Tunable quantum criticalities in an isospin extended Hubbard model simulator.

Studying strong electron correlations has been an essential driving force for pushing the frontiers of condensed matter physics. In particular, in the vicinity of correlation-driven quantum phase transitions (QPTs), quantum critical fluctuations of multiple degrees of freedom facilitate exotic many-body states and quantum critical behaviours beyond Landau's framework1. Recently, moiré heterostructures of van der Waals materials have been demonstrated as highly tunable quantum platforms for exploring fascinating, strongly correlated quantum physics2-22. Here we report the observation of tunable quantum criticalities in an experimental simulator of the extended Hubbard model with spin-valley isospins arising in chiral-stacked twisted double bilayer graphene (cTDBG). Scaling analysis shows a quantum two-stage criticality manifesting two distinct quantum critical points as the generalized Wigner crystal transits to a Fermi liquid by varying the displacement field, suggesting the emergence of a critical intermediate phase. The quantum two-stage criticality evolves into a quantum pseudo criticality as a high parallel magnetic field is applied. In such a pseudo criticality, we find that the quantum critical scaling is only valid above a critical temperature, indicating a weak first-order QPT therein. Our results demonstrate a highly tunable solid-state simulator with intricate interplay of multiple degrees of freedom for exploring exotic quantum critical states and behaviours.

Emergence and expansion of SARS-CoV-2 B.1.526 after identification in New York.

SARS-CoV-2 infections have surged across the globe in recent months, concomitant with considerable viral evolution1-3. Extensive mutations in the spike protein may threaten the efficacy of vaccines and therapeutic monoclonal antibodies4. Two signature spike mutations of concern are E484K, which has a crucial role in the loss of neutralizing activity of antibodies, and N501Y, a driver of rapid worldwide transmission of the B.1.1.7 lineage. Here we report the emergence of the variant lineage B.1.526 (also known as the Iota variant5), which contains E484K, and its rise to dominance in New York City in early 2021. This variant is partially or completely resistant to two therapeutic monoclonal antibodies that are in clinical use and is less susceptible to neutralization by plasma from individuals who had recovered from SARS-CoV-2 infection or serum from vaccinated individuals, posing a modest antigenic challenge. The presence of the B.1.526 lineage has now been reported in all 50 states in the United States and in many other countries. B.1.526 rapidly replaced earlier lineages in New York, with an estimated transmission advantage of 35%. These transmission dynamics, together with the relative antibody resistance of its E484K sub-lineage, are likely to have contributed to the sharp rise and rapid spread of B.1.526. Although SARS-CoV-2 B.1.526 initially outpaced B.1.1.7 in the region, its growth subsequently slowed concurrently with the rise of B.1.1.7 and ensuing variants.

Antibody resistance of SARS-CoV-2 variants B.1.351 and B.1.1.7.

The COVID-19 pandemic has had widespread effects across the globe, and its causative agent, SARS-CoV-2, continues to spread. Effective interventions need to be developed to end this pandemic. Single and combination therapies with monoclonal antibodies have received emergency use authorization1-3, and more treatments are under development4-7. Furthermore, multiple vaccine constructs have shown promise8, including two that have an approximately 95% protective efficacy against COVID-199,10. However, these interventions were directed against the initial SARS-CoV-2 virus that emerged in 2019. The recent detection of SARS-CoV-2 variants B.1.1.7 in the UK11 and B.1.351 in South Africa12 is of concern because of their purported ease of transmission and extensive mutations in the spike protein. Here we show that B.1.1.7 is refractory to neutralization by most monoclonal antibodies against the N-terminal domain of the spike protein and is relatively resistant to a few monoclonal antibodies against the receptor-binding domain. It is not more resistant to plasma from individuals who have recovered from COVID-19 or sera from individuals who have been vaccinated against SARS-CoV-2. The B.1.351 variant is not only refractory to neutralization by most monoclonal antibodies against the N-terminal domain but also by multiple individual monoclonal antibodies against the receptor-binding motif of the receptor-binding domain, which is mostly due to a mutation causing an E484K substitution. Moreover, compared to wild-type SARS-CoV-2, B.1.351 is markedly more resistant to neutralization by convalescent plasma (9.4-fold) and sera from individuals who have been vaccinated (10.3-12.4-fold). B.1.351 and emergent variants13,14 with similar mutations in the spike protein present new challenges for monoclonal antibody therapies and threaten the protective efficacy of current vaccines.

