state is characterized by activity of enzymes that promote the synthesis of polyunsaturated lipids. These lipids are the substrates for lipid peroxidation by lipoxygenase enzymes. This lipid metabolism creates a dependency on pathways converging on the phospholipid glutathione peroxidase (GPX4), a selenocysteine-containing enzyme that dissipates lipid peroxides and thereby prevents the iron-mediated reactions of peroxides that induce ferroptotic cell death. Dependency on GPX4 was found to exist across diverse therapy-resistant states characterized by high expression of ZEB1, including epithelial–mesenchymal transition in epithelial-derived carcinomas, TGFβ-mediated therapy-resistance in melanoma, treatment-induced neuroendocrine transdifferentiation in prostate cancer, and sarcomas, which are fixed in a mesenchymal state owing to their cells of origin. We identify vulnerability to ferroptic cell death induced by inhibition of a lipid peroxidase pathway as a feature of therapy-resistant cancer cells across diverse mesenchymal cell-state contexts.

Author: Alexandru Florin Dobrin

The strong force binds the constituents of nuclei together. Differences between the force's fundamental interactions and their mirror images were thought to have been observed in heavy-ion collisions, but new data challenge this picture.

Author: Giorgio Gratta

Neutrinos are much lighter than the other constituents of matter. One explanation for this could be that neutrinos are their own antiparticles and belong to a new class of 'Majorana' particle. An experiment sets strong constraints on this scenario.

Authors: Peter B. deMenocal & Chris Stringer

The human dispersal out of Africa that populated the world was probably paced by climate changes. This is the inference drawn from computer modelling of climate variability during the time of early human migration.

Author: Michelle C. Barton

Underactivity of the transcription factor p53 can lead to tumour development. The discovery that the SET protein binds to and inhibits p53 points to a way to unleash the tumour suppressor's activity.

Author: David W. Pfennig

Deadly coral snakes warn predators through striking red-black banding. New data confirm that many harmless snakes have evolved to resemble coral snakes, and suggest that the evolution of this Batesian mimicry is not always a one-way street.