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Recent paleo reconstructions suggest that increased carbon storage in the Southern Ocean during glacial periods contributed to low glacial atmospheric carbon dioxide concentration (pCO2). However, quantifying its contribution in three-dimensional ocean general circulation models (OGCMs) has proven challenging. Here, we show that OGCM simulation with sedimentary process considering enhanced Southern Ocean salinity stratification and iron fertilization from glaciogenic dust during glacial periods improves model-data agreement of glacial deep water with isotopically light carbon, low oxygen, and old radiocarbon ages. The glacial simulation shows a 77-ppm reduction of atmospheric pCO2, which closely matches the paleo record. The Southern Ocean salinity stratification and the iron fertilization from glaciogenic dust amplified the carbonate sedimentary feedback, which caused most of the increased carbon storage in the deep ocean and played an important role in pCO2 reduction. The model-data agreement of Southern Ocean properties is crucial for simulating glacial changes in the ocean carbon cycle., The 28th IUGG General Assembly (IUGG2023) (Berlin 2023)

Description, Single-molecule fluorescence optical tweezers studies combined with high-speed AFM reveal early events in the HBV life cycle., Self-assembly of supramolecular complexes such as viral capsids occurs prominently in nature. Nonetheless, the mechanisms underlying these processes remain poorly understood. Here, we uncover the assembly pathway of hepatitis B virus (HBV), applying fluorescence optical tweezers and high-speed atomic force microscopy. This allows tracking the assembly process in real time with single-molecule resolution. Our results identify a specific, contact-rich pentameric arrangement of HBV capsid proteins as a key on-path assembly intermediate and reveal the energy balance of the self-assembly process. Real-time nucleic acid packaging experiments show that a free energy change of ~1.4 kBT per condensed nucleotide is used to drive protein oligomerization. The finding that HBV assembly occurs via contact-rich energy minima has implications for our understanding of the assembly of HBV and other viruses and also for the development of new antiviral strategies and the rational design of self-assembling nanomaterials.

Description, Self assembled catheters with deep sub-mm diameters deliver liquids, carry out micromanipulation, and sense magnetic fields., Existing electronically integrated catheters rely on the manual assembly of separate components to integrate sensing and actuation capabilities. This strongly impedes their miniaturization and further integration. Here, we report an electronically integrated self-assembled microcatheter. Electronic components for sensing and actuation are embedded into the catheter wall through the self-assembly of photolithographically processed polymer thin films. With a diameter of only about 0.1 mm, the catheter integrates actuated digits for manipulation and a magnetic sensor for navigation and is capable of targeted delivery of liquids. Fundamental functionalities are demonstrated and evaluated with artificial model environments and ex vivo tissue. Using the integrated magnetic sensor, we develop a strategy for the magnetic tracking of medical tools that facilitates basic navigation with a high resolution below 0.1 mm. These highly flexible and microsized integrated catheters might expand the boundary of minimally invasive surgery and lead to new biomedical applications.

Diversification practices benefit biodiversity, pollination, pest control, nutrient cycling, soil fertility, and water regulation., Enhancing biodiversity in cropping systems is suggested to promote ecosystem services, thereby reducing dependency on agronomic inputs while maintaining high crop yields. We assess the impact of several diversification practices in cropping systems on above- and belowground biodiversity and ecosystem services by reviewing 98 meta-analyses and performing a second-order meta-analysis based on 5160 original studies comprising 41,946 comparisons between diversified and simplified practices. Overall, diversification enhances biodiversity, pollination, pest control, nutrient cycling, soil fertility, and water regulation without compromising crop yields. Practices targeting aboveground biodiversity boosted pest control and water regulation, while those targeting belowground biodiversity enhanced nutrient cycling, soil fertility, and water regulation. Most often, diversification practices resulted in win-win support of services and crop yields. Variability in responses and occurrence of trade-offs highlight the context dependency of outcomes. Widespread adoption of diversification practices shows promise to contribute to biodiversity conservation and food security from local to global scales.

Description, This work shows how itinerant electrons localize due to increased interactions across the Mott metal-insulator transition., In solids, strong repulsion between electrons can inhibit their movement and result in a “Mott” metal-to-insulator transition (MIT), a fundamental phenomenon whose understanding has remained a challenge for over 50 years. A key issue is how the wave-like itinerant electrons change into a localized-like state due to increased interactions. However, observing the MIT in terms of the energy- and momentum-resolved electronic structure of the system, the only direct way to probe both itinerant and localized states, has been elusive. Here we show, using angle-resolved photoemission spectroscopy (ARPES), that in V2O3, the temperature-induced MIT is characterized by the progressive disappearance of its itinerant conduction band, without any change in its energy-momentum dispersion, and the simultaneous shift to larger binding energies of a quasi-localized state initially located near the Fermi level.

Comparisons of neuroblastoma cells and relevant normal adrenal cells reveal a uniform cell state that characterizes neuroblastoma., Neuroblastoma is a childhood cancer that resembles developmental stages of the neural crest. It is not established what developmental processes neuroblastoma cancer cells represent. Here, we sought to reveal the phenotype of neuroblastoma cancer cells by comparing cancer (n = 19,723) with normal fetal adrenal single-cell transcriptomes (n = 57,972). Our principal finding was that the neuroblastoma cancer cell resembled fetal sympathoblasts, but no other fetal adrenal cell type. The sympathoblastic state was a universal feature of neuroblastoma cells, transcending cell cluster diversity, individual patients, and clinical phenotypes. We substantiated our findings in 650 neuroblastoma bulk transcriptomes and by integrating canonical features of the neuroblastoma genome with transcriptional signals. Overall, our observations indicate that a pan-neuroblastoma cancer cell state exists, which may be attractive for novel immunotherapeutic and targeted avenues.

