Alvarezsauroids are an enigmatic clade of predominantly small-bodied theropod dinosaurs that are known mainly from the Jurassic to Cretaceous periods of Asia and South America1-3. Late Cretaceous alvarezsauroids possess specialized forelimbs adapted for digging4,5, minute supernumerary teeth and heightened sensory capacities6, and are interpreted as myrmecophagous. They are hypothesized to exhibit evolutionary miniaturization coupled to their dietary specialization2. Fragmentary South American taxa are traditionally arrayed as a paraphyletic grade with respect to the Late Cretaceous Asian subclade Parvicursorinae2,3, invoking dispersal to explain their disjunct distributions. Here we describe a skeleton of the alvarezsauroid Alnashetri cerropoliciensis7 representing to our knowledge the most complete and smallest South American taxon to date. We also recognize two alvarezsauroids among historic taxa from the Northern Hemisphere. Phylogenetic analysis recovers Alnashetri among basal non-alvarezsaurids, rendering South American taxa polyphyletic. Combined with the new taxa recognized here, our biogeographical analyses infer a Pangaean ancestral distribution for Alvarezsauroidea, with vicariance dominating the early history of the clade. The early branching position of Alnashetri among larger-bodied relatives revises best-fit models of body size evolution in alvarezsauroids-we find no support for evolutionary miniaturization but, rather, find support for repeated evolution within a narrow body size range.

Orchestration of lipid production, storage and mobilization is vital for cellular and systemic homeostasis1,2. Dysfunctional plasma lipid control represents the major risk factor for cardiometabolic diseases-the leading cause of human mortality3,4. Within the cellular landscape, the endoplasmic reticulum (ER) is the central hub of lipid synthesis and secretion, particularly in metabolically active hepatocytes in the liver or enterocytes in the gut5,6. Initially assembled in the ER lumen, lipid-ferrying lipoproteins necessitate the cross-membrane transfer of both neutral and phospholipids onto the lumenal apolipoprotein B (APOB), in a poorly defined process7-10. Here we show that the ER protein CLCC1 regulates cellular lipid partition and, consequently, systemic lipid homeostasis by participating in trans-bilayer equilibration of phospholipids. CLCC1 partners with the phospholipid scramblase TMEM41B11,12 to recognize imbalanced bilayers and promote lipid scrambling, thereby supporting lipoprotein biogenesis and the subsequent bulk lipid transport. Loss of CLCC1 or TMEM41B leads to the emergence of giant lumenal lipid droplets enclosed by imbalanced ER bilayers and, consequently, accelerated pathogenesis of metabolic-dysfunction-associated liver steatohepatitis. The results reveal that phospholipid scrambling at the ER is essential for establishing a dynamic equilibrium. Considering the requirement of trans-bilayer phospholipid equilibration in numerous biological processes, ranging from catabolic autophagy to viral infection13-16, we anticipate that future work will elucidate a homeostatic control mechanism intrinsic to ER function in lipid biogenesis and distribution.

Chimeric antigen receptor (CAR)-natural killer (NK) cell therapies hold promise for solid tumours but remain limited because of poor tumour infiltration, persistence and resistance in the tumour microenvironment1-4. Here, to identify gain-of-function targets that enhance CAR-NK cell efficacy, we performed an unbiased in vivo CRISPR activation screen followed by a barcoded targeted in vivo open reading frame screen in primary human CAR-NK cells. We identified and comprehensively validated OR7A10, a G protein-coupled receptor (GPCR), as the top candidate. Engineering CAR-NK cells with OR7A10 cDNA (a CRISPR-independent method with a simple manufacturing strategy) enhanced their proliferation, activation, degranulation, cytokine production, death ligand expression, chemokine receptor expression, cytotoxicity, persistence, metabolic fitness and tumour microenvironment resistance. Moreover, exhaustion in primary human NK cells derived from multiple peripheral blood and cord blood donors was reduced. OR7A10 gain-of-function CAR-NK cells displayed strong in vivo efficacy across multiple solid tumour models. For example, 100% complete response with long-term tumour control and survival benefit in an orthotopic breast cancer mouse model were achieved. These findings establish OR7A10-engineered CAR-NK cells as a highly potent and scalable off-the-shelf therapeutic for solid tumours.

Chiral antiferromagnets1,2 host octupole order3,4 and combine the advantages of antiferromagnets and ferromagnets. Despite the development of numerous switching strategies5-9, the field-free full switching remains unknown, posing an important obstacle to their practical application in memory technology. Here we prepared a homo-junction constituted of Mn3Sn(0001) bottom layer and polycrystalline Mn3Sn top layer. The tilted Kagomé geometry in polycrystalline Mn3Sn divides the out-of-plane spin polarization from Mn3Sn(0001) layer10,11 into the out-of-Kagomé-plane and in-Kagomé-plane components, generating the symmetric (antiferromagnet-type) and asymmetric (ferromagnet-type) driving forces, respectively. The former accelerates octupole rotation, whereas the latter determines switching chirality. Field-free full switching is realized in the unconventional protocol that integrates the advantages of both antiferromagnetic and ferromagnetic switching. It goes beyond the conventional full-switching framework requiring perpendicular uniaxial anisotropy7,12. An unprecedented switching efficiency is achieved, with both current density and power consumption an order of magnitude lower than in previous configurations, by virtue of the highly efficient driving forces due to spin-torque characteristics of octupole order and the ultralow energy barrier arising from easy-plane anisotropy, overcoming their trade-off in conventional protocols. The zero-field switching also shows the advantages of octupole-programmable chirality and robustness to external magnetic field.

