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Table of Contents for this page:

  • Current Issue
  • Advanced Online Publications Articles

  • Current Issue of Nature

    Nature

  • New Antarctic iceberg echoes old problem

  • The break in the Larsen C ice shelf highlights the vulnerable nature of other Antarctic environments and the impact people are having on the continent.

  • All shook up over topology

  • Physicists and mathematicians have bonded over their shared explorations of bizarre states of matter.

  • Ditching diesel won’t clear the air

  • Arguments about the environmental benefits of petrol or diesel engines are outdated.

  • The DeepMind debacle demands dialogue on data

  • Mishandling of patient information shows how governments and companies must become more worthy of trust, says Hetan Shah.

  • Maryam Mirzakhani, quantum teleportation and the Great Red Spot

  • The week in science: 14–20 July 2017.

  • Satellite snafu masked true sea-level rise for decades

  • Revised tallies confirm that the rate of sea-level rise is accelerating as the Earth warms and ice sheets thaw.

  • Female astronomers of colour face daunting discrimination

  • Two-fifths report feeling unsafe at work, and 18% have concerns about attending conferences.

  • European Commission urges logging ban in ancient Białowieża Forest

  • Europe’s highest court will rule on Poland's policy that encourages tree-felling in biodiversity hotspot.

  • US lawmakers seek $1.1-billion boost for the NIH

  • Legislation introduced in the House of Representatives also rejects a White House plan to cut 'indirect cost' payments to research institutions.

  • Climate scientists flock to France’s call

  • President said‘Make Our Planet Great Again’ — and researchers signed up.

  • Engineered cell therapy for cancer gets thumbs up from FDA advisers

  • Treatment shows promise in young people with leukaemia, but safety risks abound.

  • The strange topology that is reshaping physics

  • Topological effects might be hiding inside perfectly ordinary materials, waiting to reveal bizarre new particles or bolster quantum computing.

  • Solve Antarctica’s sea-ice puzzle

  • John Turner and Josefino Comiso call for a coordinated push to crack the baffling rise and fall of sea ice around Antarctica.

  • Environment: A journey on plastic seas

  • Richard Thompson applauds a chronicle alerting the world to marine polymer pollution.

  • Books in brief

  • Barbara Kiser reviews five of the week's best science picks.

  • History: Tracking down a doomed Arctic expedition

  • Daniel Cressey surveys the remains of John Franklin's fatal 1845 voyage.

  • Second World War: Paris neurosurgeon's map outwitted Nazis

  • Neurosurgeon Jean Talairach (1911–2007) created his pioneering brain atlas with his colleague Gabor Szikla in 1967. Almost three decades earlier, he had painstakingly drawn a quite different map— of Paris's subterranean ossuaries (see 'Catacomb network under Paris'), a copy of which we recently unearthed

  • NASA: No cost crisis for space telescope

  • Your report on NASA's next large space telescope, the Wide-Field Infrared Survey Telescope (WFIRST), misleadingly implies that NASA's dark-energy probe faces a cost crisis (Nature546, 195;10.1038/546195a2017). NASA has not yet completed the work of estimating the costs of

  • Africa: Restrict bush fires used in animal hunts

  • Controlled small-scale fires are traditionally used in the African savannah to flush out small mammals for hunting. Poachers in Zimbabwe are carelessly deploying crude versions of this practice, causing unmanageable bush fires and large-scale destruction.For generations, experienced local hunters have ensured that the impact

  • Enterprise: Game on

  • Scientists are designing board, card and digital games to convey scientific concepts.

  • Turning point: Soft-skills sculptor

  • Career-building skills need not be hard to learn.

  • Catalogue of Items in the Chess Exhibition at the Humanities Museum, Pre-Enlightenment Wing

  • A unique insight into a remarkable game.

  • Gravitational waves: Stellar palaeontology

  • A third gravitational-wave signal has been detected with confidence, produced again by the merger of two black holes. The combined data from these detections help to reveal the histories of the stars that left these black holes behind.