Colloidal quantum dots in silver cavities result in a versatile class of laser-like plasmonic devices for on-chip use., Colloidal quantum dots are robust, efficient, and tunable emitters now used in lighting, displays, and lasers. Consequently, when the spaser—a laser-like source of high-intensity, narrow-band surface plasmons—was first proposed, quantum dots were specified as the ideal plasmonic gain medium for overcoming the significant intrinsic losses of plasmons. Many subsequent spasers, however, have required a single material to simultaneously provide gain and define the plasmonic cavity, a design unable to accommodate quantum dots and other colloidal nanomaterials. In addition, these and other designs have been ill suited for integration with other elements in a larger plasmonic circuit, limiting their use. We develop a more open architecture that decouples the gain medium from the cavity, leading to a versatile class of quantum dot–based spasers that allow controlled generation, extraction, and manipulation of plasmons. We first create aberration-corrected plasmonic cavities with high quality factors at desired locations on an ultrasmooth silver substrate. We then incorporate quantum dots into these cavities via electrohydrodynamic printing or drop-casting. Photoexcitation under ambient conditions generates monochromatic plasmons (0.65-nm linewidth at 630 nm, Q ~ 1000) above threshold. This signal is extracted, directed through an integrated amplifier, and focused at a nearby nanoscale tip, generating intense electromagnetic fields. More generally, our device platform can be straightforwardly deployed at different wavelengths, size scales, and geometries on large-area plasmonic chips for fundamental studies and applications.

We use the concept of aromaticity to create an electrochemically activated single-molecule switch., Single-molecule electronic devices provide researchers with an unprecedented ability to relate novel physical phenomena to molecular chemical structures. Typically, conjugated aromatic molecular backbones are relied upon to create electronic devices, where the aromaticity of the building blocks is used to enhance conductivity. We capitalize on the classical physical organic chemistry concept of Hückel antiaromaticity by demonstrating a single-molecule switch that exhibits low conductance in the neutral state and, upon electrochemical oxidation, reversibly switches to an antiaromatic high-conducting structure. We form single-molecule devices using the scanning tunneling microscope–based break-junction technique and observe an on/off ratio of ~70 for a thiophenylidene derivative that switches to an antiaromatic state with 6-4-6-π electrons. Through supporting nuclear magnetic resonance measurements, we show that the doubly oxidized core has antiaromatic character and we use density functional theory calculations to rationalize the origin of the high-conductance state for the oxidized single-molecule junction. Together, our work demonstrates how the concept of antiaromaticity can be exploited to create single-molecule devices that are highly conducting.

Description, Neurons regulate cardiomyocyte proliferation through clock genes., Neurons can regulate the development, pathogenesis, and regeneration of target organs. However, the role of neurons during heart development and regeneration remains unclear. We genetically inhibited sympathetic innervation in vivo, which resulted in heart enlargement with an increase in cardiomyocyte number. Transcriptomic and protein analysis showed down-regulation of the two clock gene homologs Period1/Period2 (Per1/Per2) accompanied by up-regulation of cell cycle genes. Per1/Per2 deletion increased heart size and cardiomyocyte proliferation, recapitulating sympathetic neuron–deficient hearts. Conversely, increasing sympathetic activity by norepinephrine treatment induced Per1/Per2 and suppressed cardiomyocyte proliferation. We further found that the two clock genes negatively regulate myocyte mitosis entry through the Wee1 kinase pathway. Our findings demonstrate a previously unknown link between cardiac neurons and clock genes in regulation of cardiomyocyte proliferation and heart size and provide mechanistic insights for developing neuromodulation strategies for cardiac regen5eration.

Description, Strongly confined zero-dimensional localization with weak topological design is verified by near-field optical microscopy., Topological photonic crystals (TPhCs) provide robust manipulation of light with built-in immunity to fabrication tolerances and disorder. Recently, it was shown that TPhCs based on weak topology with a dislocation inherit this robustness and further host topologically protected lower-dimensional localized modes. However, TPhCs with weak topology at optical frequencies have not been demonstrated so far. Here, we use scattering-type scanning near-field optical microscopy to verify mid-bandgap zero-dimensional light localization close to 100 THz in a TPhC with nontrivial Zak phase and an edge dislocation. We show that because of the weak topology, differently extended dislocation centers induce similarly strong light localization. The experimental results are supported by full-field simulations. Along with the underlying fundamental physics, our results lay a foundation for the application of TPhCs based on weak topology in active topological nanophotonics, and nonlinear and quantum optic integrated devices because of their strong and robust light localization.

Oral delivery of probiotics into Peyer’s patches can elicit mucosal immunity to maintain the homeostasis of the gut microbiota., Methods capable of maintaining gut microbiota homeostasis to prevent bacterial translocation and infection under external threats are critical for multiple facets of human health but have been rarely reported. Here, we describe the elicitation of mucosal immunity to modulate the gut microbiota by oral delivery of living probiotics into Peyer’s patches. Probiotics are individually camouflaged within a yeast membrane, on which the embedded β-glucan can facilitate the phagocytosis of microfold cells that locate in the intestinal epithelium. The delivery of probiotics into lymphoid follicles after oral ingestion promotes robust mucosal immune responses and notably upgrades the production of secretory immunoglobulin A. The provoked immunity positively regulates the gut microflora, which, in turn, retains gut homeostasis and provides defense against environmental attacks. In two murine models of gut barrier impairment, oral administration with camouflaged probiotics effectively prevents the breakdown of intestinal barrier and evidences limited bacterial translocation and systemic inflammation.

Description, Neuroserpin preferentially inhibits amyloid formation; a 14-mer region in neuroserpin is implicated in binding to amyloid., Neuroserpin is a secreted protease inhibitor known to inhibit amyloid formation by the Alzheimer’s beta peptide (Aβ). To test whether this effect was constrained to Aβ, we used a range of in vitro assays to demonstrate that neuroserpin inhibits amyloid formation by several different proteins and protects against the associated cytotoxicity but, unlike other known chaperones, has a poor ability to inhibit amorphous protein aggregation. Collectively, these results suggest that neuroserpin has an unusual chaperone selectivity for intermediates on the amyloid-forming pathway. Bioinformatics analyses identified a highly conserved 14-residue region containing an α helix shared between neuroserpin and the thyroxine-transport protein transthyretin, and we subsequently demonstrated that transthyretin also preferentially inhibits amyloid formation. Last, we used rationally designed neuroserpin mutants to demonstrate a direct involvement of the conserved 14-mer region in its chaperone activity. Identification of this conserved region may prove useful in the future design of anti-amyloid reagents.

