Monocytes Release Pro-Cathepsin D to Drive Blood-to-Brain Transcytosis in Diabetes.

BACKGROUND: Microvascular complications are the major outcome of type 2 diabetes progression, and the underlying mechanism remains to be determined. METHODS: High-throughput RNA sequencing was performed using human monocyte samples from controls and diabetes. The transgenic mice expressing human CTSD (cathepsin D) in the monocytes was constructed using CD68 promoter. In vivo 2-photon imaging, behavioral tests, immunofluorescence, transmission electron microscopy, Western blot analysis, vascular leakage assay, and single-cell RNA sequencing were performed to clarify the phenotype and elucidate the molecular mechanism. RESULTS: Monocytes expressed high-level CTSD in patients with type 2 diabetes. The transgenic mice expressing human CTSD in the monocytes showed increased brain microvascular permeability resembling the diabetic microvascular phenotype, accompanied by cognitive deficit. Mechanistically, the monocytes release nonenzymatic pro-CTSD to upregulate caveolin expression in brain endothelium triggering caveolae-mediated transcytosis, without affecting the paracellular route of brain microvasculature. The circulating pro-CTSD activated the caveolae-mediated transcytosis in brain endothelial cells via its binding with low-density LRP1 (lipoprotein receptor-related protein 1). Importantly, genetic ablation of CTSD in the monocytes exhibited a protective effect against the diabetes-enhanced brain microvascular transcytosis and the diabetes-induced cognitive impairment. CONCLUSIONS: These findings uncover the novel role of circulatory pro-CTSD from monocytes in the pathogenesis of cerebral microvascular lesions in diabetes. The circulatory pro-CTSD is a potential target for the intervention of microvascular complications in diabetes.

High Performance Nacre Fibers by Engineering Interfacial Entanglement.

Biological materials exhibit fascinating mechanical properties for intricate interactions at multiple interfaces to combine superb toughness with wondrous strength and stiffness. Recently, strong interlayer entanglement has emerged to replicate the powerful dissipation of natural proteins and alleviate the conflict between strength and toughness. However, designing intricate interactions in a strong entanglement network needs to be further explored. Here, we modulate interlayer entanglement by introducing multiple interactions, including hydrogen and ionic bonding, and achieve ultrahigh mechanical performance of graphene-based nacre fibers. Two essential modulating trends are directed. One is modulating dynamic hydrogen bonding to improve the strength and toughness up to 1.58 GPa and 52 MJ/m3, simultaneously. The other is tailoring ionic coordinating bonding to raise the strength and stiffness, reaching 2.3 and 253 GPa. Modulating various interactions within robust entanglement provides an effective approach to extend performance limits of bioinspired nacre and optimize multiscale interfaces in diverse composites.

Advances in Nanomaterials for Immunotherapeutic Improvement of Cancer Chemotherapy.

Immuno-stimulative effect of chemotherapy (ISECT) is recognized as a potential alternative to conventional immunotherapies, however, the clinical application is constrained by its inefficiency. Metronomic chemotherapy, though designed to overcome these limitations, offers inconsistent results, with effectiveness varying based on cancer types, stages, and patient-specific factors. In parallel, a wealth of preclinical nanomaterials holds considerable promise for ISECT improvement by modulating the cancer-immunity cycle. In the area of biomedical nanomaterials, current literature reviews mainly concentrate on a specific category of nanomaterials and nanotechnological perspectives, while two essential issues are still lacking, i.e., a comprehensive analysis addressing the causes for ISECT inefficiency and a thorough summary elaborating the nanomaterials for ISECT improvement. This review thus aims to fill these gaps and catalyze further development in this field. For the first time, this review comprehensively discusses the causes of ISECT inefficiency. It then meticulously categorizes six types of nanomaterials for improving ISECT. Subsequently, practical strategies are further proposed for addressing inefficient ISECT, along with a detailed discussion on exemplary nanomedicines. Finally, this review provides insights into the challenges and perspectives for improving chemo-immunotherapy by innovations in nanomaterials.

Liquid Crystalline Nanoparticles via Polymerization-Induced Self-Assembly: Morphology Evolution and Function Regulation.

