The immune-suppressive tumour microenvironment represents a major obstacle to effective immunotherapy1,2. Pathologically activated neutrophils, also known as polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), are a critical component of the tumour microenvironment and have crucial roles in tumour progression and therapy resistance2-4. Identification of the key molecules on PMN-MDSCs is required to selectively target these cells for tumour treatment. Here, we performed an in vivo CRISPR-Cas9 screen in a tumour mouse model and identified CD300ld as a top candidate of tumour-favouring receptors. CD300ld is specifically expressed in normal neutrophils and is upregulated in PMN-MDSCs upon tumour-bearing. CD300ld knockout inhibits the development of multiple tumour types in a PMN-MDSC-dependent manner. CD300ld is required for the recruitment of PMN-MDSCs into tumours and their function to suppress T cell activation. CD300ld acts via the STAT3-S100A8/A9 axis, and knockout of Cd300ld reverses the tumour immune-suppressive microenvironment. CD300ld is upregulated in human cancers and shows an unfavourable correlation with patient survival. Blocking CD300ld activity inhibits tumour development and has synergistic effects with anti-PD1. Our study identifies CD300ld as a critical immune suppressor present on PMN-MDSCs, being required for tumour immune resistance and providing a potential target for cancer immunotherapy.

Multimodal astrocyte-neuron communications govern brain circuitry assembly and function1. For example, through rapid glutamate release, astrocytes can control excitability, plasticity and synchronous activity2,3 of synaptic networks, while also contributing to their dysregulation in neuropsychiatric conditions4-7. For astrocytes to communicate through fast focal glutamate release, they should possess an apparatus for Ca2+-dependent exocytosis similar to neurons8-10. However, the existence of this mechanism has been questioned11-13 owing to inconsistent data14-17 and a lack of direct supporting evidence. Here we revisited the astrocyte glutamate exocytosis hypothesis by considering the emerging molecular heterogeneity of astrocytes18-21 and using molecular, bioinformatic and imaging approaches, together with cell-specific genetic tools that interfere with glutamate exocytosis in vivo. By analysing existing single-cell RNA-sequencing databases and our patch-seq data, we identified nine molecularly distinct clusters of hippocampal astrocytes, among which we found a notable subpopulation that selectively expressed synaptic-like glutamate-release machinery and localized to discrete hippocampal sites. Using GluSnFR-based glutamate imaging22 in situ and in vivo, we identified a corresponding astrocyte subgroup that responds reliably to astrocyte-selective stimulations with subsecond glutamate release events at spatially precise hotspots, which were suppressed by astrocyte-targeted deletion of vesicular glutamate transporter 1 (VGLUT1). Furthermore, deletion of this transporter or its isoform VGLUT2 revealed specific contributions of glutamatergic astrocytes in cortico-hippocampal and nigrostriatal circuits during normal behaviour and pathological processes. By uncovering this atypical subpopulation of specialized astrocytes in the adult brain, we provide insights into the complex roles of astrocytes in central nervous system (CNS) physiology and diseases, and identify a potential therapeutic target.

Development of immunocompetent T cells in the thymus is required for effective defence against all types of pathogens, including viruses, bacteria and fungi. To this end, T cells undergo a very strict educational program in the thymus, during which both non-functional and self-reactive T cell clones are eliminated by means of positive and negative selection1.Thymic epithelial cells (TECs) have an indispensable role in these processes, and previous studies have shown the notable heterogeneity of these cells2-7. Here, using multiomic analysis, we provide further insights into the functional and developmental diversity of TECs in mice, and reveal a detailed atlas of the TEC compartment according to cell transcriptional states and chromatin landscapes. Our analysis highlights unconventional TEC subsets that are similar to functionally well-defined parenchymal populations, including endocrine cells, microfold cells and myocytes. By focusing on the endocrine and microfold TEC populations, we show that endocrine TECs require Insm1 for their development and are crucial to maintaining thymus cellularity in a ghrelin-dependent manner; by contrast, microfold TECs require Spib for their development and are essential for the generation of thymic IgA+ plasma cells. Collectively, our study reveals that medullary TECs have the potential to differentiate into various types of molecularly distinct and functionally defined cells, which not only contribute to the induction of central tolerance, but also regulate the homeostasis of other thymus-resident populations.