Lithium hydride has been widely identified as the major component of the solid-electrolyte interphase of Li metal batteries (LMBs), but is often regarded as being detrimental to the stabilization of LMBs. Here, we identify the positive and important role of LiH in promoting fast diffusion of Li ions by building a unique three-dimensional (3D) Li metal anode composed of LiMg alloys uniformly confined into graphene-supported LiH nanoparticles. The built-in electric field at the interface between LiH with high Li ion conductivity and LiMg alloys effectively boosts Li diffusion kinetics toward favorable Li plating into lithiophilic LiMg alloys through the surface of LiH. Therefore, the diffusion coefficient of Li ions of the thus-formed 3D structured Li metal anode is 10 times higher than the identical anode without the presence of LiH, and it exhibits a long cycle life of over 1200 hours at 3 mA cm−2 under 5 mA hour cm−2., Description, The positive and important role of LiH in suppressing the growth of Li dendrites is identified.

Human cytomegalovirus (HCMV) encodes G protein–coupled receptors (GPCRs) US28 and US27, which facilitate viral pathogenesis through engagement of host G proteins. Here we report cryo–electron microscopy structures of US28 and US27 forming nonproductive and productive complexes with Gi and Gq, respectively, exhibiting unusual features with functional implications. The “orphan” GPCR US27 lacks a ligand-binding pocket and has captured a guanosine diphosphate–bound inactive Gi through a tenuous interaction. The docking modes of CX3CL1-US28 and US27 to Gi favor localization to endosome-like curved membranes, where US28 and US27 can function as nonproductive Gi sinks to attenuate host chemokine-dependent Gi signaling. The CX3CL1-US28-Gq/11 complex likely represents a trapped intermediate during productive signaling, providing a view of a transition state in GPCR–G protein coupling for signaling. Our collective results shed new insight into unique G protein–mediated HCMV GPCR structural mechanisms, compared to mammalian GPCR counterparts, for subversion of host immunity., Description, The HCMV GPCR-human G protein structures reveal unusual host-pathogen interactions likely critical for HCMV’s pathogenesis.

Colloidal self-assembly—the spontaneous organization of colloids into ordered structures—has been considered key to produce next-generation materials. However, the present-day staggering variety of colloidal building blocks and the limitless number of thermodynamic conditions make a systematic exploration intractable. The true challenge in this field is to turn this logic around and to develop a robust, versatile algorithm to inverse design colloids that self-assemble into a target structure. Here, we introduce a generic inverse design method to efficiently reverse-engineer crystals, quasicrystals, and liquid crystals by targeting their diffraction patterns. Our algorithm relies on the synergetic use of an evolutionary strategy for parameter optimization, and a convolutional neural network as an order parameter, and provides a way forward for the inverse design of experimentally feasible colloidal interactions, specifically optimized to stabilize the desired structure., Description, Machine learning autonomously designs particles that spontaneously self-assemble into desired phases of matter.

Estrogen receptor–α (ERα) expressed by neurons in the ventrolateral subdivision of the ventromedial hypothalamic nucleus (ERαvlVMH) regulates body weight in females, but the downstream neural circuits mediating this biology remain largely unknown. Here we identified a neural circuit mediating the metabolic effects of ERαvlVMH neurons. We found that selective activation of ERαvlVMH neurons stimulated brown adipose tissue (BAT) thermogenesis, physical activity, and core temperature and that ERαvlVMH neurons provide monosynaptic glutamatergic inputs to 5-hydroxytryptamine (5-HT) neurons in the dorsal raphe nucleus (DRN). Notably, the ERαvlVMH → DRN circuit responds to changes in ambient temperature and nutritional states. We further showed that 5-HTDRN neurons mediate the stimulatory effects of ERαvlVMH neurons on BAT thermogenesis and physical activity and that ERα expressed by DRN-projecting ERαvlVMH neurons is required for the maintenance of energy balance. Together, these findings support a model that ERαvlVMH neurons activate BAT thermogenesis and physical activity through stimulating 5-HTDRN neurons., Description, An estrogen-sensitive neural circuit mediating beneficial metabolic effects of estrogen has been identified.

Discovery of peptide domains with unique intermolecular interactions is essential for engineering peptide-based materials. Rather than attempting a brute-force approach, we instead identify a previously unexplored strategy for discovery and study of intermolecular interactions: “co-assembly of oppositely charged peptide” (CoOP), a framework that “encourages” peptide assembly by mixing two oppositely charged hexapeptides. We used an integrated computational and experimental approach, probed the free energy of association and probability of amino acid contacts during co-assembly with atomic-resolution simulations, and correlated them to the physical properties of the aggregates. We introduce CoOP with three examples: dialanine, ditryptophan, and diisoleucine. Our results indicated that the opposite charges initiate the assembly, and the subsequent stability is enhanced by the presence of an undisturbed hydrophobic core. CoOP represents a unique, simple, and elegant framework that can be used to identify the structure-property relationships of self-assembling peptide-based materials., Description, Co-assembly of oppositely charged peptides (CoOP) links intermolecular interactions and material properties.

Chondrocytes secrete massive extracellular matrix (ECM) molecules that are produced, folded, and modified in the endoplasmic reticulum (ER). Thus, the ER-associated degradation (ERAD) complex—which removes misfolded and unfolded proteins to maintain proteostasis in the ER— plays an indispensable role in building and maintaining cartilage. Here, we examined the necessity of the ERAD complex in chondrocytes for cartilage formation and maintenance. We show that ERAD gene expression is exponentially increased during chondrogenesis, and disruption of ERAD function causes severe chondrodysplasia in developing embryos and loss of adult articular cartilage. ERAD complex malfunction also causes abnormal accumulation of cartilage ECM molecules and subsequent chondrodysplasia. ERAD gene expression is decreased in damaged cartilage from patients with osteoarthritis (OA), and disruption of ERAD function in articular cartilage leads to cartilage destruction in a mouse OA model., Description, Reduced secretory activity due to the unfolded protein accumulation in chondrocytes may worsen cartilage damage and loss in osteoa.

Access to electron acceptors supports oxidized biomass synthesis and can be limiting for cancer cell proliferation, but how cancer cells overcome this limitation in tumors is incompletely understood. Nontransformed cells in tumors can help cancer cells overcome metabolic limitations, particularly in pancreatic cancer, where pancreatic stellate cells (PSCs) promote cancer cell proliferation and tumor growth. However, whether PSCs affect the redox state of cancer cells is not known. By taking advantage of the endogenous fluorescence properties of reduced nicotinamide adenine dinucleotide and oxidized flavin adenine dinucleotide cofactors we use optical imaging to assess the redox state of pancreatic cancer cells and PSCs and find that direct interactions between PSCs and cancer cells promote a more oxidized state in cancer cells. This suggests that metabolic interaction between cancer cells and PSCs is a mechanism to overcome the redox limitations of cell proliferation in pancreatic cancer., Description, Interactions between pancreatic stromal cells and pancreatic cancer cells affect the redox state of the cancer cells.