Nanobodies from camelid mice and llamas neutralize SARS-CoV-2 variants.

Since the start of the COVID-19 pandemic, SARS-CoV-2 has caused millions of deaths worldwide. Although a number of vaccines have been deployed, the continual evolution of the receptor-binding domain (RBD) of the virus has challenged their efficacy. In particular, the emerging variants B.1.1.7, B.1.351 and P.1 (first detected in the UK, South Africa and Brazil, respectively) have compromised the efficacy of sera from patients who have recovered from COVID-19 and immunotherapies that have received emergency use authorization1-3. One potential alternative to avert viral escape is the use of camelid VHHs (variable heavy chain domains of heavy chain antibody (also known as nanobodies)), which can recognize epitopes that are often inaccessible to conventional antibodies4. Here, we isolate anti-RBD nanobodies from llamas and from mice that we engineered to produce VHHs cloned from alpacas, dromedaries and Bactrian camels. We identified two groups of highly neutralizing nanobodies. Group 1 circumvents antigenic drift by recognizing an RBD region that is highly conserved in coronaviruses but rarely targeted by human antibodies. Group 2 is almost exclusively focused to the RBD-ACE2 interface and does not neutralize SARS-CoV-2 variants that carry E484K or N501Y substitutions. However, nanobodies in group 2 retain full neutralization activity against these variants when expressed as homotrimers, and-to our knowledge-rival the most potent antibodies against SARS-CoV-2 that have been produced to date. These findings suggest that multivalent nanobodies overcome SARS-CoV-2 mutations through two separate mechanisms: enhanced avidity for the ACE2-binding domain and recognition of conserved epitopes that are largely inaccessible to human antibodies. Therefore, although new SARS-CoV-2 mutants will continue to emerge, nanobodies represent promising tools to prevent COVID-19 mortality when vaccines are compromised.

Identification of SARS-CoV-2 inhibitors using lung and colonic organoids.

There is an urgent need to create novel models using human disease-relevant cells to study severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) biology and to facilitate drug screening. Here, as SARS-CoV-2 primarily infects the respiratory tract, we developed a lung organoid model using human pluripotent stem cells (hPSC-LOs). The hPSC-LOs (particularly alveolar type-II-like cells) are permissive to SARS-CoV-2 infection, and showed robust induction of chemokines following SARS-CoV-2 infection, similar to what is seen in patients with COVID-19. Nearly 25% of these patients also have gastrointestinal manifestations, which are associated with worse COVID-19 outcomes1. We therefore also generated complementary hPSC-derived colonic organoids (hPSC-COs) to explore the response of colonic cells to SARS-CoV-2 infection. We found that multiple colonic cell types, especially enterocytes, express ACE2 and are permissive to SARS-CoV-2 infection. Using hPSC-LOs, we performed a high-throughput screen of drugs approved by the FDA (US Food and Drug Administration) and identified entry inhibitors of SARS-CoV-2, including imatinib, mycophenolic acid and quinacrine dihydrochloride. Treatment at physiologically relevant levels of these drugs significantly inhibited SARS-CoV-2 infection of both hPSC-LOs and hPSC-COs. Together, these data demonstrate that hPSC-LOs and hPSC-COs infected by SARS-CoV-2 can serve as disease models to study SARS-CoV-2 infection and provide a valuable resource for drug screening to identify candidate COVID-19 therapeutics.

In situ visualizing reveals potential drive of lattice expansion on defective support toward efficient removal of nitrogen oxides.

