Search

Abstract Because of similar astronomical background, Marine Isotope Stage (MIS) 11 is viewed as an analogue of the Holocene, but the evolution of seasonal climatic instability during MIS 11 has not been well investigated. Here we present a time series of land-snail eggs—a recently-developed proxy of seasonal cooling events—from the Chinese Loess Plateau (CLP) to investigate seasonal climatic instability during MIS 11 and adjacent glacials. Due to the impact of low temperatures on egg hatching, egg-abundance peaks document seasonal cooling events. A total of five egg-abundance peaks were recorded in the CLP during MIS 12, MIS 11 and MIS 10. Three peaks are strong and occur close to glacial inception or interglacial-to-glacial transition; two weaker peaks occur during MIS11. These peaks imply seasonal climatic instability intensifies mainly during glacial initiation or transition. All these events correspond to ice-sheet growth and the loss of ice-rafted debris at high northern latitudes. Moreover, they occurred at the minima of local spring insolation during the MIS 12 and MIS 10 glacials, but at the maxima during the MIS 11 interglacial. This may contribute to the difference in the intensity of seasonal cooling events between low-eccentricity glacials and interglacials. Our results provide new evidence for understanding low-eccentricity interglacial–glacial evolution.

Scientists have been puzzled by the disparity between climate simulations of the past 12,000 years and geological records. Dong et al. reconstructed past annual and seasonal temperatures from land snail records to examine the potential seasonal bias.

Abstract Fluctuations in monsoonal climate on orbital‐ to millennial‐timescales have had a major impact on vegetation change in East Asia since the last deglaciation. However, the influence of centennial‐scale oscillations on the spatio‐temporal characteristics of vegetation and climate during the last deglaciation remains controversial. We present a well‐dated, decadal‐resolution pollen record from the sediments of annually laminated Lake Xiaolongwan in Northeast Asia, which reveals major orbital‐/millennial‐scale and minor quasi‐periodic, that is, ∼500‐year (yr) cyclic, vegetation changes from ∼19.96 to ∼10.79 Kyr ago (covering the last deglaciation). The ∼500‐yr cycles are characterized by alternations in broadleaved forest/boreal coniferous forest with tundra steppe representing warm and humid/cold and dry phases of the monsoonal climate. This cyclicity may be related to El Niño‐like/La Niña‐like state and low‐latitude atmosphere‐ocean processes, against the background of the long‐term trend of the deglacial climatic evolution. Our findings demonstrate a close relationship between ecosystem succession and climate change on centennial scale.

The magnitude and rate of the expansion of the East Asian summer monsoon (EASM) rain belt under future climatic warming are unclear. Appropriate ecological proxy data may provide an improved understanding of the spatial extension of the EASM during past warming intervals. We reconstructed the spatiotemporal pattern of the extension of the EASM since the Last Glacial Maximum (LGM), using six well-dated mollusk fossil sequences from Chinese loess sections located on the modern northern edge of the EASM. The abundance of typical dominant mollusk species indicative of EASM intensity shows a delayed response, from ∼17 ka in the southeastern sections to ∼9 ka in the northwestern sections, during the last deglacial warming. Isoline plots based on a mollusk data synthesis show that the mollusk EASM indicators have a northeast–southwest zonal distribution for both the present-day, the cold LGM, and the warm mid-Holocene, which is consistent with the spatial pattern of modern precipitation. The resulting estimated expansion rate of EASM intensity accelerated during ∼12–9 ka (∼50 km/ka), which corresponds to the early Holocene interval of rapid climatic warming, a northwestward shift of ∼150 km compared to today. This implies that the northern fringe of the EASM in northern China will become wetter in the coming century, under moderate warming scenarios.

Abstract Respiratory syncytial virus (RSV) is the major cause of bronchiolitis and pneumonia in young children and the elderly. There are currently no approved RSV-specific therapeutic small molecules available. Using high-throughput antiviral screening, we identified an oral drug, the prenylation inhibitor lonafarnib, which showed potent inhibition of the RSV fusion process. Lonafarnib exhibited antiviral activity against both the RSV A and B genotypes and showed low cytotoxicity in HEp-2 and human primary bronchial epithelial cells (HBEC). Time-of-addition and pseudovirus assays demonstrated that lonafarnib inhibits RSV entry, but has farnesyltransferase-independent antiviral efficacy. Cryo-electron microscopy revealed that lonafarnib binds to a triple-symmetric pocket within the central cavity of the RSV F metastable pre-fusion conformation. Mutants at the RSV F sites interacting with lonafarnib showed resistance to lonafarnib but remained fully sensitive to the neutralizing monoclonal antibody palivizumab. Furthermore, lonafarnib dose-dependently reduced the replication of RSV in BALB/c mice. Collectively, lonafarnib could be a potential fusion inhibitor for RSV infection.