Spin is a fundamental yet nontrivial intrinsic angular momentum property of quantum particles or fields, which appears within relativistic field theory. The spin density in wave fields is described by the theoretical Belinfante-Rosenfeld construction based on the difference between the canonical and kinetic momentum densities. These quantities are usually considered as abstract and non-observable per se. Here, we demonstrate, both theoretically and experimentally, that the Belinfante-Rosenfeld construction naturally arises in gravity (water surface) waves. There, the canonical momentum is associated with the generalized Stokes drift phenomenon, while the spin is generated by subwavelength circular motion of water particles. Thus, we directly observe these fundamental field theory properties as microscopic mechanical properties of a classical wave system. Our findings shed light onto the nature of spin and momentum in wave fields, demonstrate the universality of relativistic field theory concepts, and offer a new platform for their studies., Description, Microscopic mechanical properties of gravity (water surface) waves reveal fundamental relativistic field theory concepts.

The production of noncanonical mRNA transcripts is associated with cell transformation. Driven by our previous findings on the sensitivity of T cell acute lymphoblastic leukemia (T-ALL) cells to SF3B1 inhibitors, we identified that SF3B1 inhibition blocks T-ALL growth in vivo with no notable associated toxicity. We also revealed protein stabilization of the U2 complex component SF3B1 via deubiquitination. Our studies showed that SF3B1 inhibition perturbs exon skipping, leading to nonsense-mediated decay and diminished levels of DNA damage response–related transcripts, such as the serine/threonine kinase CHEK2, and impaired DNA damage response. We also identified that SF3B1 inhibition leads to a general decrease in R-loop formation. We further demonstrate that clinically used SF3B1 inhibitors synergize with CHEK2 inhibitors and chemotherapeutic drugs to block leukemia growth. Our study provides the proof of principle for posttranslational regulation of splicing components and associated roles and therapeutic implications for the U2 complex in T cell leukemia., Description, The splicing factor SF3B1 is regulated at the protein level and is a therapeutic target in T cell leukemia.

Conductive-bridging random access memory (CBRAM) has garnered attention as a building block of non–von Neumann architectures because of scalability and parallel processing on the crossbar array. To integrate CBRAM into the back-end-of-line (BEOL) process, amorphous switching materials have been investigated for practical usage. However, both the inherent randomness of filaments and disorders of amorphous material lead to poor reliability. In this study, a highly reliable nanoporous–defective bottom layer (NP–DBL) structure based on amorphous TiO2 is demonstrated (Ag/a-TiO2/a-TiOx/p-Si). The stoichiometries of DBL and the pore size can be manipulated to achieve the analog conductance updates and multilevel conductance by 300 states with 1.3% variation, and 10 levels, respectively. Compared with nonporous TiO2 CBRAM, endurance, retention, and uniformity can be improved by 106 pulses, 28 days at 85°C, and 6.7 times, respectively. These results suggest even amorphous-based systems, elaborately tuned structural variables, can help design more reliable CBRAMs., Description, The structural approach enables reliable multilevel memristor devices for neuromorphic computing system development.

Layer-release techniques for producing freestanding III-V epitaxial layers have been actively developed for heterointegration of single-crystalline compound semiconductors with Si platforms. However, for the release of target epitaxial layers from III-V heterostructures, it is required to embed a mechanically or chemically weak sacrificial buffer beneath the target layers. This requirement severely limits the scope of processable materials and their epi-structures and makes the growth and layer-release process complicated. Here, we report that epitaxial layers in commonly used III-V heterostructures can be precisely released with an atomic-scale surface flatness via a buffer-free separation technique. This result shows that heteroepitaxial interfaces of a normal lattice-matched III-V heterostructure can be mechanically separated without a sacrificial buffer and the target interface for separation can be selectively determined by adjusting process conditions. This technique of selective release of epitaxial layers in III-V heterostructures will provide high fabrication flexibility in compound semiconductor technology., Description, Epi-layers of III-V heterostructures can be selectively released at target interfaces without an embedded sacrificial buffer.

Although atherosclerosis preferentially develops at arterial curvatures and bifurcations where disturbed flow (DF) activates endothelium, therapies targeting flow-dependent mechanosensing pathways in the vasculature are unavailable. Here, we provided experimental evidence demonstrating a previously unidentified causal role of DF-induced endothelial TXNDC5 (thioredoxin domain containing 5) in atherosclerosis. TXNDC5 was increased in human and mouse atherosclerotic lesions and induced in endothelium subjected to DF. Endothelium-specific Txndc5 deletion markedly reduced atherosclerosis in ApoE−/− mice. Mechanistically, DF-induced TXNDC5 increases proteasome-mediated degradation of heat shock factor 1, leading to reduced heat shock protein 90 and accelerated eNOS (endothelial nitric oxide synthase) protein degradation. Moreover, nanoparticles formulated to deliver Txndc5-targeting CRISPR-Cas9 plasmids driven by an endothelium-specific promoter (CDH5) significantly increase eNOS protein and reduce atherosclerosis in ApoE−/− mice. These results delineate a new molecular paradigm that DF-induced endothelial TXNDC5 promotes atherosclerosis and establish a proof of concept of targeting endothelial mechanosensitive pathways in vivo against atherosclerosis., Description, Targeting flow-sensitive TXNDC5, an ER protein driving endothelial dysfunction by destabilizing eNOS, lessens atherosclerosis.

One of the rate-limiting steps in analyzing immune responses to vaccines or infections is the isolation and characterization of monoclonal antibodies. Here, we present a hybrid structural and bioinformatic approach to directly assign the heavy and light chains, identify complementarity-determining regions, and discover sequences from cryoEM density maps of serum-derived polyclonal antibodies bound to an antigen. When combined with next-generation sequencing of immune repertoires, we were able to specifically identify clonal family members, synthesize the monoclonal antibodies, and confirm that they interact with the antigen in a manner equivalent to the corresponding polyclonal antibodies. This structure-based approach for identification of monoclonal antibodies from polyclonal sera opens new avenues for analysis of immune responses and iterative vaccine design., Description, CryoEM and next-generation sequencing were used to identify monoclonal antibodies elicited by HIV Env vaccine candidates.