Liquid crystalline nanoparticles (LC NPs) are a kind of polymer NPs with LC mesogens, which can form special anisotropic morphologies due to the influence of LC ordering. Owing to the stimuli-responsiveness of the LC blocks, LC NPs show abundant morphology evolution behaviors in response to external regulation. LC NPs have great application potential in nano-devices, drug delivery, special fibers and other fields. Polymerization-induced self-assembly (PISA) method can synthesize LC NPs at high solid content, reducing the harsh demand for reaction solvent of the LC polymers, being a better choice for large-scale production. In this review, we introduced recent research progress of PISA-LC NPs by dividing them into several parts according to the LC mesogen, and discussed the improvement of experimental conditions and the potential application of these polymers.

Hyperoside induces cell cycle arrest and suppresses tumorigenesis in bladder cancer through the interaction of EGFR-Ras and Fas signaling pathways.

Hyperoside is a natural flavonol glycoside widely found in plants and has been reported to have a variety of pharmacological effects, including anticancer abilities. In this study, we demonstrated for the first time that hyperoside inhibited the proliferation of bladder cancer cells in vitro and in vivo. Moreover, hyperoside could not only induce cell cycle arrest, but also induce apoptosis of a few bladder cancer cells. Quantitative proteomics, bioinformatics analysis and Western blotting confirmed that hyperoside induced the overexpression of EGFR, Ras and Fas proteins, which affects a variety of synergistic and antagonistic downstream signaling pathways, including MAPKs and Akt, ultimately contributing to its anticancer effects in bladder cancer cells. This study reveals that hyperoside could be a promising therapeutic strategy for the prevention of bladder cancer.

Association between risk of preterm birth and long-term and short-term exposure to ambient carbon monoxide during pregnancy in chongqing, China: a study from 2016-2020.

BACKGROUND: Preterm birth (PTB) is an important predictor of perinatal morbidity and mortality. Previous researches have reported a correlation between air pollution and an increased risk of preterm birth. However, the specific relationship between short-term and long-term exposure to carbon monoxide (CO) and preterm birth remains less explored. METHODS: A population-based study was conducted among 515,498 pregnant women in Chongqing, China, to assess short-term and long-term effects of CO on preterm and very preterm births. Generalized additive models (GAM) were applied to evaluate short-term effects, and exposure-response correlation curves were plotted after adjusting for confounding factors. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated using COX proportional hazard models to estimate the long-term effect. RESULTS: The daily incidence of preterm and very preterm birth was 5.99% and 0.41%, respectively. A positive association between a 100 µg/m³ increase in CO and PTB was observed at lag 0-3 days and 12-21 days, with a maximum relative risk (RR) of 1.021(95%CI: 1.001-1.043). The exposure-response curves (lag 0 day) revealed a rapid increase in PTB due to CO. Regarding long-term exposure, positive associations were found between a 100 µg/m3 CO increase for each trimester(Model 2 for trimester 1: HR = 1.054, 95%CI: 1.048-1.060; Model 2 for trimester 2: HR = 1.066, 95%CI: 1.060-1.073; Model 2 for trimester 3: HR = 1.007, 95%CI: 1.001-1.013; Model 2 for entire pregnancy: HR = 1.080, 95%CI: 1.073-1.088) and higher HRs of very preterm birth. Multiplicative interactions between air pollution and CO on the risk of preterm and very preterm birth were detected (P- interaction<0.05). CONCLUSIONS: Our findings suggest that short-term exposure to low levels of CO may have protective effects against preterm birth, while long-term exposure to low concentrations of CO may reduce the risk of both preterm and very preterm birth. Moreover, our study indicated that very preterm birth is more susceptible to the influence of long-term exposure to CO during pregnancy, with acute CO exposure exhibiting a greater impact on preterm birth. It is imperative for pregnant women to minimize exposure to ambient air pollutants.

JcSEUSS1 negatively regulates reproductive organ development in perennial woody Jatropha curcas.