As a sustainable and promising approach of removing of nitrogen oxides (NOx), catalytic reduction of NOx with H2 is highly desirable with a precise understanding to the structure-activity relationship of supported catalysts. In particular, the dynamic evolution of support at microscopic scale may play a critical role in heterogeneous catalysis, however, identifying the in situ structural change of support under working condition with atomic precision and revealing its role in catalysis is still a grand challenge. Herein, we visually capture the surface lattice expansion of WO3-x support in Pt-WO3-x catalyst induced by NO in the exemplified reduction of NO with H2 using in situ transmission electron microscopy and first reveal its important role in enhancing catalysis. We find that NO can adsorb on the oxygen vacancy sites of WO3-x and favorably induce the reversible stretching of W-O-W bonds during the reaction, which can reduce the adsorption energy of NO on Pt4 centers and the energy barrier of the rate-determining step. The comprehensive studies reveal that lattice expansion of WO3-x support can tune the catalytic performance of Pt-WO3-x catalyst, leading to 20% catalytic activity enhancement for the exemplified reduction of NO with H2. This work reveals that the lattice expansion of defective support can tune and optimize the catalytic performance at the atomic scale.

Oxygen-bridging Fe, Co dual-metal dimers boost reversible oxygen electrocatalysis for rechargeable Zn-air batteries.

Rechargeable zinc-air batteries (ZABs) are regarded as a remarkably promising alternative to current lithium-ion batteries, addressing the requirements for large-scale high-energy storage. Nevertheless, the sluggish kinetics involving oxygen reduction reaction (ORR) and oxygen evolution reaction (OER) hamper the widespread application of ZABs, necessitating the development of high-efficiency and durable bifunctional electrocatalysts. Here, we report oxygen atom-bridged Fe, Co dual-metal dimers (FeOCo-SAD), in which the active site Fe-O-Co-N6 moiety boosts exceptional reversible activity toward ORR and OER in alkaline electrolytes. Specifically, FeOCo-SAD achieves a half-wave potential (E1/2) of 0.87 V for ORR and an overpotential of 310 mV at a current density of 10 mA cm-2 for OER, with a potential gap (ΔE) of only 0.67 V. Meanwhile, FeOCo-SAD manifests high performance with a peak power density of 241.24 mW cm-2 in realistic rechargeable ZABs. Theoretical calculations demonstrate that the introduction of an oxygen bridge in the Fe, Co dimer induced charge spatial redistribution around Fe and Co atoms. This enhances the activation of oxygen and optimizes the adsorption/desorption dynamics of reaction intermediates. Consequently, energy barriers are effectively reduced, leading to a strong promotion of intrinsic activity toward ORR and OER. This work suggests that oxygen-bridging dual-metal dimers offer promising prospects for significantly enhancing the performance of reversible oxygen electrocatalysis and for creating innovative catalysts that exhibit synergistic effects and electronic states.

Tirofiban for Stroke without Large or Medium-Sized Vessel Occlusion.

BACKGROUND: The effects of the glycoprotein IIb/IIIa receptor inhibitor tirofiban in patients with acute ischemic stroke but who have no evidence of complete occlusion of large or medium-sized vessels have not been extensively studied. METHODS: In a multicenter trial in China, we enrolled patients with ischemic stroke without occlusion of large or medium-sized vessels and with a National Institutes of Health Stroke Scale score of 5 or more and at least one moderately to severely weak limb. Eligible patients had any of four clinical presentations: ineligible for thrombolysis or thrombectomy and within 24 hours after the patient was last known to be well; progression of stroke symptoms 24 to 96 hours after onset; early neurologic deterioration after thrombolysis; or thrombolysis with no improvement at 4 to 24 hours. Patients were assigned to receive intravenous tirofiban (plus oral placebo) or oral aspirin (100 mg per day, plus intravenous placebo) for 2 days; all patients then received oral aspirin until day 90. The primary efficacy end point was an excellent outcome, defined as a score of 0 or 1 on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]) at 90 days. Secondary end points included functional independence at 90 days and a quality-of-life score. The primary safety end points were death and symptomatic intracranial hemorrhage. RESULTS: A total of 606 patients were assigned to the tirofiban group and 571 to the aspirin group. Most patients had small infarctions that were presumed to be atherosclerotic. The percentage of patients with a score of 0 or 1 on the modified Rankin scale at 90 days was 29.1% with tirofiban and 22.2% with aspirin (adjusted risk ratio, 1.26; 95% confidence interval, 1.04 to 1.53, P = 0.02). Results for secondary end points were generally not consistent with the results of the primary analysis. Mortality was similar in the two groups. The incidence of symptomatic intracranial hemorrhage was 1.0% in the tirofiban group and 0% in the aspirin group. CONCLUSIONS: In this trial involving heterogeneous groups of patients with stroke of recent onset or progression of stroke symptoms and nonoccluded large and medium-sized cerebral vessels, intravenous tirofiban was associated with a greater likelihood of an excellent outcome than low-dose aspirin. Incidences of intracranial hemorrhages were low but slightly higher with tirofiban. (Funded by the National Natural Science Foundation of China; RESCUE BT2 Chinese Clinical Trial Registry number, ChiCTR2000029502.).