Histone acetylation is governed by nuclear acetyl-CoA pools generated, in part, from local acetate by metabolic enzyme acetyl-CoA synthetase 2 (ACSS2). We hypothesize that during gene activation, a local transfer of intact acetate occurs via sequential action of epigenetic and metabolic enzymes. Using stable isotope labeling, we detect transfer between histone acetylation sites both in vitro using purified mammalian enzymes and in vivo using quiescence exit in Saccharomyces cerevisiae as a change-of-state model. We show that Acs2, the yeast ortholog of ACSS2, is recruited to chromatin during quiescence exit and observe dynamic histone acetylation changes proximal to Acs2 peaks. We find that Acs2 is preferentially associated with the most up-regulated genes, suggesting that acetyl group transfer plays an important role in gene activation. Overall, our data reveal direct transfer of acetate between histone lysine residues to facilitate rapid transcriptional induction, an exchange that may be critical during changes in nutrient availability., Description, Intact acetate is transferred between histone lysine residues for rapid gene activation.

De novo truncations in Interferon Regulatory Factor 2 Binding Protein Like (IRF2BPL) lead to severe childhood-onset neurodegenerative disorders. To determine how loss of IRF2BPL causes neural dysfunction, we examined its function in Drosophila and zebrafish. Overexpression of either IRF2BPL or Pits, the Drosophila ortholog, represses Wnt transcription in flies. In contrast, neuronal depletion of Pits leads to increased wingless (wg) levels in the brain and is associated with axonal loss, whereas inhibition of Wg signaling is neuroprotective. Moreover, increased neuronal expression of wg in flies is sufficient to cause age-dependent axonal loss, similar to reduction of Pits. Loss of irf2bpl in zebrafish also causes neurological defects with an associated increase in wnt1 transcription and downstream signaling. WNT1 is also increased in patient-derived astrocytes, and pharmacological inhibition of Wnt suppresses the neurological phenotypes. Last, IRF2BPL and the Wnt antagonist, CKIα, physically and genetically interact, showing that IRF2BPL and CkIα antagonize Wnt transcription and signaling., Description, Up-regulated neuronal Wnt transcription in adult brains is sufficient to cause progressive neurodegenerative phenotypes in vivo.

Injectable hydrogels are desired in many biomedical applications due to their minimally invasive deployment to the body and their ability to introduce drugs. However, current injectables suffer from mechanical mismatch with tissue, fragility, water expulsion, and high viscosity. To address these issues, we design brush-like macromolecules that concurrently provide softness, firmness, strength, fluidity, and swellability. The synthesized linear-bottlebrush-linear (LBL) copolymers facilitate improved injectability as the compact conformation of bottlebrush blocks results in low solution viscosity, while the thermoresponsive linear blocks permit prompt gelation at 37°C. The resulting hydrogels mimic the deformation response of supersoft tissues such as adipose and brain while withstanding deformations of 700% and precluding water expulsion upon gelation. Given their low cytotoxicity and mild inflammation in vivo, the developed materials will have vital implications for reconstructive surgery, tissue engineering, and drug delivery applications., Description, Minimally invasive injection yields robust hydrogels that mimic the mechanics and water fraction of surrounding tissue.

Inappropriate expansion of antibody-secreting cells (ASCs) is typical of systemic lupus erythematosus (SLE), but the regulatory signaling of pathogenic ASCs is unclear. The present study shows that brain-derived neurotrophic factor precursor (proBDNF) and its high-affinity pan-75 neurotrophin receptor (p75NTR) are highly expressed in CD19+CD27hiCD38hi ASCs in patients with SLE and in CD19+CD44hiCD138+ ASCs in lupus-like mice. The increased proBDNF+ ASCs were positively correlated with clinical symptoms and higher titers of autoantibodies in SLE. Administration of monoclonal antibodies against proBDNF or specific knockout of p75NTR in CD19+ B cells exerted a therapeutic effect on lupus mice by limiting the proportion of ASCs, reducing the production of autoantibodies and attenuating kidney injury. Blocking the biological function of proBDNF or p75NTR also inhibits ASC differentiation and antibody production in vitro. Together, these findings suggest that proBDNF-p75NTR signaling plays a critical pathogenic role in SLE through promoting ASC dysfunction., Description, ProBDNF/p75NTR signaling drives systemic lupus erythematosus by dysregulating antibody-secreting cells.

Security is a prevailing concern in communication as conventional encryption methods are challenged by progressively powerful supercomputers. Here, we show that biometrics-protected optical communication can be constructed by synergizing triboelectric and nanophotonic technology. The synergy enables the loading of biometric information into the optical domain and the multiplexing of digital and biometric information at zero power consumption. The multiplexing process seals digital signals with a biometric envelope to avoid disrupting the original high-speed digital information and enhance the complexity of transmitted information. The system can perform demultiplexing, recover high-speed digital information, and implement deep learning to identify 15 users with around 95% accuracy, irrespective of biometric information data types (electrical, optical, or demultiplexed optical). Secure communication between users and the cloud is established after user identification for document exchange and smart home control. Through integrating triboelectric and photonics technology, our system provides a low-cost, easy-to-access, and ubiquitous solution for secure communication., Description, Biometrics-protected communication is realized by superimposing biometric signals on optical data using TENG/photonic interface.

There are substantial, unexplained racial disparities in women’s health. Some of the most pronounced involve elevated rates of preterm delivery (PTD) and cardiovascular disease (CVD) among Black women. We hypothesized that stress associated with excessive use of force by police may contribute to these disparities. In two prospective cohorts derived from electronic health records (pregnancy cohort, N = 67,976; CVD cohort, N = 6773), we linked formal complaints of excessive police force in patients’ neighborhoods with health outcomes. Exposed Black women were 1.19 times as likely to experience PTD [95% confidence interval (CI): 1.04 to 1.35] and 1.42 times as likely to develop CVD (95% CI: 1.12 to 1.79), even after adjustment for neighborhood disadvantage and homicide. The excess risks of PTD were also observed in maternal fixed-effects analyses comparing births to the same woman. These findings suggest police violence may be an unrecognized contributor to health inequity for Black women., Description, Neighborhood police violence may contribute to increased risk of preterm birth and cardiovascular disease among Black women.

