Giorgia Quadrato, Tuan Nguyen, Evan Z. Macosko…Steven A. McCarroll & Paola Arlotta
In vitro models of the developing brain such as three-dimensional brain organoids offer an unprecedented opportunity to study aspects of human brain development and disease. However, the cells generated within organoids and the extent to which they recapitulate the regional complexity, cellular diversity and circuit functionality of the brain remain undefined. Here we analyse gene expression in over 80,000 individual cells isolated from 31 human brain organoids. We find that organoids can generate a broad diversity of cells, which are related to endogenous classes, including cells from the cerebral cortex and the retina. Organoids could be developed over extended periods (more than 9 months), allowing for the establishment of relatively mature features, including the formation of dendritic spines and spontaneously active neuronal networks. Finally, neuronal activity within organoids could be controlled using light stimulation of photosensitive cells, which may offer a way to probe the functionality of human neuronal circuits using physiological sensory stimuli.
Fikri Birey, Jimena Andersen, Christopher D. Makinson…John R. Huguenard & Sergiu P. Paşca
The development of the nervous system involves a coordinated succession of events including the migration of GABAergic (γ-aminobutyric-acid-releasing) neurons from ventral to dorsal forebrain and their integration into cortical circuits. However, these interregional interactions have not yet been modelled with human cells. Here we generate three-dimensional spheroids from human pluripotent stem cells that resemble either the dorsal or ventral forebrain and contain cortical glutamatergic or GABAergic neurons. These subdomain-specific forebrain spheroids can be assembled in vitro to recapitulate the saltatory migration of interneurons observed in the fetal forebrain. Using this system, we find that in Timothy syndrome—a neurodevelopmental disorder that is caused by mutations in the CaV1.2 calcium channel—interneurons display abnormal migratory saltations. We also show that after migration, interneurons functionally integrate with glutamatergic neurons to form a microphysiological system. We anticipate that this approach will be useful for studying neural development and disease, and for deriving spheroids that resemble other brain regions to assemble circuits in vitro.
Alexander C. Huang, Michael A. Postow, Robert J. Orlowski…Tara C. Gangadhar & E. John Wherry
Despite the success of monotherapies based on blockade of programmed cell death 1 (PD-1) in human melanoma, most patients do not experience durable clinical benefit. Pre-existing T-cell infiltration and/or the presence of PD-L1 in tumours may be used as indicators of clinical response; however, blood-based profiling to understand the mechanisms of PD-1 blockade has not been widely explored. Here we use immune profiling of peripheral blood from patients with stage IV melanoma before and after treatment with the PD-1-targeting antibody pembrolizumab and identify pharmacodynamic changes in circulating exhausted-phenotype CD8 T cells (Tex cells). Most of the patients demonstrated an immunological response to pembrolizumab. Clinical failure in many patients was not solely due to an inability to induce immune reinvigoration, but rather resulted from an imbalance between T-cell reinvigoration and tumour burden. The magnitude of reinvigoration of circulating Tex cells determined in relation to pretreatment tumour burden correlated with clinical response. By focused profiling of a mechanistically relevant circulating T-cell subpopulation calibrated to pretreatment disease burden, we identify a clinically accessible potential on-treatment predictor of response to PD-1 blockade.
Marscha Hirschi, Zachary Lee Johnson & Seok-Yong Le
Membrane transporters move substrates across the membrane by alternating access of their binding sites between the opposite sides of the membrane. An emerging model of this process is the elevator mechanism, in which a substrate-binding transport domain moves a large distance across the membrane. This mechanism has been characterized by a transition between two states, but the conformational path that leads to the transition is not yet known, largely because the available structural information has been limited to the two end states. Here we present crystal structures of the inward-facing, intermediate, and outward-facing states of a concentrative nucleoside transporter from Neisseria wadsworthii. Notably, we determined the structures of multiple intermediate conformations, in which the transport domain is captured halfway through its elevator motion. Our structures present a trajectory of the conformational transition in the elevator model, revealing multiple intermediate steps and state-dependent conformational changes within the transport domain that are associated with the elevator-like motion.