  • Archaeology: Early signs of human presence in Australia

  • It emerges that people reached Australia earlier than was thought. This finding casts light on the technology used by the travellers, and their possible interactions with animal species that became extinct. See Article p.306

  • 50 aamp; 100 Years Ago

  • 50 Years AgoOne of the problems that continually faces electron microscopists is deciding whether organelles with the same fine structure have identical chemical composition and cellular function...does this apply to structurally simple organelles such as microtubules? Are they identical?Microtubules...occur in specifically arranged aggregates

  • Materials science: Chemistry and physics happily wed

  • A major advance in the quantum theory of solids allows materials to be identified whose electronic states have a non-trivial topology. Such materials could have many computing and electronics applications. See Article p.298

  • Immunology: Nervous crosstalk to make antibodies

  • Immune cells called T cells help immune-system B cells mature to produce antibodies. This entails signalling between cells using the molecule dopamine— a surprising immunological role for this neurotransmitter. See Article p.318

  • Imaging techniques: X-rays used to watch spins in 3D

  • Complex nanoscale magnetization patterns have been resolved in 3D using advanced X-ray microscopy. This could spur the design of magnetic devices that have unique properties and functions. See Letter p.328

  • Cancer: Keeping it real to kill glioblastoma

  • The results of in vitro and in vivo screens to identify genes that are essential for the survival of a type of brain cancer show almost no overlap, underlining the need for caution when interpreting in vitro studies. See Letter p355.

  • Ribosomes are optimized for autocatalytic production

  • Many fine-scale features of ribosomes have been explained in terms of function, revealing a molecular machine that is optimized for error-correction, speed and control. Here we demonstrate mathematically that many less well understood, larger-scale features of ribosomes—such as why a few ribosomal RNA molecules dominate

  • Topological quantum chemistry

  • Since the discovery of topological insulators and semimetals, there has been much research into predicting and experimentally discovering distinct classes of these materials, in which the topology of electronic states leads to robust surface states and electromagnetic responses. This apparent success, however, masks a fundamental

  • Human occupation of northern Australia by 65,000 years ago

  • The time of arrival of people in Australia is an unresolved question. It is relevant to debates about when modern humans first dispersed out of Africa and when their descendants incorporated genetic material from Neanderthals, Denisovans and possibly other hominins. Humans have also been implicated

  • The whole-genome landscape of medulloblastoma subtypes

  • Current therapies for medulloblastoma, a highly malignant childhood brain tumour, impose debilitating effects on the developing child, and highlight the need for molecularly targeted treatments with reduced toxicity. Previous studies have been unable to identify the full spectrum of driver genes and molecular processes that

  • TFH-derived dopamine accelerates productive synapses in germinal centres

  • Protective high-affinity antibody responses depend on competitive selection of B cells carrying somatically mutated B-cell receptors by follicular helper T (TFH) cells in germinal centres. The rapid T–B-cell interactions that occur during this process are reminiscent of neural synaptic transmission pathways. Here we

  • Experimental signatures of the mixed axial–gravitational anomaly in the Weyl semimetal NbP

  • The conservation laws, such as those of charge, energy and momentum, have a central role in physics. In some special cases, classical conservation laws are broken at the quantum level by quantum fluctuations, in which case the theory is said to have quantum anomalies. One of the most prominent examples is the chiral anomaly, which involves massless chiral fermions. These particles have their spin, or internal angular momentum, aligned either parallel or antiparallel with their linear momentum, labelled as left and right chirality, respectively. In three spatial dimensions, the chiral anomaly is the breakdown (as a result of externally applied parallel electric and magnetic fields) of the classical conservation law that dictates that the number of massless fermions of each chirality are separately conserved. The current that measures the difference between left- and right-handed particles is called the axial current and is not conserved at the quantum level. In addition, an underlying curved space-time provides a distinct contribution to a chiral imbalance, an effect known as the mixed axial–gravitational anomaly, but this anomaly has yet to be confirmed experimentally. However, the presence of a mixed gauge–gravitational anomaly has recently been tied to thermoelectrical transport in a magnetic field, even in flat space-time, suggesting that such types of mixed anomaly could be experimentally probed in condensed matter systems known as Weyl semimetals. Here, using a temperature gradient, we observe experimentally a positive magneto-thermoelectric conductance in the Weyl semimetal niobium phosphide (NbP) for collinear temperature gradients and magnetic fields that vanishes in the ultra-quantum limit, when only a single Landau level is occupied. This observation is consistent with the presence of a mixed axial–gravitational anomaly, providing clear evidence for a theoretical concept that has so far eluded experimental detection.