Tumors display widespread transcriptome alterations, but the full repertoire of isoform-level alternative splicing in cancer is unknown. We developed a long-read (LR) RNA sequencing and analytical platform that identifies and annotates full-length isoforms and infers tumor-specific splicing events. Application of this platform to breast cancer samples identifies thousands of previously unannotated isoforms; ~30% affect protein coding exons and are predicted to alter protein localization and function. We performed extensive cross-validation with -omics datasets to support transcription and translation of novel isoforms. We identified 3059 breast tumor–specific splicing events, including 35 that are significantly associated with patient survival. Of these, 21 are absent from GENCODE and 10 are enriched in specific breast cancer subtypes. Together, our results demonstrate the complexity, cancer subtype specificity, and clinical relevance of previously unidentified isoforms and splicing events in breast cancer that are only annotatable by LR-seq and provide a rich resource of immuno-oncology therapeutic targets., Description, Breast cancer long-read transcriptome profiling reveals patient-enriched isoforms, with implications for disease progression.

Normal cell counterparts of solid and myeloid tumors accumulate mutations years before disease onset; whether this occurs in B lymphocytes before lymphoma remains uncertain. We sequenced multiple stages of the B lineage in elderly individuals and patients with lymphoplasmacytic lymphoma, a singular disease for studying lymphomagenesis because of the high prevalence of mutated MYD88. We observed similar accumulation of random mutations in B lineages from both cohorts and unexpectedly found MYD88L265P in normal precursor and mature B lymphocytes from patients with lymphoma. We uncovered genetic and transcriptional pathways driving malignant transformation and leveraged these to model lymphoplasmacytic lymphoma in mice, based on mutated MYD88 in B cell precursors and BCL2 overexpression. Thus, MYD88L265P is a preneoplastic event, which challenges the current understanding of lymphomagenesis and may have implications for early detection of B cell lymphomas., Description, MYD88L265P occurs in between a normal mutated lymphopoiesis and additional genetic alterations during lymphomagenesis.

Budding uninhibited by benzimidazoles (BUB1) contributes to multiple mitotic processes. Here, we describe the first two patients with biallelic BUB1 germline mutations, who both display microcephaly, intellectual disability, and several patient-specific features. The identified mutations cause variable degrees of reduced total protein level and kinase activity, leading to distinct mitotic defects. Both patients’ cells show prolonged mitosis duration, chromosome segregation errors, and an overall functional spindle assembly checkpoint. However, while BUB1 levels mostly affect BUBR1 kinetochore recruitment, impaired kinase activity prohibits centromeric recruitment of Aurora B, SGO1, and TOP2A, correlating with anaphase bridges, aneuploidy, and defective sister chromatid cohesion. We do not observe accelerated cohesion fatigue. We hypothesize that unresolved DNA catenanes increase cohesion strength, with concomitant increase in anaphase bridges. In conclusion, BUB1 mutations cause a neurodevelopmental disorder, with clinical and cellular phenotypes that partially resemble previously described syndromes, including autosomal recessive primary microcephaly, mosaic variegated aneuploidy, and cohesinopathies., Description, Biallelic germline mutations in a gene important for mitotic fidelity, BUB1, are first described and functionally assessed.

Description, Infrared spectroscopy in high magnetic fields reveals the lowest quantum limit in a Weyl semimetal., Topological semimetals are predicted to exhibit unconventional electrodynamics, but a central experimental challenge is singling out the contributions from the topological bands. TaAs is the prototypical example, where 24 Weyl points and 8 trivial Fermi surfaces make the interpretation of any experiment in terms of band topology ambiguous. We report magneto-infrared reflection spectroscopy measurements on TaAs. We observed sharp inter-Landau level transitions from a single pocket of Weyl Fermions in magnetic fields as low as 0.4 tesla. We determine the W2 Weyl point to be 8.3 meV below the Fermi energy, corresponding to a quantum limit—the field required to reach the lowest LL—of 0.8 tesla—unprecedentedly low for Weyl Fermions. LL spectroscopy allows us to isolate these Weyl Fermions from all other carriers in TaAs, and our result provides a way for directly exploring the more exotic quantum phenomena in Weyl semimetals, such as the chiral anomaly.

Description, eCD4Ig has an in vivo IC50 of 25 μg/ml, and it may induce ART-free virus control if produced continually at 105 μg/day or more., The engineered protein eCD4Ig has emerged as a promising approach to achieve HIV remission in the absence of antiviral therapy. eCD4Ig neutralizes nearly all HIV-1 isolates and induces antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro. To characterize the in vivo antiviral neutralization and possible ADCC effects of eCD4Ig, we fit mathematical models to eCD4Ig, anti–eCD4Ig-drug antibody (ADA), and viral load kinetics from healthy and simian-human immunodeficiency virus AD8 (SHIV-AD8) infected nonhuman primates that were treated with single or sequentially dosed eCD4Ig passive administrations. Our model predicts that eCD4Ig transiently decreases SHIV viral loads due to neutralization only with an in vivo IC50 of ~25 μg/ml but with limited effect due to ADA. Simulations suggest that endogenous, continuous expression of eCD4Ig at levels greater than 105 μg/day, as is possible with Adeno-associated virus (AAV) vector-based production, could overcome the diminishing effects of ADA and allow for long-term remission of SHIV viremia in nonhuman primates.

Description, Expression of miR-3607 in embryonic mammalian cerebral cortex was lost in rodents, limiting progenitor cell proliferation., The evolutionary expansion and folding of the mammalian cerebral cortex resulted from amplification of progenitor cells during embryonic development. This process was reversed in the rodent lineage after splitting from primates, leading to smaller and smooth brains. Genetic mechanisms underlying this secondary loss in rodent evolution remain unknown. We show that microRNA miR-3607 is expressed embryonically in the large cortex of primates and ferret, distant from the primate-rodent lineage, but not in mouse. Experimental expression of miR-3607 in embryonic mouse cortex led to increased Wnt/β-catenin signaling, amplification of radial glia cells (RGCs), and expansion of the ventricular zone (VZ), via blocking the β-catenin inhibitor APC (adenomatous polyposis coli). Accordingly, loss of endogenous miR-3607 in ferret reduced RGC proliferation, while overexpression in human cerebral organoids promoted VZ expansion. Our results identify a gene selected for secondary loss during mammalian evolution to limit RGC amplification and, potentially, cortex size in rodents.