M. M. Desjardins, J. J. Viennot, M. C. Dartiailh…A. Cottet & T. Kontos
（导读 唐诗语）研究者揭示了在近藤效应范围内电子转移的电荷动力学原理。实验发现，在运输测量（transport measurement）中可以被观测到的近藤共振现象，对于被高质量腔所捕获的微波光子而言是“透明”的。 因此，在这样一个多体共振现象中，用库伦作用冷冻的电荷可以实现有限的传导能力。
The ability to control electronic states at the nanoscale has contributed to our modern understanding of condensed matter. In particular, quantum dot circuits represent model systems for the study of strong electronic correlations, epitomized by the Kondo effect1,2, 3. We use circuit quantum electrodynamics architectures to study the internal degrees of freedom of this many-body phenomenon. Specifically, we couple a quantum dot to a high-quality-factor microwave cavity to measure with exceptional sensitivity the dot’s electronic compressibility, that is, its ability to accommodate charges. Because electronic compressibility corresponds solely to the charge response of the electronic system, it is not equivalent to the conductance, which generally involves other degrees of freedom such as spin. Here, by performing dual conductance and compressibility measurements in the Kondo regime, we uncover directly the charge dynamics of this peculiar mechanism of electron transfer. The Kondo resonance, visible in transport measurements, is found to be ‘transparent’ to microwave photons trapped in the high-quality cavity, thereby revealing that (in such a many-body resonance) finite conduction is achieved from a charge frozen by Coulomb interaction. This freezing of charge dynamics4, 5, 6 is in contrast to the physics of a free electron gas. We anticipate that the tools of cavity quantum electrodynamics could be used in other types of mesoscopic circuits with many-body correlations7, 8, providing a model system in which to perform quantum simulation of fermion–boson problems.
Mitali Banerjee, Moty Heiblum, Amir Rosenblatt, Yuval Oreg, Dima E. Feldman, Ady Stern & Vladimir Umansky
（导读 唐诗语）研究者测量了在砷化镓-铝砷化镓复合结构（GaAs–AlGaAs heterostructures）高迁移率二维电子气在粒子状态和空穴状态下的热传导性。实验结果揭示了部分带电和电中性状态下热传导性的量子化规律。同时也说明，对任意子热流的测量可以作为对传导性测量的一种有效补充。（4.5/5）
The quantum of thermal conductance of ballistic (collisionless) one-dimensional channels is a unique fundamental constant1. Although the quantization of the electrical conductance of one-dimensional ballistic conductors has long been experimentally established2, demonstrating the quantization of thermal conductance has been challenging as it necessitated an accurate measurement of very small temperature increase. It has been accomplished for weakly interacting systems of phonons3, 4, photons5 and electronic Fermi liquids6, 7, 8; however, it should theoretically also hold in strongly interacting systems, such as those in which the fractional quantum Hall effect is observed. This effect describes the fractionalization of electrons into anyons and chargeless quasiparticles, which in some cases can be Majorana fermions2. Because the bulk is incompressible in the fractional quantum Hall regime, it is not expected to contribute substantially to the thermal conductance, which is instead determined by chiral, one-dimensional edge modes. The thermal conductance thus reflects the topological properties of the fractional quantum Hall electronic system, to which measurements of the electrical conductance give no access9, 10, 11, 12. Here we report measurements of thermal conductance in particle-like (Laughlin–Jain series) states and the more complex (and less studied) hole-like states in a high-mobility two-dimensional electron gas in GaAs–AlGaAs heterostructures. Hole-like states, which have fractional Landau-level fillings of 1/2 to 1, support downstream charged modes as well as upstream neutral modes13, and are expected to have a thermal conductance that is determined by the net chirality of all of their downstream and upstream edge modes. Our results establish the universality of the quantization of thermal conductance for fractionally charged and neutral modes. Measurements of anyonic heat flow provide access to information that is not easily accessible from measurements of conductance.