  • Three-dimensional magnetization structures revealed with X-ray vector nanotomography

  • In soft ferromagnetic materials, the smoothly varying magnetization leads to the formation of fundamental patterns such as domains, vortices and domain walls. These have been studied extensively in thin films of thicknesses up to around 200 nanometres, in which the magnetization is accessible with current transmission imaging methods that make use of electrons or soft X-rays. In thicker samples, however, in which the magnetization structure varies throughout the thickness and is intrinsically three dimensional, determining the complex magnetic structure directly still represents a challenge. We have developed hard-X-ray vector nanotomography with which to determine the three-dimensional magnetic configuration at the nanoscale within micrometre-sized samples. We imaged the structure of the magnetization within a soft magnetic pillar of diameter 5 micrometres with a spatial resolution of 100 nanometres and, within the bulk, observed a complex magnetic configuration that consists of vortices and antivortices that form cross-tie walls and vortex walls along intersecting planes. At the intersections of these structures, magnetic singularities—Bloch points—occur. These were predicted more than fifty years ago but have so far not been directly observed. Here we image the three-dimensional magnetic structure in the vicinity of the Bloch points, which until now has been accessible only through micromagnetic simulations, and identify two possible magnetization configurations: a circulating magnetization structure and a twisted state that appears to correspond to an ‘anti-Bloch point’. Our imaging method enables the nanoscale study of topological magnetic structures in systems with sizes of the order of tens of micrometres. Knowledge of internal nanomagnetic textures is critical for understanding macroscopic magnetic properties and for designing bulk magnets for technological applications.

  • Nitrogen reduction and functionalization by a multimetallic uranium nitride complex

  • Molecular nitrogen (N2) is cheap and widely available, but its unreactive nature is a challenge when attempting to functionalize it under mild conditions with other widely available substrates (such as carbon monoxide, CO) to produce value-added compounds. Biological N2 fixation can do this, but the industrial Haber–Bosch process for ammonia production operates under harsh conditions (450 degrees Celsius and 300 bar), even though both processes are thought to involve multimetallic catalytic sites. And although molecular complexes capable of binding and even reducing N2 under mild conditions are known, with co-operativity between metal centres considered crucial for the N2 reduction step, the multimetallic species involved are usually not well defined, and further transformation of N2-binding complexes to achieve N–H or N–C bond formation is rare. Haber noted, before an iron-based catalyst was adopted for the industrial Haber–Bosch process, that uranium and uranium nitride materials are very effective heterogeneous catalysts for ammonia production from N2. However, few examples of uranium complexes binding N2 are known, and soluble uranium complexes capable of transforming N2 into ammonia or organonitrogen compounds have not yet been identified. Here we report the four-electron reduction of N2 under ambient conditions by a fully characterized complex with two Uiii ions and three K+ centres held together by a nitride group and a flexible metalloligand framework. The addition of H2 and/or protons, or CO to the resulting complex results in the complete cleavage of N2 with concomitant N2 functionalization through N–H or N–C bond-forming reactions. These observations establish that a molecular uranium complex can promote the stoichiometric transformation of N2 into NH3 or cyanate, and that a flexible, electron-rich, multimetallic, nitride-bridged core unit is a promising starting point for the design of molecular complexes capable of cleaving and functionalizing N2 under mild conditions.