MAIN CONCLUSION: Overexpression of JcSEUSS1 resulted in late flowering, reduced flower number, wrinkled kernels, and decreased seed yield in Jatopha curcas, while downregulation of JcSEUSS1 increased flower number and seed production. The seed oil of Jatropha curcas is suitable as an ideal alternative for diesel fuel, yet the seed yield of Jatropha is restricted by its small number of female flowers and low seed setting rate. Therefore, it is crucial to identify genes that regulate flowering and seed set, and hence improve seed yield. In this study, overexpression of JcSEUSS1 resulted in late flowering, fewer flowers and fruits, and smaller fruits and seeds, causing reduced seed production and oil content. In contrast, the downregulation of JcSEUSS1 by RNA interference (RNAi) technology caused an increase in the flower number and seed yield. However, the flowering time, seed number per fruit, seed weight, and size exhibited no obvious changes in JcSEUSS1-RNAi plants. Moreover, the fatty acid composition also changed in JcSEUSS1 overexpression and RNAi plants, the percentage of unsaturated fatty acids (FAs) was increased in overexpression plants, and the saturated FAs were increased in RNAi plants. These results indicate that JcSEUSS1 played a negative role in regulating reproductive growth and worked redundantly with other genes in the regulation of flowering time, seed number per fruit, seed weight, and size.

Telecom-wavelength conversion in a high optical depth cold atomic system.

We experimentally investigate the frequency down-conversion through the four-wave mixing (FWM) process in a cold 85Rb atomic ensemble, with a diamond-level configuration. An atomic cloud with a high optical depth (OD) of 190 is prepared to achieve a high efficiency frequency conversion. Here, we convert a signal pulse field (795 nm) attenuated to a single-photon level, into a telecom light at 1529.3 nm within near C-band range and the frequency-conversion efficiency can reach up to 32%. We find that the OD is an essential factor affecting conversion efficiency and the efficiency may exceed 32% with an improvement in the OD. Moreover, we note the signal-to-noise ratio of the detected telecom field is higher than 10 while the mean signal count is larger than 0.2. Our work may be combined with quantum memories based on cold 85Rb ensemble at 795 nm and serve for long-distance quantum networks.

Optical memory for arbitrary perfect Poincaré states in an atomic ensemble.

Inherent spin angular momentum (SAM) and orbital angular momentum (OAM), which manifest as polarization and spatial degrees of freedom (DOFs) of photons, hold a promise of large capability for applications in classical and quantum information processing. To enable these photonic spin and orbital dynamic properties strongly coupled with each other, Poincaré states have been proposed and offer advantages in data multiplexing, information encryption, precision metrology, and quantum memory. However, since the transverse size of Laguerre-Gaussian beams strongly depends on their topological charge numbers | l |, it is difficult to store asymmetric Poincaré states due to the significantly different light-matter interaction for distinct spatial modes. Here, we experimentally realize the storage of perfect Poincaré states with arbitrary OAM quanta using the perfect optical vortex, in which 121 arbitrarily selected perfect Poincaré states have been stored with high fidelity. The reported work has great prospects in optical communication and quantum networks for dramatically increased encoding flexibility of information.

Highly Efficient Storage of 25-Dimensional Photonic Qudit in a Cold-Atom-Based Quantum Memory.

Building an efficient quantum memory in high-dimensional Hilbert spaces is one of the fundamental requirements for establishing high-dimensional quantum repeaters, where it offers many advantages over two-dimensional quantum systems, such as a larger information capacity and enhanced noise resilience. To date, it remains a challenge to develop an efficient high-dimensional quantum memory. Here, we experimentally realize a quantum memory that is operational in Hilbert spaces of up to 25 dimensions with a storage efficiency of close to 60% and a fidelity of 84.2±0.6%. The proposed approach exploits the spatial-mode-independent interaction between atoms and photons which are encoded in transverse-size-invariant vortex modes. In particular, our memory features uniform storage efficiency and low crosstalk disturbance for 25 individual spatial modes of photons, thus allowing the storing of qudit states programmed from 25 eigenstates within the high-dimensional Hilbert spaces. These results have great prospects for the implementation of long-distance high-dimensional quantum networks and quantum information processing.

Pirh2 restricts influenza A virus replication by modulating short-chain ubiquitination of its nucleoprotein.