Abstract Recombinant adeno-associated viruses (rAAVs) have emerged as promising gene therapy vectors due to their proven efficacy and safety in clinical applications. In non-human primates (NHPs), rAAVs are administered via suprachoroidal injection at a higher dose. However, high doses of rAAVs tend to increase additional safety risks. Here, we present a novel AAV capsid (AAVv128), which exhibits significantly enhanced transduction efficiency for photoreceptors and retinal pigment epithelial (RPE) cells, along with a broader distribution across the layers of retinal tissues in different animal models (mice, rabbits, and NHPs) following intraocular injection. Notably, the suprachoroidal delivery of AAVv128-anti-VEGF vector completely suppresses the Grade IV lesions in a laser-induced choroidal neovascularization (CNV) NHP model for neovascular age-related macular degeneration (nAMD). Furthermore, cryo-EM analysis at 2.1 Å resolution reveals that the critical residues of AAVv128 exhibit a more robust advantage in AAV binding, the nuclear uptake and endosome escaping. Collectively, our findings highlight the potential of AAVv128 as a next generation ocular gene therapy vector, particularly using the suprachoroidal delivery route.

Abstract The SARS-CoV-2 Omicron variant evades most currently approved neutralizing antibodies (nAbs) and caused drastic decrease of plasma neutralizing activity elicited by vaccination or prior infection, urging the need for the development of pan-variant antivirals. Breakthrough infection induces a hybrid immunological response with potentially broad, potent and durable protection against variants, therefore, convalescent plasma from breakthrough infection may provide a broadened repertoire for identifying elite nAbs. We performed single-cell RNA sequencing (scRNA-seq) and BCR sequencing (scBCR-seq) of B cells from BA.1 breakthrough-infected patients who received 2 or 3 previous doses of inactivated vaccine. Elite nAbs, mainly derived from the IGHV2–5 and IGHV3-66/53 germlines, showed potent neutralizing activity across Wuhan-Hu-1, Delta, Omicron sublineages BA.1 and BA.2 at picomolar NT50 values. Cryo-EM analysis revealed diverse modes of spike recognition and guides the design of cocktail therapy. A single injection of paired antibodies cocktail provided potent protection in the K18-hACE2 transgenic female mouse model of SARS-CoV-2 infection.

Metafibers expand the functionalities of conventional optical fibres to unprecedented nanoscale light manipulations by integrating metasurfaces on the fibre tips, becoming an emerging light-coupling platform for both the nanoscience and fibre optics communities. Current metafibers remain proof-of-concept demonstrations that mostly explore isolated bare fibres owing to the lack of standard interfaces with universal fibre networks. Here, we develop methodologies for fabricating well-defined plasmonic metasurfaces directly on the end facets of commercial single -mode fibre jumpers using standard planar technologies and provide the first demonstration of their practical applications in the nonlinear plasmonic regime. Featuring plug-and-play connections with fibre circuitry and arbitrary metasurface landscapes, the metafibers with tunable plasmonic resonances are implemented into fibre laser cavities, yielding all-fibre sub-picosecond (minimum 513 fs) soliton mode locked lasers at optical wavelengths of 1.5 μm and 2 μm, demonstrating their unusual polarimetric nonlinear transfer functions and superior saturation absorption responses. The nanofabrication process flow is compatible with existing cleanroom technologies, offering metafibers an avenue to become a regular member of functionalised fibre components. This work paves the way toward the next generation of ultrafast lasers, optical frequency combs, and ultracompact ‘all-in-fibre’ optical systems.

Neutralizing antibodies are currently one versatile strategy to treat SARS-CoV-2 infection. Here, Li et al. characterize three monoclonal antibodies neutralizing authentic virus infection in vitro and in vivo by targeting the receptor binding domain as evidenced by Cryo-EM.

Objective: Chronic inflammatory response plays a prominent role in obesity-related nonalcoholic fatty liver disease (NAFLD). However, the intrahepatic triggering mechanism of inflammation remains obscure. This study aimed to elucidate the role of serum amyloid A1 (SAA1), an acute-phase response protein, in the obesity-induced hepatic inflammation and NAFLD. Methods: Male mice were fed a high fat diet (HFD) for 16 weeks, and insulin resistance, hepatic steatosis, and inflammation in mice were monitored. Murine SAA1/2 was genetically manipulated to investigate the role of SAA1 in NAFLD. Results: We found that SAA1 was increased in the NAFLD liver in both humans and mice. Knockout of SAA1/2 or knockdown of hepatic SAA1/2 promoted energy expenditure and alleviated HFD-induced metabolic disorder, hepatic steatosis, and inflammation. Endogenous overexpression of SAA1 in hepatocytes by adeno-associated virus 8 (AAV8) transfection aggravated overnutrition-associated gain of body weight, insulin resistance, hepatic lipid accumulation, and liver injury, which were markedly alleviated by knockout of murine toll-like receptor 4 (TLR4). Mechanistically, SAA1 directly bound with TLR4/myeloid differentiation 2 (MD2) to induce TLR4 internalization, leading to the activation of nuclear factor (NF)-κB signaling and production of both SAA1 and other inflammatory cytokines, including interleukin (IL)-6 and C–C chemokine ligand (CCL2) in hepatocytes. Administration of HFD mice with an AAV8-shRNA-SAA1/2 showed a therapeutic effect on hepatic inflammation and NAFLD progression. Conclusions: These results demonstrate that SAA1 triggers hepatic steatosis and intrahepatic inflammatory response by forming a SAA1/TLR4/NF-κB/SAA1 feedforward regulatory circuit, which, in turn, leads to NAFLD progression. SAA1 may act as a potential target for the disease intervention.