USP13 Cooperates with MARCH8 to Inhibit Antiviral Signaling by Targeting MAVS for Autophagic Degradation in Teleost.

Mitochondrial antiviral signaling protein (MAVS), as a central adapter protein in retinoic acid-inducible gene I-like receptor signaling, is indispensable for innate antiviral immunity. Yet, the molecular mechanisms modulating the stability of MAVS are not fully understood in low vertebrates. In this study, we report that the deubiquitinase ubiquitin-specific protease 13 (USP13) acts as a negative regulator of antiviral immunity by targeting MAVS for selective autophagic degradation in teleost fish. USP13 is induced by RNA virus or polyinosinic:polycytidylic acid stimulation and acts as a negative regulator to potentiate viral replication in fish cells. Mechanistically, USP13 functions as a scaffold to enhance the interaction between MAVS and the E3 ubiquitin ligase MARCH8, thus promoting MARCH8 to catalyze MAVS through K27-linked polyubiquitination for selective autophagic degradation. Taken together, to our knowledge, our study demonstrates a novel mechanism by which viruses evade host antiviral immunity via USP13 in fish and provides a new idea for mammalian innate antiviral immunity.

Potent neutralizing antibodies against multiple epitopes on SARS-CoV-2 spike.

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic continues, with devasting consequences for human lives and the global economy1,2. The discovery and development of virus-neutralizing monoclonal antibodies could be one approach to treat or prevent infection by this coronavirus. Here we report the isolation of sixty-one SARS-CoV-2-neutralizing monoclonal antibodies from five patients infected with SARS-CoV-2 and admitted to hospital with severe coronavirus disease 2019 (COVID-19). Among these are nineteen antibodies that potently neutralized authentic SARS-CoV-2 in vitro, nine of which exhibited very high potency, with 50% virus-inhibitory concentrations of 0.7 to 9 ng ml-1. Epitope mapping showed that this collection of nineteen antibodies was about equally divided between those directed against the receptor-binding domain (RBD) and those directed against the N-terminal domain (NTD), indicating that both of these regions at the top of the viral spike are immunogenic. In addition, two other powerful neutralizing antibodies recognized quaternary epitopes that overlap with the domains at the top of the spike. Cryo-electron microscopy reconstructions of one antibody that targets the RBD, a second that targets the NTD, and a third that bridges two separate RBDs showed that the antibodies recognize the closed, 'all RBD-down' conformation of the spike. Several of these monoclonal antibodies are promising candidates for clinical development as potential therapeutic and/or prophylactic agents against SARS-CoV-2.

Selective hydroxyl generation for efficient pollutant degradation by electronic structure modulation at Fe sites.

Hydrogen peroxide (H2O2) is an important green oxidant in the field of sewage treatment, and how to improve its activation efficiency and generate free radicals with stronger oxidation performance is a key issue in current research. Herein, we synthesized a Cu-doped α-Fe2O3 catalyst (7% Cu-Fe2O3) for activation of H2O2 under visible light for degradation of organic pollutants. The introduction of a Cu dopant changed the d-band center of Fe closer to the Fermi level, which enhanced the adsorption and activation of the Fe site for H2O2, and the cleavage pathway of H2O2 changed from heterolytic cleavage to homolytic cleavage, thereby improving the selectivity of •OH generation. In addition, Cu doping also promoted the light absorption ability of α-Fe2O3 and the separation of hole-electron pairs, which enhanced its photocatalytic activities. Benefiting from the high selectivity of •OH, 7% Cu-Fe2O3 exhibited efficient degradation activities against ciprofloxacin, the degradation rate was 3.6 times as much as that of α-Fe2O3, and it had good degradation efficiency for a variety of organic pollutants.