  • Large-scale physical activity data reveal worldwide activity inequality

  • To be able to curb the global pandemic of physical inactivity and the associated 5.3 million deaths per year, we need to understand the basic principles that govern physical activity. However, there is a lack of large-scale measurements of physical activity patterns across free-living populations worldwide. Here we leverage the wide usage of smartphones with built-in accelerometry to measure physical activity at the global scale. We study a dataset consisting of 68 million days of physical activity for 717,527 people, giving us a window into activity in 111 countries across the globe. We find inequality in how activity is distributed within countries and that this inequality is a better predictor of obesity prevalence in the population than average activity volume. Reduced activity in females contributes to a large portion of the observed activity inequality. Aspects of the built environment, such as the walkability of a city, are associated with a smaller gender gap in activity and lower activity inequality. In more walkable cities, activity is greater throughout the day and throughout the week, across age, gender, and body mass index (BMI) groups, with the greatest increases in activity found for females. Our findings have implications for global public health policy and urban planning and highlight the role of activity inequality and the built environment in improving physical activity and health.

  • Infant viewing of social scenes is under genetic control and is atypical in autism

  • Long before infants reach, crawl or walk, they explore the world by looking: they look to learn and to engage, giving preferential attention to social stimuli, including faces, face-like stimuli and biological motion. This capacity—social visual engagement—shapes typical infant development from birth and is pathognomonically impaired in children affected by autism. Here we show that variation in viewing of social scenes, including levels of preferential attention and the timing, direction and targeting of individual eye movements, is strongly influenced by genetic factors, with effects directly traceable to the active seeking of social information. In a series of eye-tracking experiments conducted with 338 toddlers, including 166 epidemiologically ascertained twins (enrolled by representative sampling from the general population), 88 non-twins with autism and 84 singleton controls, we find high monozygotic twin–twin concordance (0.91) and relatively low dizygotic concordance (0.35). Moreover, the characteristics that are the most highly heritable, preferential attention to eye and mouth regions of the face,are also those that are differentially decreased in children with autism (χ2 = 64.03, P llt; 0.0001). These results implicate social visual engagement as a neurodevelopmental endophenotype not only for autism, but also for population-wide variation in social-information seeking. In addition, these results reveal a means of human biological niche construction, with phenotypic differences emerging from the interaction of individual genotypes with early life experience.

  • CRISPR–Cas encoding of a digital movie into the genomes of a population of living bacteria

  • DNA is an excellent medium for archiving data. Recent efforts have illustrated the potential for information storage in DNA using synthesized oligonucleotides assembled in vitro. A relatively unexplored avenue of information storage in DNA is the ability to write information into the genome of a living cell by the addition of nucleotides over time. Using the Cas1–Cas2 integrase, the CRISPR–Cas microbial immune system stores the nucleotide content of invading viruses to confer adaptive immunity. When harnessed, this system has the potential to write arbitrary information into the genome. Here we use the CRISPR–Cas system to encode the pixel values of black and white images and a short movie into the genomes of a population of living bacteria. In doing so, we push the technical limits of this information storage system and optimize strategies to minimize those limitations. We also uncover underlying principles of the CRISPR–Cas adaptation system, including sequence determinants of spacer acquisition that are relevant for understanding both the basic biology of bacterial adaptation and its technological applications. This work demonstrates that this system can capture and stably store practical amounts of real data within the genomes of populations of living cells.

  • Cholangiocytes act as facultative liver stem cells during impaired hepatocyte regeneration

  • After liver injury, regeneration occurs through self-replication of hepatocytes. In severe liver injury, hepatocyte proliferation is impaired—a feature of human chronic liver disease. It is unclear whether other liver cell types can regenerate hepatocytes. Here we use two independent systems to impair hepatocyte proliferation during liver injury to evaluate the contribution of non-hepatocytes to parenchymal regeneration. First, loss of β1-integrin in hepatocytes with liver injury triggered a ductular reaction of cholangiocyte origin, with approximately 25% of hepatocytes being derived from a non-hepatocyte origin. Second, cholangiocytes were lineage traced with concurrent inhibition of hepatocyte proliferation by β1-integrin knockdown or p21 overexpression, resulting in the significant emergence of cholangiocyte-derived hepatocytes. We describe a model of combined liver injury and inhibition of hepatocyte proliferation that causes physiologically significant levels of regeneration of functional hepatocytes from biliary cells.