Two-dimensional (2D) van der Waals (vdW) heterostructures have attracted considerable attention in recent years1-5. The most widely used method of fabrication is to stack mechanically exfoliated micrometre-sized flakes6-18, but this process is not scalable for practical applications. Despite thousands of 2D materials being created, using various stacking combinations1-3,19-21, hardly any large 2D superconductors can be stacked intact into vdW heterostructures, greatly restricting the applications for such devices. Here we report a high-to-low temperature strategy for controllably growing stacks of multiple-layered vdW superconductor heterostructure (vdWSH) films at a wafer scale. The number of layers of 2D superconductors in the vdWSHs can be precisely controlled, and we have successfully grown 27 double-block, 15 triple-block, 5 four-block and 3 five-block vdWSH films (where one block represents one 2D material). Morphological, spectroscopic and atomic-scale structural analyses reveal the presence of parallel, clean and atomically sharp vdW interfaces on a large scale, with very little contamination between neighbouring layers. The intact vdW interfaces allow us to achieve proximity-induced superconductivity and superconducting Josephson junctions on a centimetre scale. Our process for making multiple-layered vdWSHs can easily be generalized to other situations involving 2D materials, potentially accelerating the design of next-generation functional devices and applications22-24.

In both cancer and infections, diseased cells are presented to human Vγ9Vδ2 T cells through an 'inside out' signalling process whereby structurally diverse phosphoantigen (pAg) molecules are sensed by the intracellular domain of butyrophilin BTN3A11-4. Here we show how-in both humans and alpaca-multiple pAgs function as 'molecular glues' to promote heteromeric association between the intracellular domains of BTN3A1 and the structurally similar butyrophilin BTN2A1. X-ray crystallography studies visualized that engagement of BTN3A1 with pAgs forms a composite interface for direct binding to BTN2A1, with various pAg molecules each positioned at the centre of the interface and gluing the butyrophilins with distinct affinities. Our structural insights guided mutagenesis experiments that led to disruption of the intracellular BTN3A1-BTN2A1 association, abolishing pAg-mediated Vγ9Vδ2 T cell activation. Analyses using structure-based molecular-dynamics simulations, 19F-NMR investigations, chimeric receptor engineering and direct measurement of intercellular binding force revealed how pAg-mediated BTN2A1 association drives BTN3A1 intracellular fluctuations outwards in a thermodynamically favourable manner, thereby enabling BTN3A1 to push off from the BTN2A1 ectodomain to initiate T cell receptor-mediated γδ T cell activation. Practically, we harnessed the molecular-glue model for immunotherapeutics design, demonstrating chemical principles for developing both small-molecule activators and inhibitors of human γδ T cell function.

The functionalization of C-H bonds in organic molecules is one of the most direct approaches for chemical synthesis. Recent advances in catalysis have allowed native chemical groups such as carboxylic acids, ketones and amines to control and direct C(sp3)-H activation1-4. However, alcohols, among the most common functionalities in organic chemistry5, have remained intractable because of their low affinity for late transition-metal catalysts6,7. Here we describe ligands that enable alcohol-directed arylation of δ-C(sp3)-H bonds. We use charge balance and a secondary-coordination-sphere hydrogen-bonding interaction-evidenced by structure-activity relationship studies, computational modelling and crystallographic data-to stabilize L-type hydroxyl coordination to palladium, thereby facilitating the assembly of the key C-H cleavage transition state. In contrast to previous studies in C-H activation, in which secondary interactions were used to control selectivity in the context of established reactivity8-13, this report demonstrates the feasibility of using secondary interactions to enable challenging, previously unknown reactivity by enhancing substrate-catalyst affinity.

Magnetic fields are fundamental to the evolution of galaxies, playing a key role in the astrophysics of the interstellar medium and star formation. Large-scale ordered magnetic fields have been mapped in the Milky Way and nearby galaxies1,2, but it is not known how early in the Universe such structures formed3. Here we report the detection of linearly polarized thermal emission from dust grains in a strongly lensed, intrinsically luminous galaxy that is forming stars at a rate more than 1,000 times that of the Milky Way at redshift 2.6, within 2.5 Gyr of the Big Bang4,5. The polarized emission arises from the alignment of dust grains with the local magnetic field6,7. The median polarization fraction is of the order of 1%, similar to nearby spiral galaxies8. Our observations support the presence of a 5-kiloparsec-scale ordered magnetic field with a strength of around 500 μG or lower, oriented parallel to the molecular gas disk. This confirms that such structures can be rapidly formed in galaxies, early in cosmic history.