Superexchange-induced Pt-O-Ti3+ site on single photocatalyst for efficient H2 production with organics degradation in wastewater.

Efficient photocatalytic H2 production from wastewater instead of pure water is a dual solution to the environmental and energy crisis, but due to the rapid recombination of photoinduced charge in the photocatalyst and inevitable electron depletion caused by organic pollutants, a significant challenge of dual-functional photocatalysis (simultaneous oxidative and reductive reactions) in single catalyst is designing spatial separation path for photogenerated charges at atomic level. Here, we designed a Pt-doped BaTiO3 single catalyst with oxygen vacancies (BTPOv) that features Pt-O-Ti3+ short charge separation site, which enables excellent H2 production performance (1519 µmol·g-1·h-1) while oxidizing moxifloxacin (k = 0.048 min-1), almost 43 and 98 times than that of pristine BaTiO3 (35 µmol·g-1·h-1 and k = 0.00049 min-1). The efficient charge separation path is demonstrated that the oxygen vacancies extract photoinduced charge from photocatalyst to catalytic surface, and the adjacent Ti3+ defects allow rapid migration of electrons to Pt atoms through the superexchange effect for H* adsorption and reduction, while the holes will be confined in Ti3+ defects for oxidation of moxifloxacin. Impressively, the BTPOv shows an exceptional atomic economy and potential for practical applications, a best H2 production TOF (370.4 h-1) among the recent reported dual-functional photocatalysts and exhibiting excellent H2 production activity in multiple types of wastewaters.

Generating dual-active species by triple-atom sites through peroxymonosulfate activation for treating micropollutants in complex water.

The peroxymonosulfate (PMS)-triggered radical and nonradical active species can synergistically guarantee selectively removing micropollutants in complex wastewater; however, realizing this on heterogeneous metal-based catalysts with single active sites remains challenging due to insufficient electron cycle. Herein, we design asymmetric Co-O-Bi triple-atom sites in Co-doped Bi2O2CO3 to facilitate PMS oxidation and reduction simultaneously by enhancing the electron transfer between the active sites. We propose that the asymmetric Co-O-Bi sites result in an electron density increase in the Bi sites and decrease in the Co sites, thereby PMS undergoes a reduction reaction to generate SO4•- and •OH at the Bi site and an oxidation reaction to generate 1O2 at the Co site. We suggest that the synergistic effect of SO4•-, •OH, and 1O2 enables efficient removal and mineralization of micropollutants without interference from organic and inorganic compounds under the environmental background. As a result, the Co-doped Bi2O2CO3 achieves almost 99.3% sulfamethoxazole degradation in 3 min with a k-value as high as 82.95 min-1 M-1, which is superior to the existing catalysts reported so far. This work provides a structural regulation of the active sites approach to control the catalytic function, which will guide the rational design of Fenton-like catalysts.

In situ formation of cocatalytic sites boosts single-atom catalysts for nitrogen oxide reduction.

Nitrogen oxide (NOx) pollution presents a severe threat to the environment and human health. Catalytic reduction of NOx with H2 using single-atom catalysts poses considerable potential in the remediation of air pollution; however, the unfavorable process of H2 dissociation limits its practical application. Herein, we report that the in situ formation of PtTi cocatalytic sites (which are stabilized by Pt-Ti bonds) over Pt1/TiO2 significantly increases NOx conversion by reducing the energy barrier of H2 activation. We demonstrate that two H atoms of H2 molecule are absorbed by adjacent Pt atoms in Pt-O and Pt-Ti, respectively, which can promote the cleave of H-H bonds. Besides, PtTi sites facilitate the adsorption of NO molecules and further lower the activation barrier of the whole de-NOx reaction. Extending the concept to Pt1/Nb2O5 and Pd1/TiO2 systems also sees enhanced catalytic activities, demonstrating that engineering the cocatalytic sites can be a general strategy for the design of high-efficiency catalysts that can benefit environmental sustainability.

Single cobalt atoms anchored on Ti3C2Tx with dual reaction sites for efficient adsorption-degradation of antibiotic resistance genes.