Ge Wu, Ka-Cheung Chan, Linli Zhu, Ligang Sun & Jian Lu
It is not easy to fabricate materials that exhibit their theoretical ‘ideal’ strength. Most methods of producing stronger materials are based on controlling defects to impede the motion of dislocations, but such methods have their limitations. For example, industrial single-phase nanocrystalline alloys1, 2 and single-phase metallic glasses3 can be very strong, but they typically soften at relatively low strains (less than two per cent) because of, respectively, the reverse Hall–Petch effect4 and shear-band formation. Here we describe an approach that combines the strengthening benefits of nanocrystallinity with those of amorphization to produce a dual-phase material that exhibits near-ideal strength at room temperature and without sample size effects. Our magnesium-alloy system consists of nanocrystalline cores embedded in amorphous glassy shells, and the strength of the resulting dual-phase material is a near-ideal 3.3 gigapascals—making this the strongest magnesium-alloy thin film yet achieved. We propose a mechanism, supported by constitutive modelling, in which the crystalline phase (consisting of almost-dislocation-free grains of around six nanometres in diameter) blocks the propagation of localized shear bands when under strain; moreover, within any shear bands that do appear, embedded crystalline grains divide and rotate, contributing to hardening and countering the softening effect of the shear band.
Francisco Juliá-Hernández, Toni Moragas, Josep Cornella & Ruben Martin
Catalytic carbon–carbon bond formation has enabled the streamlining of synthetic routes when assembling complex molecules1. It is particularly important when incorporating saturated hydrocarbons, which are common motifs in petrochemicals and biologically relevant molecules. However, cross-coupling methods that involve alkyl electrophiles result in catalytic bond formation only at specific and previously functionalized sites2. Here we describe a catalytic method that is capable of promoting carboxylation reactions at remote and unfunctionalized aliphatic sites with carbon dioxide at atmospheric pressure. The reaction occurs via selective migration of the catalyst along the hydrocarbon side-chain3 with excellent regio- and chemoselectivity, representing a remarkable reactivity relay when compared with classical cross-coupling reactions. Our results demonstrate that site-selectivity can be switched and controlled, enabling the functionalization of less-reactive positions in the presence of a priori more reactive ones. Furthermore, we show that raw materials obtained in bulk from petroleum processing, such as alkanes and unrefined mixtures of olefins, can be used as substrates. This offers an opportunity to integrate a catalytic platform en route to valuable fatty acids by transforming petroleum-derived feedstocks directly4.
Cédric Aria & Jean-Bernard Caron
Retracing the evolutionary history of arthropods has been one of the greatest challenges in biology1. During the past decade, phylogenetic analyses of morphological and molecular data2,3, 4 have coalesced towards the conclusion that Mandibulata, the most diverse and abundant group of animals, is a distinct clade from Chelicerata, in that its members possess post-oral head appendages specialized for food processing, notably the mandible2, 5. The origin of the mandibulate body plan, however, which encompasses myriapods, crustaceans and hexapods, has remained poorly documented1, 6. Here we show that Tokummia katalepsis gen. et sp. nov., a large bivalved arthropod from the 508 million-year-old Marble Canyon fossil deposit (Burgess Shale, British Columbia), has unequivocal mandibulate synapomorphies, including mandibles and maxillipeds, as well as characters typically found in crustaceans, such as enditic, subdivided basipods and ring-shaped trunk segments. Tokummia and its closest relative, Branchiocaris (in Protocarididae, emended), also have an anteriormost structure housing a probable bilobed organ, which could support the appendicular origin of the labrum7. Protocaridids are retrieved with Canadaspis and Odaraia (in Hymenocarina, emended) as part of an expanded mandibulate clade, refuting the idea that these problematic bivalved taxa, as well as other related forms, are representatives of the basalmost euarthropods8, 9. Hymenocarines now illustrate that the subdivision of the basipod and the presence of proximal endites are likely to have been ancestral conditions critical for the evolution of coxal and pre-coxal features in mandibulates10, 11. The presence of crustaceomorph traits in the Cambrian larvae of various clades basal to Mandibulata is reinterpreted as evidence for the existence of distinct ontogenetic niches among stem arthropods. Larvae would therefore have constituted an important source of morphological novelty during the Cambrian period, and, through heterochronic processes, may have contributed to the rapid acquisition of crown-group characters and thus to greater evolutionary rates during the early radiation of euarthropods12.