Influenza A viruses (IAVs) rely on viral ribonucleoprotein (vRNP) complexes to control transcription and replication. Each vRNP consists of one viral genomic RNA segment associated with multiple nucleoproteins (NP) and a trimeric IAV RNA polymerase complex. Previous studies showed that post-translational modifications of vRNP components, such as NP, by host factors would in turn affect the IAV life cycle or modulate host anti-viral response. In this study, we found host E3 ubiquitin ligase Pirh2 interacted with NP and mediated short-chain ubiquitination of NP at lysine 351, which suppressed NP-PB2 interaction and vRNP formation. In addition, we showed that knockdown of Pirh2 promoted IAV replication, whereas overexpression of Pirh2 inhibited IAV replication. However, Pirh2-ΔRING lacking E3 ligase activity failed to inhibit IAV infection. Moreover, we showed that Pirh2 had no effect on the replication of a rescued virus, WSN-K351R, carrying lysine-to-arginine substitution at residue 351. Interestingly, by analyzing human and avian IAVs from 2011 to 2020 in influenza research databases, we found that 99.18% of 26 977 human IAVs encode lysine, but 95.3% of 9956 avian IAVs encode arginine at residue 351 of NP protein. Consistently, knockdown of Pirh2 failed to promote propagation of two avian-like influenza viruses, H9N2-W1 and H9N2-C1, which naturally encode arginine at residue 351 of NP. Taken together, we demonstrated that Pirh2 is a host factor restricting IAV infection by modulating short-chain ubiquitination of NP. Meanwhile, it is noteworthy that residue 351 of NP targeted by Pirh2 may associate with the evasion of human anti-viral response against avian-like influenza viruses.

Pseudorabies virus kinase UL13 phosphorylates H2AX to foster viral replication.

The DNA damage response (DDR) pathway is critical for maintaining genomic integrity and sustaining organismal development. Viruses can either utilize or circumvent the DDR to facilitate their replication. Pseudorabies virus (PRV) infection was shown to induce apoptosis via stimulating DDR. However, the underlying mechanisms have not been fully explored to date. This study showed that PRV infection robustly activates the ATM and DNA-PK signaling pathways shortly after infection. However, inhibition of ATM, but not DNA-PK, could dampen PRV replication in cells. Importantly, we found that PRV-encoded serine/threonine kinase UL13 interacts with and subsequently phosphorylates H2AX. Furthermore, we found that UL13 deletion largely attenuates PRV neuroinvasiveness and virulence in vivo. In addtion, we showed that UL13 contributes to H2AX phosphorylation upon PRV infection both in vitro and in vivo, but does not affect ATM phosphorylation. Finally, we showed that knockdown of H2AX reduces PRV replication, while this reduction can be further enhanced by deletion of UL13. Taken together, we conclude that PRV-encoded kinase UL13 regulates DNA damage marker γH2AX and UL13-mediated H2AX phosphorylation plays a pivotal role in efficient PRV replication and progeny production.

In Situ Transformation of Metal Molybdates into Polymetallic Sulfides with Enriched Edge Sites for High-Performance Supercapacitors.

An effective approach to synthesize polycrystalline Ni-Co-Mo sulfide (NiCoMoS) is developed through doping engineering coupled with chemical transformation. The polycrystalline NiCoMoS with enriched active edge sites is designed and fabricated on a Ni foam (NF) via a facile hydrothermal calcination and post-sulfidation approach, where the polycrystalline NiCoMoO4 precursor is elaborately prepared by doping Co ions into the NiMoO4 lattice and subsequently in-situ-converted into NiCoMoS with 3D architectures of ordered nanoneedle arrays. Benefiting from the unique 3D structure and synergistic effects of each component, the optimized needle-like NiCoMoS(2.0) arraying on a NF as a self-standing electrode exhibits superior electrochemical performances with a high specific charge (920.0 C g-1 at 1.0 A g-1), excellent rate capability, and good long-term stability. Furthermore, the assembled NiCoMoS//activated carbon hybrid device presents a satisfactory supercapacitor performance, affording an energy density of 35.2 W h kg-1 at a power density of 800.0 W kg-1 and competitive long-term stability (83.8% retention at 15 A g-1 after 10,000 cycles). Such a novel strategy may pave a new route for exploring other polymetallic sulfides with enriched, exposed active edge sites for energy-related applications.