Immune checkpoint blockade (ICB) benefits some patients with triple-negative breast cancer, but what distinguishes responders from non-responders is unclear1. Because ICB targets cell-cell interactions2, we investigated the impact of multicellular spatial organization on response, and explored how ICB remodels the tumour microenvironment. We show that cell phenotype, activation state and spatial location are intimately linked, influence ICB effect and differ in sensitive versus resistant tumours early on-treatment. We used imaging mass cytometry3 to profile the in situ expression of 43 proteins in tumours from patients in a randomized trial of neoadjuvant ICB, sampled at three timepoints (baseline, n = 243; early on-treatment, n = 207; post-treatment, n = 210). Multivariate modelling showed that the fractions of proliferating CD8+TCF1+T cells and MHCII+ cancer cells were dominant predictors of response, followed by cancer-immune interactions with B cells and granzyme B+ T cells. On-treatment, responsive tumours contained abundant granzyme B+ T cells, whereas resistant tumours were characterized by CD15+ cancer cells. Response was best predicted by combining tissue features before and on-treatment, pointing to a role for early biopsies in guiding adaptive therapy. Our findings show that multicellular spatial organization is a major determinant of ICB effect and suggest that its systematic enumeration in situ could help realize precision immuno-oncology.

The ability to study human post-implantation development remains limited due to ethical and technical challenges associated with intrauterine development after implantation1. Embryo-like models with spatially organized morphogenesis of all defining embryonic and extra-embryonic tissues of the post-implantation human conceptus (i.e., embryonic disk, bilaminar disk, yolk- and chorionic sacs, surrounding trophoblasts) remain lacking2. Mouse naïve embryonic stem cells (ESCs) have recently been shown to give rise to embryonic and extra-embryonic stem cells capable of self-assembling into post-gastrulation mouse Structured Stem cell-based Embryo Models with spatially organized morphogenesis (SEMs)3. Here, we extend these findings to humans, while using only genetically unmodified human naïve ESCs (in HENSM conditions)4. Such human fully integrated SEMs recapitulate the organization of nearly all known lineages and compartments of post-implantation human embryos including epiblast, hypoblast, extra-embryonic mesoderm, and trophoblast surrounding the latter layers. These human complete SEMs demonstrated developmental growth dynamics that resemble key hallmarks of post-implantation stage embryogenesis up to 13-14 days post-fertilization (dpf) (Carnegie stage 6a). This includes embryonic disk and bilaminar disk formation, epiblast lumenogenesis, polarized amniogenesis, anterior-posterior symmetry breaking, PGC specification, polarized yolk sac with visceral and parietal endoderm, extra-embryonic mesoderm expansion that defines a chorionic cavity and a connecting stalk, a trophoblast surrounding compartment demonstrating syncytium and lacunae formation. This SEM platform may enable the experimental interrogation of previously inaccessible windows of human early post-implantation up to peri-gastrulation development.

Clostridioides difficile infection (CDI) is a major cause of healthcare-associated gastrointestinal infections1,2. The exaggerated colonic inflammation caused by C. difficile toxins such as toxin B (TcdB) damages tissues and promotes C. difficile colonization3-6, but how TcdB causes inflammation is unclear. Here we report that TcdB induces neurogenic inflammation by targeting gut-innervating afferent neurons and pericytes, mediated by receptors including Frizzled 1/2/7 (FZD1/2/7) in neurons and chondroitin sulfate proteoglycan 4 (CSPG4) in pericytes. TcdB action stimulates secretion of the neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP) from neurons and pro-inflammatory cytokines from pericytes. Targeted delivery of the TcdB enzymatic domain, through fusion with a detoxified diphtheria toxin (DT), into peptidergic sensory neurons that express exogeneous DT receptor (an approach we termed toxogenetics) is sufficient to induce neurogenic inflammation and recapitulates major colonic histopathology associated with CDI. Conversely, mice lacking SP, CGRP, or the SP receptor (NK1R) show reduced pathology in both models of cecal TcdB injection and CDI. Blocking SP or CGRP signaling reduces tissue damage and C. difficile burden in mice infected with a standard C. difficile strain or hypervirulent strains expressing the TcdB2 variant. Thus, targeting neurogenic inflammation provides a host-oriented therapeutic approach for treating CDI.