The assimilation of antibiotic resistance genes (ARGs) by pathogenic bacteria poses a severe threat to public health. Here, we reported a dual-reaction-site-modified CoSA/Ti3C2Tx (single cobalt atoms immobilized on Ti3C2Tx MXene) for effectively deactivating extracellular ARGs via peroxymonosulfate (PMS) activation. The enhanced removal of ARGs was attributed to the synergistic effect of adsorption (Ti sites) and degradation (Co-O3 sites). The Ti sites on CoSA/Ti3C2Tx nanosheets bound with PO43- on the phosphate skeletons of ARGs via Ti-O-P coordination interactions, achieving excellent adsorption capacity (10.21 × 1010 copies mg-1) for tetA, and the Co-O3 sites activated PMS into surface-bond hydroxyl radicals (•OHsurface), which can quickly attack the backbones and bases of the adsorbed ARGs, resulting in the efficient in situ degradation of ARGs into inactive small molecular organics and NO3. This dual-reaction-site Fenton-like system exhibited ultrahigh extracellular ARG degradation rate (k > 0.9 min-1) and showed the potential for practical wastewater treatment in a membrane filtration process, which provided insights for extracellular ARG removal via catalysts design.

The strong metal-support interactions induced electrocatalytic three-electron oxygen reduction to hydroxyl radicals for water treatment.

As a promising environmental remediation technology, the electro-Fenton (EF) process is mainly limited by the two rate-limiting steps, which are H2O2 generation and activation. The electrocatalytic three-electron oxygen reduction reaction (3e- ORR) can directly activate oxygen to hydroxyl radicals (•OH), which is expected to break through the rate-limiting steps of the EF process. However, limited success has been achieved in the design of 3e- ORR electrocatalysts. Herein, we propose Cu/CoSe2/C with the strong metal-support interactions to enhance the 3e- ORR process, exhibiting remarkable reactivity and stability for •OH generation. Both experiment and DFT calculation results reveal that CoSe2 is conducive to the generation of H2O2. Meanwhile, the metallic Cu can enhance the adsorption strength of *H2O2 intermediates and thus promotes the one-electron reduction to •OH. The Cu/CoSe2/C catalyst exhibits the electron-transfer number close to 3.0 during the ORR process, and exhibits the outstanding •OH generation performance, achieving a higher apparent rate constant (6.0 times faster) toward ciprofloxacin compared with its analogy without the SMSI effect. Our work represents that the SMSI effect endows Cu/CoSe2/C high activity and selectivity for •OH generation, providing a unique perspective for the design of a high-efficiency 3e- ORR catalyst.

Autophagy promotes organelle clearance and organized cell separation of living root cap cells in Arabidopsis thaliana.

The root cap is a multilayered tissue covering the tip of a plant root that directs root growth through its unique functions, such as gravity sensing and rhizosphere interaction. To maintain the structure and function of the root cap, its constituent cells are constantly turned over through balanced cell division and cell detachment in the inner and outer cell layers, respectively. Upon displacement toward the outermost layer, columella cells at the central root cap domain functionally transition from gravity-sensing cells to secretory cells, but the mechanisms underlying this drastic cell fate transition are largely unknown. Here, using live-cell tracking microscopy, we show that organelles in the outermost cell layer undergo dramatic rearrangements. This rearrangement depends, at least partially, on spatiotemporally regulated activation of autophagy. Notably, this root cap autophagy does not lead to immediate cell death, but is instead necessary for organized separation of living root cap cells, highlighting a previously undescribed role of developmentally regulated autophagy in plants. This article has an associated 'The people behind the papers' interview.

EFHD2 cooperates with E3 ubiquitin ligase Smurf1 to facilitate virus infection by promoting the degradation of TRAF6 in teleost fish.