Timothy S. Luongo, Jonathan P. Lambert, Polina Gross…Steven R. Houser & John W. Elrod
Mitochondrial calcium (mCa2+) has a central role in both metabolic regulation and cell death signalling, however its role in homeostatic function and disease is controversial1.Slc8b1 encodes the mitochondrial Na+/Ca2+ exchanger (NCLX), which is proposed to be the primary mechanism formCa2+ extrusion in excitable cells2, 3. Here we show that tamoxifen-induced deletion of Slc8b1 in adult mouse hearts causes sudden death, with less than 13% of affected mice surviving after 14 days. Lethality correlated with severe myocardial dysfunction and fulminant heart failure. Mechanistically, cardiac pathology was attributed to mCa2+ overload driving increased generation of superoxide and necrotic cell death, which was rescued by genetic inhibition of mitochondrial permeability transition pore activation. Corroborating these findings, overexpression of NCLX in the mouse heart by conditional transgenesis had the beneficial effect of augmenting mCa2+ clearance, preventing permeability transition and protecting against ischaemia-induced cardiomyocyte necrosis and heart failure. These results demonstrate the essential nature of mCa2+ efflux in cellular function and suggest that augmenting mCa2+ efflux may be a viable therapeutic strategy in disease.
11 Tumour ischaemia by interferon-γ resembles physiological blood vessel regression
Thomas Kammertoens, Christian Friese, Ainhoa Arina…Hans Schreiber & Thomas Blankenstein
The relative contribution of the effector molecules produced by T cells to tumour rejection is unclear, but interferon-γ (IFNγ) is critical in most of the analysed models1. Although IFNγ can impede tumour growth by acting directly on cancer cells2, 3, it must also act on the tumour stroma for effective rejection of large, established tumours4, 5. However, which stroma cells respond to IFNγ and by which mechanism IFNγ contributes to tumour rejection through stromal targeting have remained unknown. Here we use a model of IFNγ induction and an IFNγ–GFP fusion protein in large, vascularized tumours growing in mice that express the IFNγ receptor exclusively in defined cell types. Responsiveness to IFNγ by myeloid cells and other haematopoietic cells, including T cells or fibroblasts, was not sufficient for IFNγ-induced tumour regression, whereas responsiveness of endothelial cells to IFNγ was necessary and sufficient. Intravital microscopy revealed IFNγ-induced regression of the tumour vasculature, resulting in arrest of blood flow and subsequent collapse of tumours, similar to non-haemorrhagic necrosis in ischaemia and unlike haemorrhagic necrosis induced by tumour necrosis factor. The early events of IFNγ-induced tumour ischaemia resemble non-apoptotic blood vessel regression during development, wound healing or IFNγ-mediated, pregnancy-induced remodelling of uterine arteries6, 7, 8. A better mechanistic understanding of how solid tumours are rejected may aid the design of more effective protocols for adoptive T-cell therapy.
12 Transmission of cytokinesis forces via E-cadherin dilution and actomyosin flows
Diana Pinheiro, Edouard Hannezo, Sophie Herszterg…Olga Markova & Yohanns Bellaïche
During epithelial cytokinesis, the remodelling of adhesive cell–cell contacts between the dividing cell and its neighbours has profound implications for the integrity, arrangement and morphogenesis of proliferative tissues1, 2, 3, 4, 5, 6, 7. In both vertebrates and invertebrates, this remodelling requires the activity of non-muscle myosin II (MyoII) in the interphasic cells neighbouring the dividing cell1, 3, 5. However, the mechanisms that coordinate cytokinesis and MyoII activity in the neighbours are unknown. Here we show that in the Drosophila notum epithelium, each cell division is associated with a mechanosensing and transmission event that controls MyoII dynamics in neighbouring cells. We find that the ring pulling forces promote local junction elongation, which results in local E-cadherin dilution at the ingressing adherens junction. In turn, the reduction in E-cadherin concentration and the contractility of the neighbouring cells promote self-organized actomyosin flows, ultimately leading to accumulation of MyoII at the base of the ingressing junction. Although force transduction has been extensively studied in the context of adherens junction reinforcement to stabilize adhesive cell–cell contacts8, we propose an alternative mechanosensing mechanism that coordinates actomyosin dynamics between epithelial cells and sustains the remodelling of the adherens junction in response to mechanical forces.