  • Transcription elongation factors represent in vivo cancer dependencies in glioblastoma

  • Glioblastoma is a universally lethal cancer with a median survival time of approximately 15 months. Despite substantial efforts to define druggable targets, there are no therapeutic options that notably extend the lifespan of patients with glioblastoma. While previous work has largely focused on in vitro cellular models, here we demonstrate a more physiologically relevant approach to target discovery in glioblastoma. We adapted pooled RNA interference (RNAi) screening technology for use in orthotopic patient-derived xenograft models, creating a high-throughput negative-selection screening platform in a functional in vivo tumour microenvironment. Using this approach, we performed parallel in vivo and in vitro screens and discovered that the chromatin and transcriptional regulators needed for cell survival in vivo are non-overlapping with those required in vitro. We identified transcription pause–release and elongation factors as one set of in vivo-specific cancer dependencies, and determined that these factors are necessary for enhancer-mediated transcriptional adaptations that enable cells to survive the tumour microenvironment. Our lead hit, JMJD6, mediates the upregulation of in vivostress and stimulus response pathways through enhancer-mediated transcriptional pause–release, promoting cell survival specifically in vivo. Targeting JMJD6 or other identified elongation factors extends survival in orthotopic xenograft mouse models, suggesting that targeting transcription elongation machinery may be an effective therapeutic strategy for glioblastoma. More broadly, this study demonstrates the power of in vivo phenotypic screening to identify new classes of ‘cancer dependencies’ not identified by previous in vitro approaches, and could supply new opportunities for therapeutic intervention.

  • Open and closed structures reveal allostery and pliability in the HIV-1 envelope spike

  • For many enveloped viruses, binding to a receptor(s) on a host cell acts as the first step in a series of events culminating in fusion with the host cell membrane and transfer of genetic material for replication. The envelope glycoprotein (Env) trimer on the surface of HIV is responsible for receptor binding and fusion. Although Env can tolerate a high degree of mutation in five variable regions (V1–V5), and also at N-linked glycosylation sites that contribute roughly half the mass of Env, the functional sites for recognition of receptor CD4 and co-receptor CXCR4/CCR5 are conserved and essential for viral fitness. Soluble SOSIP Env trimers are structural and antigenic mimics of the pre-fusion native, surface-presented Env, and are targets of broadly neutralizing antibodies. Thus, they are attractive immunogens for vaccine development. Here we present high-resolution cryo-electron microscopy structures of subtype B B41 SOSIP Env trimers in complex with CD4 and antibody 17b, or with antibody b12, at resolutions of 3.7 Å and 3.6 Å, respectively. We compare these to cryo-electron microscopy reconstructions of B41 SOSIP Env trimers with no ligand or in complex with either CD4 or the CD4-binding-site antibody PGV04 at 5.6 Å, 5.2 Å and 7.4 Å resolution, respectively. Consequently, we present the most complete description yet, to our knowledge, of the CD4–17b-induced intermediate and provide the molecular basis of the receptor-binding-induced conformational change required for HIV-1 entry into host cells. Both CD4 and b12 induce large, previously uncharacterized conformational rearrangements in the gp41 subunits, and the fusion peptide becomes buried in a newly formed pocket. These structures provide key details on the biological function of the type I viral fusion machine from HIV-1 as well as new templates for inhibitor design.