Biogeochemical controls on climatically active gases and atmospheric sulfate aerosols in the western Pacific.

The Pacific Ocean plays an important role in regulating the budget of climatically active gases and the burden of sulfate aerosols. Here, a field investigation was conducted to clarify the key processes and factors controlling climatically active gases, including dimethyl sulfide (DMS), carbonyl sulfide (OCS), carbon disulfide (CS2), and carbon dioxide (CO2), in both surface seawater and the lower atmosphere of the western Pacific. In addition, the relative contributions of different sources to atmospheric sulfate aerosols were quantitatively estimated, and their causes were explored. The maximum concentrations of DMS, OCS and CS2 and the minimum partial pressure of CO2 (pCO2) were observed in the Kuroshio-Oyashio Extension. Kuroshio-induced mesoscale eddies brought abundant nutrients and organic matter from the subsurface layer of Oyashio into the euphotic layer, thus enhancing primary productivity and accelerating the photoreaction of organic matter. These processes led to higher concentrations of DMS, OCS and CS2 and lower pCO2. However, the oligotrophic subsurface layer in the subtropical gyre and the strong barrier layer in the equatorial waters suppressed the upward fluxes of nutrients and organic matter, resulting in lower surface concentrations of DMS, OCS, and CS2 in these areas. Being far from the continents, atmospheric concentrations of DMS, OCS and CS2 and pCO2 in the western Pacific generally were observed to depend on the local sea-to-air exchange and may be regulated by atmospheric oxidation and mixing of air masses. In general, oceanic DMS emissions played an important role in the formation of sulfate aerosols in the western Pacific (accounting for ∼19.5% of total sulfate aerosols), especially in the Kuroshio-Oyashio Extension (∼32.3%). These processes in seawater may also determine the variations and emissions of other climatically active gases from biogenic and photochemical sources.

The mechanism of acid resistance by ornithine decarboxylase in Trichinella spiralis.

Trichinella spiralis is a zoonotic parasite with worldwide distribution that can seriously harm human health and animal husbandry. Ornithine decarboxylase is a component of the acid resistance (AR) system in Escherichia coli. The aim of this study was to investigate the role that T. spiralis ornithine decarboxylase (TsODC) plays in the acid resistance mechanism of T. spiralis. This study involved assessing the transcription and expression of TsODC in worms under acidic conditions. According to mRNA sequences published by NCBI and the results of molecular biology experiments, the complete TsODC sequence was cloned and expressed. rTsODC had good immunogenicity, and immunofluorescence analysis revealed that TsODC was principally localized on the surface tissues of the nematode, especially at the head and tail. qRT‒PCR and Western blotting analysis indicated that the relative expression levels of TsODC mRNA and protein were highest when cultured at pH 2.5 for 2 h. The muscle larvae (ML) of T. spiralis were treated with curcumin and rapamycin, as well as arginine and TsODC polyantisera. The expression levels of TsODC mRNA and protein were significantly increased by arginine and suppressed by curcumin and rapamycin. After reducing the amount of TsODC, the relative expression of TsODC mRNA and the survival rate of T. spiralis ML were both reduced when compared to these values in the phosphate-buffered saline (PBS) group. The results indicated that TsODC is a member of the T. spiralis AR system and different treatments on TsODC have different effects; thus, these treatments might be a new way to prevent T. spiralis infection.

Research Progress on the Structural Modification of Magnolol and Honokiol and the Biological Activities of Their Derivatives.

Magnolol and Honokiol are the primary active components that have been identified and extracted from Magnolia officinalis, and several investigations have demonstrated that they have significant pharmacological effects. Despite their therapeutic benefits for a wide range of illnesses, research on and the implementation of these compounds have been hindered by their poor water solubility and low bioavailability. Researchers are continually using chemical methods to alter their structures to make them more effective in treating and preventing diseases. Researchers are also continuously developing derivative drugs with high efficacy and few adverse effects. This article summarizes and analyzes derivatives with significant biological activities reported in recent research obtained by structural modification. The modification sites have mainly focused on the phenolic hydroxy groups, benzene rings, and diene bonds. Changes to the allyl bisphenol structure will result in unexpected benefits, including high activity, low toxicity, and good bioavailability. Furthermore, alongside earlier experimental research in our laboratory, the structure-activity relationships of magnolol and honokiol were preliminarily summarized, providing experimental evidence for improving their development and utilization.