Antimicrobial drug resistance poses a global health challenge that necessitates the identification of new druggable targets1-3. The essential lipid II flippase MurJ is a promising yet underexplored antimicrobial target in bacterial cell wall biosynthesis4-7. The only known inhibitors of Gram-negative (diderm) MurJ are the single-gene lysis proteins (Sgls) from the lytic single-strand RNA phages M (SglM) and PP7 (SglPP7)8,9. SglM and SglPP7 have distinct evolutionary origins and share no sequence similarity. Here we describe a common mechanism of MurJ inhibition by these phage-encoded Sgls. We determined the structures of MurJ-bound SglM and SglPP7 and discovered a third distinct MurJ-targeting Sgl from the predicted phage Changjiang3 (SglCJ3) that we also characterized structurally. Our findings demonstrate that all three Sgls evolved convergently to trap MurJ in a periplasm-open conformation through a common MurJ interface, revealing a pathway for drug design.

Cold stress restricts plant growth and inorganic phosphate (Pi) uptake, reducing yield and increasing fertilizer demand1-3. Enhancing both cold tolerance and phosphorus use efficiency (PUE) is crucial for sustainable crop productivity. Here we identify the SPX-domain-containing E3 ubiquitin ligase NITROGEN LIMITATION ADAPTATION (NLA) as a central regulator that links cold signalling to Pi homeostasis in maize (Zea mays L.). Under cold conditions, NLA promotes the degradation of the transcriptional repressor JAZ11, activating jasmonate signalling to enhance cold tolerance; however, NLA also simultaneously represses Pi uptake, through inositol polyphosphate (InsP)-dependent ubiquitination of the Pi transporter PT4. A ubiquitinome-informed genome-wide association study identified a natural PT4(K267A) (lysine-to-alanine substitution) variant that attenuates NLA-mediated degradation and increases Pi uptake in cold conditions. To overcome this nutrient-stress trade-off, we combined artificial-intelligence-guided structural modelling and ligand docking with genome editing to generate the nlaΔ12 allele, which encodes an NLA variant in which binding to InsP is impaired but JAZ11 targeting is retained. The Δ12 modification selectively redirects the activity of NLA towards jasmonate signalling, resulting in improved cold resilience, higher PUE and increased yield in multi-site field trials. These findings reveal a tunable SPX regulatory module that integrates environmental and nutrient signals, and provide a molecular framework for engineering climate-resilient, nutrient-efficient crops.

Cellular solids ubiquitously exist in natural systems and are crucial for living organisms1,2. Their unique smooth branch and node morphologies are often seen as adaptations for enhanced mechanical performance3,4. Exploring alternative evolutionary functions can enrich the understanding of cellular solids, but it is frequently neglected. Here we show that the biomineralized cellular solids in echinoderm stereom (for example, sea urchin spine) have unexpected mechanoelectrical perception with response potential and response time, both of which are one to three orders of magnitude greater than those of echinoderm vision5. This exceptional perception originates from the gradient cellular solids (with varying void- or solid-phase diameters) along the [001] spine axis, generating a differential charge density across the stereom surface during liquid flow. Inspired by this natural wisdom, we create artificial spine-like structures using three-dimensional printing technology that exhibit three-fold higher voltage output and eight-fold greater amplitude differential than gradient-free samples, as well as a nature-inspired metamaterial mechanoreceptor capable of time-resolved self-monitoring information underwater. Our findings advance the understanding of load-sensitive biomimetic cellular solids (such as wood, sponge and trabecular bone), with the potential to develop functional gradient cellular materials towards underwater spatiotemporal sensing and water resource utilization.

Imbalances in lipid storage and secretion lead to hepatic steatosis, the accumulation of lipid droplets in hepatocytes1,2. Our understanding of the mechanisms that govern the channelling of neutral lipids in hepatocytes towards cytosolic lipid droplets or secreted lipoproteins remains incomplete3,4. Here we performed a series of CRISPR-Cas9 screens under different metabolic states that led to the identification of CLCC1 as a critical regulator of neutral lipid storage and secretion in hepatocytes. Loss of CLCC1 resulted in the buildup of large lipid droplets in hepatoma cells and Clcc1 knockout in mice caused liver steatosis. Lipid droplets were present in the lumen of the endoplasmic reticulum of the Clcc1-knockout hepatocytes and exhibited properties of lipoproteins, indicating a profound shift in neutral lipid flux. The loss of CLCC1 also led to the accumulation of nuclear membrane herniations accompanied by a reduction in nuclear pores. Remote homology searches identified a domain in CLCC1 that is homologous to yeast Brl1 and Brr6, factors that promote nuclear envelope fusion during nuclear pore complex assembly. Molecular dynamics simulations and mutagenesis studies support a model in which CLCC1 mediates membrane bending and fusion. We propose that CLCC1 mediates membrane fusion to promote hepatic neutral lipid flux and nuclear pore complex assembly.