  • K2P2.1 (TREK-1)–activator complexes reveal a cryptic selectivity filter binding site

  • Polymodal thermo- and mechanosensitive two-pore domain potassium (K2P) channels of the TREK subfamily generate‘leak’ currents that regulate neuronal excitability, respond to lipids, temperature and mechanical stretch, and influence pain, temperature perception and anaesthetic responses. These dimeric voltage-gated ion channel (VGIC) superfamily members have a unique topology comprising two pore-formingregions per subunit. In contrast to other potassium channels, K2P channels use a selectivity filter ‘C-type’ gate as the principal gating site. Despite recent advances, poor pharmacological profiles of K2P channels limit mechanistic and biological studies. Here we describe a class of small-molecule TREK activators that directly stimulate the C-type gate by acting as molecular wedges that restrict interdomain interface movement behind the selectivity filter. Structures of K2P2.1 (also known as TREK-1) alone and with two selective K2P2.1 (TREK-1) and K2P10.1 (TREK-2) activators—an N-aryl-sulfonamide, ML335, and a thiophene-carboxamide, ML402—define a cryptic binding pocket unlike other ion channel small-molecule binding sites and, together with functional studies, identify a cation–π interaction that controls selectivity. Together, our data reveal a druggable K2P site that stabilizes the C-type gate ‘leak mode’ and provide direct evidence for K2P selectivity filter gating.

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    Nature -Advance Online Publications

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    Nature AOP

  • Cognition: Neurons couple up to make decisions

  • 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.

  • Cancer: A precision approach to tumour treatment

  • 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.

  • Metabolism: Energy sensing through a sugar diphosphate

  • 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.

  • Maternal H3K27me3 controls DNA methylation-independent imprinting

  • Analysis of parental allele-specific chromatin accessibility genome-wide in mouse zygotes and morula embryos, and investigation of the epigenetic mechanisms underlying these allelic sites, identifying maternal H3K27me3 as a DNA methylation-independent mechanism for genomic imprinting.

  • In vivo CRISPR screening identifies Ptpn2 as a cancer immunotherapy target

  • In vivo CRISPR screening reveals that loss of Ptpn2 increases the response of tumour cells to immunotherapy and increases IFNγ signalling, suggesting that PTPN2 inhibition may potentiate the effect of immunotherapies that invoke an IFNγ response.

  • Global forest loss disproportionately erodes biodiversity in intact landscapes

  • 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 RedList 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.

  • The lysosomal potassium channel TMEM175 adopts a novel tetrameric architecture

  • 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.

  • Cysteine protease cathepsin B mediates radiation-induced bystander effects

  • 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.

  • Distinct timescales of population coding across cortex

  • 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 cortexneurons 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 choiceinformation 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.

  • Fructose-1,6-bisphosphate and aldolase mediate glucose sensing by AMPK

  • 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.

  • Visible-light-driven methane formation from CO2 with a molecular iron catalyst

  • 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.

  • Biomechanics: How fish feel the flow

  • 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.

  • Neurobiology: Synapses get together for vision

  • 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.

  • Synaptic organization of visual space in primary visual cortex

  • 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.

  • A novel mechanism for mechanosensory-based rheotaxis in larval zebrafish

  • 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.

  • Corrigendum: Splicing factor 1 modulates dietary restriction and TORC1 pathway longevity in C. elegans

  • Corrigendum: Crystal structure of the GLP-1 receptor bound to a peptide agonist

  • Corrigendum: Molecular mechanism for the regulation of yeast separase by securin

  • Crystal structures of agonist-bound human cannabinoid receptor CB1

  • The cannabinoid receptor 1 (CB1) is the principal target of the psychoactive constituent of marijuana, the partial agonistΔ9-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 syntheticcannabinoids. 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.

  • Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway

  • 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.

  • Erratum: Structure of the Cpf1 endonuclease R-loop complex after target DNA cleavage

  • Particle physics: No sign of asymmetry in the strong force

  • 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.

  • 50 aamp; 100 Years Ago

  • Particle physics: Search for neutrinoless double-β decay

  • 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.

  • Human migration: Climate and the peopling of the world

  • 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.

  • Cancer: Acidic shield puts a chink in p53's armour

  • 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.

  • Evolutionary biology: To mimicry and back again

  • 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.

  • Addendum

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