The ubiquitin-proteasome system is one of the most important protein stability regulation systems. It can precisely regulate host immune responses by targeting signaling proteins. TRAF6 is a crucial E3 ubiquitin ligase in host antiviral signaling pathway. Here, we discovered that EF-hand domain-containing protein D2 (EFHD2) collaborated with the E3 ubiquitin ligase Smurf1 to potentiate the degradation of TRAF6, hence facilitating RNA virus Siniperca chuatsi rhabdovirus infection. The mechanism analysis revealed that EFHD2 interacted with Smurf1 and enhanced its protein stability by impairing K48-linked polyubiquitination of Smurf1, thereby promoting Smurf1-catalyzed degradation of TRAF6. This study initially demonstrated a novel mechanism by which viruses utilize host EFHD2 to achieve immune escape and provided a new perspective on the exploration of mammalian innate immunity.IMPORTANCEViruses induce host cells to activate several antiviral signaling pathways. TNF receptor-associated factor 6 (TRAF6) plays an essential role in these pathways. Numerous studies have been done on the mechanisms of TRAF6-mediated resistance to viral invasion. However, little is known about the strategies that viruses employ to antagonize TRAF6-mediated antiviral signaling pathway. Here, we discovered that EFHD2 functions as a host factor to promote viral replication. Mechanistically, EFHD2 potentiates Smurf1 to catalyze the ubiquitin-proteasomal degradation of TRAF6 by promoting the deubiquitination and stability of Smurf1, which in turn inhibits the production of proinflammatory cytokines and interferons. Our study also provides a new perspective on mammalian resistance to viral invasion.

VP2 mediates the release of the feline calicivirus RNA genome by puncturing the endosome membrane of infected cells.

Feline calicivirus (FCV) is one of the few members of the Caliciviridae family that grows well in cell lines and, therefore, serves as a surrogate to study the biology of other viruses in the family. Conley et al. (14) demonstrated that upon the receptor engagement to the capsid, FCV VP2 forms a portal-like assembly, which might provide a channel for RNA release. However, the process of calicivirus RNA release is not yet fully understood. Our findings suggest that the separation of the FCV capsid from its genome RNA (gRNA) occurs rapidly in the early endosomes of infected cells. Using a liposome model decorated with the FCV cell receptor fJAM-A, we demonstrate that FCV releases its gRNA into the liposomes by penetrating membranes under low pH conditions. Furthermore, we found that VP2, which is rich in hydrophobic residues at its N-terminus, functions as the pore-forming protein. When we substituted the VP2 N-terminal hydrophobic residues, the gRNA release efficacy of the FCV mutants decreased. In conclusion, our results suggest that in the acidic environment of early endosomes, FCV VP2 functions as the pore-forming protein to mediate gRNA release into the cytoplasm of infected cells. This provides insight into the mechanism of calicivirus genome release.IMPORTANCEResearch on the biology and pathogenicity of certain caliciviruses, such as Norovirus and Sapovirus, is hindered by the lack of easy-to-use cell culture system. Feline calicivirus (FCV), which grows effectively in cell lines, is used as a substitute. At present, there is limited understanding of the genome release mechanism in caliciviruses. Our findings suggest that FCV uses VP2 to pierce the endosome membrane for genome release and provide new insights into the calicivirus gRNA release mechanism.

HTCL-DDI: a hierarchical triple-view contrastive learning framework for drug-drug interaction prediction.

Drug-drug interaction (DDI) prediction can discover potential risks of drug combinations in advance by detecting drug pairs that are likely to interact with each other, sparking an increasing demand for computational methods of DDI prediction. However, existing computational DDI methods mostly rely on the single-view paradigm, failing to handle the complex features and intricate patterns of DDIs due to the limited expressiveness of the single view. To this end, we propose a Hierarchical Triple-view Contrastive Learning framework for Drug-Drug Interaction prediction (HTCL-DDI), leveraging the molecular, structural and semantic views to model the complicated information involved in DDI prediction. To aggregate the intra-molecular compositional and structural information, we present a dual attention-aware network in the molecular view. Based on the molecular view, to further capture inter-molecular information, we utilize the one-hop neighboring information and high-order semantic relations in the structural view and semantic view, respectively. Then, we introduce contrastive learning to enhance drug representation learning from multifaceted aspects and improve the robustness of HTCL-DDI. Finally, we conduct extensive experiments on three real-world datasets. All the experimental results show the significant improvement of HTCL-DDI over the state-of-the-art methods, which also demonstrates that HTCL-DDI opens new avenues for ensuring medication safety and identifying synergistic drug combinations.