Non-segmented negative-strand RNA viruses (nsNSVs) including Ebola virus (EBOV), rabies virus, human respiratory syncytial virus and pneumoviruses can cause respiratory infections, hemorrhagic fever and encephalitis in the humans and animals, and are considered as substantial health and economic burden worldwide1. Replication and transcription of the viral genome are executed by the large L polymerase that is a promising target for the development of antiviral drugs. Here, using EBOV L polymerase as a representative, we showed that de novo replication of L polymerase is controlled by the specific 3' leader sequence of EBOV genome in an enzymatic assay, and formation of at least three base pairs can effectively drive the elongation process of RNA synthesis independent of the specific RNA sequence. We then determined the high-resolution structures of EBOV L-VP35-RNA complex and found that the 3' leader RNA binds in the template entry channel with a distinctive stable bend conformation. Further mutagenesis work confirmed that the bend conformation of RNA is required for the de novo replication activity and revealed the key residues of L protein that stabilize the RNA conformation. These findings have provided a new mechanistic understanding of RNA synthesis for nsNSV polymerases, and revealed important targets for the development of antiviral drugs.

Nirmatrelvir is a specific antiviral targeting the main protease (Mpro) of SARS-CoV-2, and has been approved to treat COVID-191,2. As an RNA virus characterized by high mutation rates, whether SARS-CoV-2 will develop resistance to nirmatrelvir is a concern. Our previous studies have shown that several mutational pathways confer resistance to nirmatrelvir but some result in a loss of viral replicative fitness, which in turn are compensated by additional mutations3. The molecular mechanisms for this observed resistance are yet unknown. Here we combined biochemical and structural methods to demonstrate that mutations at the substrate binding pocket of the Mpro can allow SARS-CoV-2 to develop resistance to nirmatrelvir in two distinct ways. Comprehensive studies of 14 complex structures of Mpro mutants with drugs or substrate revealed that mutations at the S1 and S4 subsites significantly decreased inhibitor binding, while mutations at the S2 and S4' subsites unexpectedly increased protease activity. Both mechanisms contributed to nirmatrelvir resistance, whereas the latter compensated for the loss in enzymatic activity of the former, which in turn accounted for the restoration of viral replicative fitness as we have observed previously3. Such a profile was also observed for ensitrelvir, another clinically relevant Mpro inhibitor. These results shed light on the mechanisms by which SARS-CoV-2 evolves to develop resistance to the current generation of protease inhibitors and provide the basis for the design of next-generation Mpro inhibitors.

Metal halide perovskite solar cells (PSCs) represent a promising low-cost, thin-film photovoltaic (PV) technology, with unprecedented power conversion efficiencies (PCEs) obtained for both single-junction and tandem applications1-8. To push PSCs toward commercialization, it is critical, albeit challenging, to understand device reliability under real-world outdoor conditions where multiple stress factors (e.g., light, heat, humidity) coexist, generating complicated degradation behaviors9-13. It is necessary to identify accelerated indoor testing protocols-which can correlate specific stressors with observed degradation modes in fielded devices-to quickly guide PSC development. Here, we use a state-of-the-art p-i-n PSC stack (with PCE up to ~25.5%) to show that indoor accelerated stability tests can predict our 6-month outdoor aging tests. Device degradation rates under illumination and at elevated temperatures are most instructive for understanding outdoor device reliability. We also find that the indium tin oxide (ITO)/self-assembled monolayer (SAM)-based hole transport layer (HTL)/perovskite interface most strongly affects our device operation stability. Improving the ion-blocking properties of the SAM HTL increases averaged device operational stability at 50°C-85°C by a factor of ~2.8, reaching over 1000 h at 85°C and to near 8200 h at 50°C with a projected 20% degradation, which is among the best to date for high-efficiency p-i-n PSCs14-17.