[A glass micropipette vacuum technique of cerebrospinal fluid sampling in C57BL/6 mice].

The purpose of this study was to establish a suitable method for extracting cerebrospinal fluid (CSF) from C57BL/6 mice. A patch clamp electrode puller was used to draw a glass micropipette, and a brain stereotaxic device was used to fix the mouse's head at an angle of 135° from the body. Under a stereoscopic microscope, the skin and muscle tissue on the back of the mouse's head were separated, and the dura mater at the cerebellomedullary cistern was exposed. The glass micropipette (with an angle of 20° to 30° from the dura mater) was used to puncture at a point 1 mm inboard of Y-shaped dorsal vertebral artery for CSF sampling. After the first extraction, the glass micropipette was connected with a 1 mL sterile syringe to form a negative pressure device for the second extraction. The results showed that the successful rate of CSF extraction was 83.33% (30/36). Average CSF extraction amount was (7.16 ± 0.43) µL per mouse. In addition, C57BL/6 mice were given intranasally ferric ammonium citrate (FAC) to establish a model of brain iron accumulation, and the CSF extraction technique established in the present study was used for sampling. The results showed that iron content in the CSF from the normal saline control group was not detected, while the iron content in the CSF from FAC-treated group was (76.24 ± 38.53) µmol/L, and the difference was significant. These results suggest that glass micropipette vacuum technique of CSF sampling established in the present study has the advantages of simplicity, high success rate, large extraction volume, and low bleeding rate, and is suitable for the research on C57BL/6 mouse neurological disease models.

[Clinical efficacy of omalizumab for treatment of moderate or severe allergic asthma in children with serum immunoglobulin E levels >1 500 IU/mL: a prospective study]. / å¥¥é©¬ç å•æŠ—æ²»ç–—è¡€æ¸ æ€»IgE>1 500 IU/mLçš„ä¸­é‡åº¦è¿‡æ•æ€§å“®å–˜å„¿ç«¥çš„å‰çž»æ€§ç ”ç©¶.

OBJECTIVES: To evaluate the clinical efficacy of omalizumab in the treatment of moderate or severe allergic asthma in children with serum total immunoglobulin E (IgE) levels >1 500 IU/mL. METHODS: A total of 95 children with moderate or severe allergic asthma, who were treated at the Department of Respiratory Medicine in Anhui Provincial Children's Hospital from December 2020 to May 2022, were enrolled. Based on their serum total IgE levels and whether they received omalizumab treatment, they were divided into a control group (IgE >1 500 IU/mL, no omalizumab treatment), a normal treatment group (IgE levels between 30 and 1 500 IU/mL, omalizumab treatment), and an ultra-high IgE treatment group (IgE >1 500 IU/mL, omalizumab treatment). The differences in clinical characteristics, Childhood Asthma Control Test (C-ACT) scores before and after treatment, the proportion of acute attacks, IgE levels, pulmonary function indicators, and fractional exhaled nitric oxide (FeNO) concentrations were analyzed among the three groups. RESULTS: At the 8th week of treatment, the normal treatment group and the ultra-high IgE treatment group had higher C-ACT scores, forced expiratory volume in first second (FEV1) as a percentage of predicted value (FEV1%pred), FEV1/forced vital capacity (FVC) ratio (FEV1/FVC), and peak expiratory flow (PEF) as a percentage of predicted value (PEF%pred), as well as a lower proportion of acute attacks and FeNO concentration compared to the control group (P<0.05). There were no statistically significant differences in the comparison of various indicators between the ultra-high IgE treatment group and the normal treatment group (P>0.05). At the 16th week of treatment, the normal treatment group and the ultra-high IgE treatment group had higher C-ACT scores and pulmonary function indicators including FEV1%pred, FEV1/FVC, PEF%pred, and forced expiratory flow at 25% vital capacity (FEF25) as a percentage of predicted value (FEF25%pred) compared to the control group (P<0.05). The proportion of acute attacks and FeNO concentration in the ultra-high IgE treatment group were lower than those in the control group (P<0.05). There were no statistically significant differences in the comparison of various indicators between the ultra-high IgE treatment group and the normal treatment group (P>0.05). CONCLUSIONS: Omalizumab therapy has a certain clinical efficacy in children with moderate or severe allergic asthma and serum total IgE levels >1 500 IU/mL, with no significant difference in efficacy compared to children with serum total IgE levels between 30 and 1 500 IU/mL.