Description, Electronic Raman scattering activates the investigation of d-d excitations and electron-spin coupling in 2D antiferromagnets., Correlated-electron systems have long been an important platform for various interesting phenomena and fundamental questions in condensed matter physics. As a pivotal process in these systems, d-d transitions have been suggested as a key factor toward realizing optical spin control in two-dimensional (2D) magnets. However, it remains unclear how d-d excitations behave in quasi-2D systems with strong electronic correlation and spin-charge coupling. Here, we present a systematic electronic Raman spectroscopy investigation on d-d transitions in a 2D antiferromagnet—NiPS3, from bulk to atomically thin samples. Two electronic Raman modes originating from the scattering of incident photons with d electrons in Ni2+ ions are observed at ~1.0 eV. This electronic process persists down to trilayer flakes and exhibits insensitivity to the spin ordering of NiPS3. Our study demonstrates the utility of electronic Raman scattering in investigating the unique electronic structure and its coupling to magnetism in correlated 2D magnets.

Description, Machine learning unveils molecular transport mechanisms obscured by entropy-enthalpy compensation in polymeric membranes., Designing single-species selective membranes for high-precision separations requires a fundamental understanding of the molecular interactions governing solute transport. Here, we comprehensively assess molecular-level features that influence the separation of 18 different anions by nanoporous cellulose acetate membranes. Our analysis identifies the limitations of bulk solvation characteristics to explain ion transport, highlighted by the poor correlation between hydration energy and the measured permselectivity (R2 = 0.37). Entropy-enthalpy compensation, spanning 40 kilojoules per mole, leads to a free-energy barrier (∆G‡) variation of only ~8 kilojoules per mole across all anions. We apply machine learning to elucidate descriptors for energetic barriers from a set of 126 collected features. Notably, electrostatic features account for 75% of the overall features used to describe ∆G‡, despite the relatively uncharged state of cellulose acetate. Our work presents an approach for studying ion transport across nanoporous membranes that could enable the design of ion-selective membranes.

Description, In a major step toward the development of a quantum battery, superabsorption has been achieved in an organic microcavity., The rate at which matter emits or absorbs light can be modified by its environment, as markedly exemplified by the widely studied phenomenon of superradiance. The reverse process, superabsorption, is harder to demonstrate because of the challenges of probing ultrafast processes and has only been seen for small numbers of atoms. Its central idea—superextensive scaling of absorption, meaning larger systems absorb faster—is also the key idea underpinning quantum batteries. Here, we implement experimentally a paradigmatic model of a quantum battery, constructed of a microcavity enclosing a molecular dye. Ultrafast optical spectroscopy allows us to observe charging dynamics at femtosecond resolution to demonstrate superextensive charging rates and storage capacity, in agreement with our theoretical modeling. We find that decoherence plays an important role in stabilizing energy storage. Our work opens future opportunities for harnessing collective effects in light-matter coupling for nanoscale energy capture, storage, and transport technologies.

Description, Enhanced anthropogenic and biogenic interaction by approaching typhoons deteriorates cross-regional ozone pollution in China., Ozone pollution that threatens human health and the ecosystem is a global environmental challenge. In megacities, ozone pollution has long been mainly attributed to anthropogenic sources. However, the processes and mechanisms of cross-regional transport of ozone and its precursors under interactions between mixed sources remain unclear. Here, we show that Northwest Pacific typhoons could intensify the chemical interactions between anthropogenic and biogenic emissions, resulting in extreme ozone pollution in two main city clusters in China. By integrating field and satellite observations together with model simulations, we show that biogenic emission and cross-regional ozone transport are greatly enhanced by approaching typhoons, with the increments reaching up to 78.0 and 22.5%, respectively. Ozone formation efficiency has more than doubled because of abundant precursors and active photochemistry. This study highlights the importance of natural emissions in areas with intensive human activity, which needs to be considered in future air pollution control in China.

Description, An imidazolium-based zwitterionic polymer is reported with dual functions of antivirus and antifouling with broad applicability., To reduce the severe health risk and the huge economic impact associated with the fomite transmission of SARS-CoV-2, an imidazolium-based zwitterionic polymer was designed, synthesized, and demonstrated to achieve contact deactivation of a human coronavirus under dry ambient conditions that resemble fomite transmission. The zwitterionic polymer further demonstrated excellent antifouling properties, reducing the adhesion of coronavirus and the formation of bacteria biofilms under wetted conditions. The polymer was synthesized using a substrate-independent and solvent-free process, leveraging an all-dry technique named initiated chemical vapor deposition (iCVD). The broad applicability of this approach was demonstrated by applying the polymer to a range of substrates that are curved and/or with high-aspect-ratio nano/microporous structures, which remained intact after the coating process. The zwitterionic polymer and the synthesis approach reported here present an effective solution to mitigate viral transmission without the need for manual disinfection, reducing the health and economic impact of the ongoing pandemic.

Description, Wide-aperture free-space limiter with enhanced damage threshold provides protection from high-power millimeter-wave radiation., Millimeter-wave (mm-wave) communications and radar receivers must be protected from high-power signals, which can damage their sensitive components. Many of these systems arguably can be protected by using photonic limiting techniques, in addition to electronic limiting circuits in receiver front-ends. Here we demonstrate, experimentally and numerically, a free-space, reflective mm-wave limiter based on a multilayer structure involving a nanolayer of vanadium dioxide VO2, which experiences a heat-related insulator-to-metal phase transition. The multilayer acts as a variable reflector, controlled by the incident wave intensity. At low intensities VO2 remains dielectric, and the multilayer exhibits strong resonant transmittance. When the incident intensity exceeds a threshold level, the emerging metallic phase renders the multilayer highly reflective while safely dissipating a small portion of the input power, without damage to the limiter. In the case of a Gaussian beam, the limiter has a nearly constant output above the limiting threshold input.