The Berry curvature and quantum metric are the imaginary part and real part, respectively, of the quantum geometric tensor, which characterizes the topology of quantum states1. The Berry curvature is known to generate a number of important transport phenomena, such as the quantum Hall effect and the anomalous Hall effect2,3; however, the consequences of the quantum metric have rarely been probed by transport measurements. Here we report the observation of quantum-metric-induced nonlinear transport, including both a nonlinear anomalous Hall effect and a diode-like non-reciprocal longitudinal response, in thin films of a topological antiferromagnet, MnBi2Te4. Our observations reveal that the transverse and longitudinal nonlinear conductivities reverse signs when reversing the antiferromagnetic order, diminish above the Néel temperature and are insensitive to disorder scattering, thus verifying their origin in the band-structure topology. They also flip signs between electron- and hole-doped regions, in agreement with theoretical calculations. Our work provides a means to probe the quantum metric through nonlinear transport and to design magnetic nonlinear devices.

Mitochondria import nearly all of their approximately 1,000-2,000 constituent proteins from the cytosol across their double-membrane envelope1-5. Genetic and biochemical studies have shown that the conserved protein translocase, termed the TIM23 complex, mediates import of presequence-containing proteins (preproteins) into the mitochondrial matrix and inner membrane. Among about ten different subunits of the TIM23 complex, the essential multipass membrane protein Tim23, together with the evolutionarily related protein Tim17, has long been postulated to form a protein-conducting channel6-11. However, the mechanism by which these subunits form a translocation path in the membrane and enable the import process remains unclear due to a lack of structural information. Here we determined the cryo-electron microscopy structure of the core TIM23 complex (heterotrimeric Tim17-Tim23-Tim44) from Saccharomyces cerevisiae. Contrary to the prevailing model, Tim23 and Tim17 themselves do not form a water-filled channel, but instead have separate, lipid-exposed concave cavities that face in opposite directions. Our structural and biochemical analyses show that the cavity of Tim17, but not Tim23, forms the protein translocation path, whereas Tim23 probably has a structural role. The results further suggest that, during translocation of substrate polypeptides, the nonessential subunit Mgr2 seals the lateral opening of the Tim17 cavity to facilitate the translocation process. We propose a new model for the TIM23-mediated protein import and sorting mechanism, a central pathway in mitochondrial biogenesis.

The interplay between spontaneous symmetry breaking and topology can result in exotic quantum states of matter. A celebrated example is the quantum anomalous Hall (QAH) state, which exhibits an integer quantum Hall effect at zero magnetic field due to intrinsic ferromagnetism1-3. In the presence of strong electron-electron interactions, fractional-QAH (FQAH) states at zero magnetic field can emerge4-8. These states could host fractional excitations, including non-Abelian anyons - crucial building blocks for topological quantum computation9. Here, we report experimental signatures of FQAH states in twisted MoTe2 bilayer. Magnetic circular dichroism measurements reveal robust ferromagnetic states at fractionally hole filled moiré minibands. Using trion photoluminescence as a sensor10, we obtain a Landau fan diagram showing linear shifts in carrier densities corresponding to the v = -2/3 and -3/5 ferromagnetic states with applied magnetic field. These shifts match the Streda formula dispersion of FQAH states with fractionally quantized Hall conductance of [Formula: see text] and [Formula: see text], respectively. Moreover, the v = -1 state exhibits a dispersion corresponding to Chern number -1, consistent with the predicted QAH state11-14. In comparison, several non-ferromagnetic states on the electron doping side do not disperse, i.e., are trivial correlated insulators. The observed topological states can be electrically driven into topologically trivial states. Our findings provide evidence of the long-sought FQAH states, demonstrating MoTe2 moiré superlattices as a fascinating platform for exploring fractional excitations.