A New Segmented Virus Associated with Human Febrile Illness in China.

BACKGROUND: In 2017, surveillance for tickborne diseases in China led to the identification of a patient who presented to a hospital in Inner Mongolia with a febrile illness that had an unknown cause. The clinical manifestation of the illness was similar to that of tickborne encephalitis virus (TBEV) infection, but neither TBEV RNA nor antibodies against the virus were detected. METHODS: We obtained a blood specimen from the index patient and attempted to isolate and identify a causative pathogen, using genome sequence analysis and electron microscopy. We also initiated a heightened surveillance program in the same hospital to screen for other patients who presented with fever, headache, and a history of tick bites. We used reverse-transcriptase-polymerase-chain-reaction (RT-PCR) and cell-culture assays to detect the pathogen and immunofluorescence and neutralization assays to determine the levels of virus-specific antibodies in serum specimens from the patients. RESULTS: We found that the index patient was infected with a previously unknown segmented RNA virus, which we designated Alongshan virus (ALSV) and which belongs to the jingmenvirus group of the family Flaviviridae. ALSV infection was confirmed by RT-PCR assay in 86 patients from Inner Mongolia and Heilongjiang who presented with fever, headache, and a history of tick bites. Serologic assays showed that seroconversion had occurred in all 19 patients for whom specimens were available from the acute phase and the convalescent phase of the illness. CONCLUSIONS: A newly discovered segmented virus was found to be associated with a febrile illness in northeastern China. (Funded by the National Key Research and Development Program of China and the National Natural Science Foundation of China.).

Porcine Epidemic Diarrhea Virus Infection Induces Caspase-8-Mediated G3BP1 Cleavage and Subverts Stress Granules To Promote Viral Replication.

Porcine epidemic diarrhea virus (PEDV) is an α-coronavirus causing severe diarrhea and high mortality rates in suckling piglets and posing significant economic impact. PEDV replication is completed and results in a large amount of RNA in the cytoplasm. Stress granules (SGs) are dynamic cytosolic RNA granules formed under various stress conditions, including viral infections. Several previous studies suggested that SGs were involved in the antiviral activity of host cells to limit viral propagation. However, the underlying mechanisms are poorly understood. This study aimed to delineate the molecular mechanisms regulating the SG response to PEDV infection. SG formation is induced early during PEDV infection, but as infection proceeds, this ability is lost and SGs disappear at late stages of infection (>18 h postinfection). PEDV infection resulted in the cleavage of Ras-GTPase-activating protein-binding protein 1 (G3BP1) mediated by caspase-8. Using mutational analysis, the PEDV-induced cleavage site within G3BP1 was identified, which differed from the 3C protease cleavage site previously identified. Furthermore, G3BP1 cleavage by caspase-8 at D168 and D169 was confirmed in vitro as well as in vivo The overexpression of cleavage-resistant G3BP1 conferred persistent SG formation and suppression of viral replication. Additionally, the knockdown of endogenous G3BP1 abolished SG formation and potentiated viral replication. Taken together, these data provide new insights into novel strategies in which PEDV limits the host stress response and antiviral responses and indicate that caspase-8-mediated G3BP1 cleavage is important in the failure of host defense against PEDV infection.IMPORTANCE Coronaviruses (CoVs) are drawing extensive attention again since the outbreaks of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 2019. CoVs are prone to variation and own the transmission capability by crossing the species barrier resulting in reemergence. How CoVs manipulate the antiviral responses of their hosts needs to be explored. Overall, the study provides new insight into how porcine epidemic diarrhea virus (PEDV) impaired SG assembly by targeting G3BP1 via the host proteinase caspase-8. These findings enhanced the understanding of PEDV infection and might help identify new antiviral targets that could inhibit viral replication and limit the pathogenesis of PEDV.