13 Polyglutamine tracts regulate beclin 1-dependent autophagy
Avraham Ashkenazi, Carla F. Bento, Thomas Ricketts…Fiona M. Menzies & David C. Rubinsztein
Nine neurodegenerative diseases are caused by expanded polyglutamine (polyQ) tracts in different proteins, such as huntingtin in Huntington’s disease and ataxin 3 in spinocerebellar ataxia type 3 (SCA3)1, 2. Age at onset of disease decreases with increasing polyglutamine length in these proteins and the normal length also varies3. PolyQ expansions drive pathogenesis in these diseases, as isolated polyQ tracts are toxic, and an N-terminal huntingtin fragment comprising exon 1, which occurs in vivo as a result of alternative splicing4, causes toxicity. Although such mutant proteins are prone to aggregation5, toxicity is also associated with soluble forms of the proteins6. The function of the polyQ tracts in many normal cytoplasmic proteins is unclear. One such protein is the deubiquitinating enzyme ataxin 3 (refs 7, 8), which is widely expressed in the brain9, 10. Here we show that the polyQ domain enables wild-type ataxin 3 to interact with beclin 1, a key initiator of autophagy11. This interaction allows the deubiquitinase activity of ataxin 3 to protect beclin 1 from proteasome-mediated degradation and thereby enables autophagy. Starvation-induced autophagy, which is regulated by beclin 1, was particularly inhibited in ataxin-3-depleted human cell lines and mouse primary neurons, and in vivo in mice. This activity of ataxin 3 and its polyQ-mediated interaction with beclin 1 was competed for by other soluble proteins with polyQ tracts in a length-dependent fashion. This competition resulted in impairment of starvation-induced autophagy in cells expressing mutant huntingtin exon 1, and this impairment was recapitulated in the brains of a mouse model of Huntington’s disease and in cells from patients. A similar phenomenon was also seen with other polyQ disease proteins, including mutant ataxin 3 itself. Our data thus describe a specific function for a wild-type polyQ tract that is abrogated by a competing longer polyQ mutation in a disease protein, and identify a deleterious function of such mutations distinct from their propensity to aggregate.
14 Structural insight into allosteric modulation of protease-activated receptor 2
Robert K. Y. Cheng, Cédric Fiez-Vandal, Oliver Schlenker…Fiona H. Marshall & Niek Dekker
Protease-activated receptors (PARs) are a family of G-protein-coupled receptors (GPCRs) that are irreversibly activated by proteolytic cleavage of the N terminus, which unmasks a tethered peptide ligand that binds and activates the transmembrane receptor domain, eliciting a cellular cascade in response to inflammatory signals and other stimuli. PARs are implicated in a wide range of diseases, such as cancer and inflammation1, 2, 3. PARs have been the subject of major pharmaceutical research efforts3 but the discovery of small-molecule antagonists that effectively bind them has proved challenging. The only marketed drug targeting a PAR is vorapaxar4, a selective antagonist of PAR1 used to prevent thrombosis. The structure of PAR1 in complex with vorapaxar has been reported previously5. Despite sequence homology across the PAR isoforms, discovery of PAR2 antagonists has been less successful, although GB88 has been described as a weak antagonist6. Here we report crystal structures of PAR2 in complex with two distinct antagonists and a blocking antibody. The antagonist AZ8838 binds in a fully occluded pocket near the extracellular surface. Functional and binding studies reveal that AZ8838 exhibits slow binding kinetics, which is an attractive feature for a PAR2 antagonist competing against a tethered ligand. Antagonist AZ3451 binds to a remote allosteric site outside the helical bundle. We propose that antagonist binding prevents structural rearrangements required for receptor activation and signalling. We also show that a blocking antibody antigen-binding fragment binds to the extracellular surface of PAR2, preventing access of the tethered ligand to the peptide-binding site. These structures provide a basis for the development of selective PAR2 antagonists for a range of therapeutic uses.
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