Chern insulators, which are the lattice analogs of the quantum Hall states, can potentially manifest high-temperature topological orders at zero magnetic field to enable next-generation topological quantum devices 1-3. To date, integer Chern insulators have been experimentally demonstrated in several systems at zero magnetic field 3, 4-8, but fractional Chern insulators have been reported only in graphene-based systems under a finite magnetic field 9,10. The emergence of semiconductor moiré materials 11, which support tunable topological flat bands 12,13, opens a new opportunity to realize fractional Chern insulators 13-16. Here, we report thermodynamic evidence of both integer and fractional Chern insulators at zero magnetic field in small-angle twisted bilayer MoTe2 by combining the local electronic compressibility and magneto-optical measurements. At hole filling factor [Formula: see text] = 1 and 2/3, the system is incompressible and spontaneously breaks time reversal symmetry. We show that they are integer and fractional Chern insulators, respectively, from the dispersion of the state in filling factor with applied magnetic field. We further demonstrate electric-field-tuned topological phase transitions involving the Chern insulators. Our findings pave the way for demonstration of quantized fractional Hall conductance and anyonic excitation and braiding 17 in semiconductor moiré materials.

Although high-transition-temperature (high-Tc) superconductivity in cuprates has been known for more than three decades, the underlying mechanism remains unknown1-4. Cuprates are the only unconventional superconductors that exhibit bulk superconductivity with Tc above the liquid-nitrogen boiling temperature of 77 K. Here we observe that high-pressure resistance and mutual inductive magnetic susceptibility measurements showed signatures of superconductivity in single crystals of La3Ni2O7 with maximum Tc of 80 K at pressures between 14.0 GPa and 43.5 GPa. The superconducting phase under high pressure has an orthorhombic structure of Fmmm space group with the [Formula: see text] and [Formula: see text] orbitals of Ni cations strongly mixing with oxygen 2p orbitals. Our density functional theory calculations indicate that the superconductivity emerges coincidently with the metallization of the σ-bonding bands under the Fermi level, consisting of the [Formula: see text] orbitals with the apical oxygen ions connecting the Ni-O bilayers. Thus, our discoveries provide not only important clues for the high-Tc superconductivity in this Ruddlesden-Popper double-layered perovskite nickelates but also a previously unknown family of compounds to investigate the high-Tc superconductivity mechanism.

The Saturn-mass exoplanet WASP-39b has been the subject of extensive efforts to determine its atmospheric properties using transmission spectroscopy1-4. However, these efforts have been hampered by modelling degeneracies between composition and cloud properties that are caused by limited data quality5-9. Here, we present the transmission spectrum of WASP-39 b obtained using the SOSS mode of the NIRISS instrument on JWST. This spectrum spans 0.6-2.8𝝻m in wavelength and reveals multiple water absorption bands, the potassium resonance doublet, and signatures of clouds. The precision and broad wavelength coverage of NIRISS-SOSS allows us to break model degeneracies between cloud properties and the atmospheric composition of WASP-39b, favouring a heavy element enhancement ("metallicity") of ~10-30x the solar value, a sub-solar carbon-to-oxygen (C/O) ratio, and a solar-to-super-solar potassium-to-oxygen (K/O) ratio. The observations are also best explained by wavelength-dependent, non-gray clouds with inhomogeneous coverage of the planet's terminator.

Measuring the abundances of carbon and oxygen in exoplanet atmospheres is considered a crucial avenue for unlocking the formation and evolution of exoplanetary systems1,2. Access to an exoplanet's chemical inventory requires high precision observations, often inferred from individual molecular detections with low-resolution space-based3-5 and high-resolution ground-based6-8 facilities. Here we report the medium-resolution (R≈600) transmission spectrum of an exoplanet atmosphere between 3-5 μm covering multiple absorption features for the Saturn-mass exoplanet WASP-39b9, obtained with JWST NIRSpec G395H. Our observations achieve 1.46[Formula: see text] photon precision, providing an average transit depth uncertainty of 221 ppm per spectroscopic bin, and present minimal impacts from systematic effects. We detect significant absorption from CO2 (28.5[Formula: see text]) and H2O (21.5[Formula: see text]), and identify SO2 as the source of absorption at 4.1 [Formula: see text]m (4.8[Formula: see text]). Best-fit atmospheric models range between 3[Formula: see text] and 10[Formula: see text] solar metallicity, with sub-solar to solar C/O ratios. These results, including the detection of SO2, underscore the importance of characterising the chemistry in exoplanet atmospheres, and showcase NIRSpec G395H as an excellent mode for time series observations over this critical wavelength range10.