Description, Pressure-modulated ion transport through single graphene nanopores reveals a nonlinear electrohydrodynamic coupling phenomenon., Mechanosensitivity is one of the essential functionalities of biological ion channels. Synthesizing an artificial nanofluidic system to mimic such sensations will not only improve our understanding of these fluidic systems but also inspire applications. In contrast to the electrohydrodynamic ion transport in long nanoslits and nanotubes, coupling hydrodynamical and ion transport at the single-atom thickness remains challenging. Here, we report the pressure-modulated ion conduction in graphene nanopores featuring nonlinear electrohydrodynamic coupling. Increase of ionic conductance, ranging from a few percent to 204.5% induced by the pressure—an effect that was not predicted by the classical linear coupling of molecular streaming to voltage-driven ion transport—was observed experimentally. Computational and theoretical studies reveal that the pressure sensitivity of graphene nanopores arises from the transport of capacitively accumulated ions near the graphene surface. Our findings may help understand the electrohydrodynamic ion transport in nanopores and offer a new ion transport controlling methodology.

Description, Ancient DNA identifies elite equids in Bronze Age Mesopotamia as the first human-bred hybrid animals, the enigmatic kungas., Before the introduction of domestic horses in Mesopotamia in the late third millennium BCE, contemporary cuneiform tablets and seals document intentional breeding of highly valued equids called kungas for use in diplomacy, ceremony, and warfare. Their precise zoological classification, however, has never been conclusively determined. Morphometric analysis of equids uncovered in rich Early Bronze Age burials at Umm el-Marra, Syria, placed them beyond the ranges reported for other known equid species. We sequenced the genomes of one of these ~4500-year-old equids, together with an ~11,000-year-old Syrian wild ass (hemippe) from Göbekli Tepe and two of the last surviving hemippes. We conclude that kungas were F1 hybrids between female domestic donkeys and male hemippes, thus documenting the earliest evidence of hybrid animal breeding.

Somma-Vesuvius is one of the most iconic active volcanoes with historic and archeological records of numerous hazardous eruptions. Petrologic studies of eruptive products provide insights into the evolution of the magma reservoir before eruption. Here, we quantify the duration of shallow crustal storage and document the evolution of phonolitic magmas before major eruptions of Somma-Vesuvius. Garnet uranium-thorium petrochronology suggests progressively shorter pre-eruption residence times throughout the lifetime of the volcano. Residence times mirror the repose intervals between eruptions, implying that distinct phonolite magma batches were present throughout most of the volcano’s evolution, thereby controlling the eruption dynamics by preventing the ascent of mafic magmas from longer-lived and deeper reservoirs. Frequent lower-energy eruptions during the recent history sample this deeper reservoir and suggest that future Plinian eruptions are unlikely without centuries of volcanic quiescence. Crystal residence times from other volcanoes reveal that long-lived deep-seated reservoirs and transient upper crustal magma chambers are common features of subvolcanic plumbing systems., Science Advances, 8 (2), ISSN:2375-2548

Description, Experiments show the performance of quantum holography using undetected photons., Holography exploits the interference of a light field reflected/transmitted from an object with a reference beam to obtain a reconstruction of the spatial shape of the object. Classical holography techniques have been very successful in diverse areas such as microscopy, manufacturing technology, and basic science. However, detection constraints for wavelengths outside the visible range restrict the applications for imaging and sensing in general. For overcoming these detection limitations, we implement phase-shifting holography with nonclassical states of light, where we exploit quantum interference between two-photon probability amplitudes in a nonlinear interferometer. We demonstrate that it allows retrieving the spatial shape (amplitude and phase) of the photons transmitted/reflected from the object and thus obtaining an image of the object despite those photons are never detected. Moreover, there is no need to use a well-characterized reference beam, since the two-photon scheme already makes use of one of the photons as reference for holography.

Description, A room-temperature on-chip orbital angular momentum source that emits well-collimated single photons has been demonstrated., On-chip photon sources carrying orbital angular momentum (OAM) are in demand for high-capacity optical information processing in both classical and quantum regimes. However, currently exploited integrated OAM sources have been primarily limited to the classical regime. Here, we demonstrate a room-temperature on-chip integrated OAM source that emits well-collimated single photons, with a single-photon purity of g(2)(0) ≈ 0.22, carrying entangled spin and OAM states and forming two spatially separated entangled radiation channels with different polarization properties. The OAM-encoded single photons are generated by efficiently outcoupling diverging surface plasmon polaritons excited with a deterministically positioned quantum emitter via Archimedean spiral gratings. Our OAM single-photon source platform bridges the gap between conventional OAM manipulation and nonclassical light sources, enabling high-dimensional and large-scale photonic quantum systems for quantum information processing.

Description, Optimization of DTD-tRNA code and mito-tRNA(Gly) discriminator base is important for emergence of mitochondria., Mitochondria emerged through an endosymbiotic event involving a proteobacterium and an archaeal host. However, the process of optimization of cellular processes required for the successful evolution and survival of mitochondria, which integrates components from two evolutionarily distinct ancestors as well as novel eukaryotic elements, is not well understood. We identify two key switches in the translational machinery—one in the discriminator recognition code of a chiral proofreader DTD [d-aminoacyl–transfer RNA (tRNA) deacylase] and the other in mitochondrial tRNAGly—that enable the compatibility between disparate elements essential for survival. Notably, the mito-tRNAGly discriminator element is the only one to switch from pyrimidine to purine during the bacteria-to-mitochondria transition. We capture this code transition in the Jakobida, an early diverging eukaryotic clade bearing the most bacterial-like mito-genome, wherein both discriminator elements are present. This study underscores the need to explore the fundamental integration strategies critical for mitochondrial and eukaryotic evolution.

Description, Trio-based whole-genome sequencing identified the role of chromatin modification in OCD pathology., Obsessive-compulsive disorder (OCD) is a chronic anxiety disorder with a substantial genetic basis and a broadly undiscovered etiology. Recent studies of de novo mutation (DNM) exome-sequencing studies for OCD have reinforced the hypothesis that rare variation contributes to the risk. We performed, to our knowledge, the first whole-genome sequencing on 53 parent-offspring families with offspring affected with OCD to investigate all rare de novo variants and insertions/deletions. We observed higher mutation rates in promoter-anchored chromatin loops (empirical P = 0.0015) and regions with high frequencies of histone marks (empirical P = 0.0001). Mutations affecting coding regions were significantly enriched within coexpression modules of genes involved in chromatin modification during human brain development. Four genes—SETD5, KDM3B, ASXL3, and FBL—had strong aggregated evidence and functionally converged on transcription’s epigenetic regulation, suggesting an important OCD risk mechanism. Our data characterized different genome-wide DNMs and highlighted the contribution of chromatin modification in the etiology of OCD.