Structural insights into the functional mechanism of the ubiquitin ligase E6AP.

E6AP dysfunction is associated with Angelman syndrome and Autism spectrum disorder. Additionally, the host E6AP is hijacked by the high-risk HPV E6 to aberrantly ubiquitinate the tumor suppressor p53, which is linked with development of multiple types of cancer, including most cervical cancers. Here we show that E6AP and the E6AP/E6 complex exist, respectively, as a monomer and a dimer of the E6AP/E6 protomer. The short α1-helix of E6AP transforms into a longer helical structure when in complex with E6. The extended α1-helices of the dimer intersect symmetrically and contribute to the dimerization. The two protomers sway around the crossed region of the two α1-helices to promote the attachment and detachment of substrates to the catalytic C-lobe of E6AP, thus facilitating ubiquitin transfer. These findings, complemented by mutagenesis analysis, suggest that the α1-helix, through conformational transformations, controls the transition between the inactive monomer and the active dimer of E6AP.

Prospects of polyglycolic acid sheets for the treatment of esophageal stricture after esophageal endoscopic submucosal dissection.

Esophageal cancer is the seventh most common type of cancer and the sixth leading cause of cancer -related mortality worldwide. Endoscopic submucosal dissection (ESD) is widely used for the resection of early esophageal cancer. However, post-ESD esophageal stricture is a common long-term complication, which requires attention. Patients with post-ESD esophageal stricture often experience dysphagia and require multiple dilatations, which greatly affects their quality of life and increases healthcare costs. Therefore, to manage post-ESD esophageal stricture, researchers are actively exploring various strategies, such as pharmaceutical interventions, endoscopic balloon dilation, and esophageal stenting. Although steroids-based therapy has achieved some success, steroids can lead to complications such as osteoporosis and infection. Meanwhile, endoscopic balloon dilatation is effective in the short term, but is prone to recurrence and perforation. Additionally, esophageal stenting can alleviate the stricture, but is associated with discomfort during stenting and the complication of easy displacement also present challenges. Tissue engineering has evolved rapidly in recent years, and hydrogel materials have good biodegradability and biocompatibility. A novel type of polyglycolic acid (PGA) sheets has been found to be effective in preventing esophageal stricture after ESD, with the advantages of a simple operation and low complication rate. PGA membranes act as a biophysical barrier to cover the wound as well as facilitate the delivery of medications to promote wound repair and healing. However, there is still a lack of multicenter, large-sample randomized controlled clinical studies focused on the treatment of post-ESD esophageal strictures with PGA membrane, which will be a promising direction for future advancements in this field.

Translation and psychometric testing of the Chinese version of the Perinatal Missed Care Survey.

Objective: This study aimed to translate and evaluate the psychometric properties of the Perinatal Missed Care Survey in China. Methods: The Perinatal Missed Care Survey was translated according to the guidelines of the cross-cultural debugging scale recommended by the American Academy of Orthopaedic Surgeons Evidence-Based Medicine Committee, including forward translation, back translation, cultural adaption, and content validation, and its Chinese version was used in a cross-sectional study conducted from February to April in 2023. A total of 491 midwives from 14 different level hospitals in southwest China were recruited through a convenience sampling method. The discrimination ability of the items was tested through item analysis, and construct validity was assessed through exploratory factory and confirmatory factor analyses. The content validity index and Cronbach's α coefficients evaluated content validity and reliability, respectively. Results: The Chinese version's item-total correlation coefficients ranged from 0.641 to 0.866 in part A and from 0.644 to 0.819 in part B (P < 0.001). Parts A and B's scale-level content validity indexes were 0.95, and the item-level content validity indexes were from 0.86 to 1.00. The three common factors of part A (necessary care, basic care, and postnatal care) and part B (communication, labor resources, and material resources) were extracted, accounting for 70.186% and 71.984% of the total variance, respectively. Confirmatory factor analysis indicated that the good fit of the three-factor models was acceptable. The Cronbach's α coefficients were 0.968 (part A) and 0.940 (part B). Conclusion: The Chinese version of the Perinatal Missed Care Survey is a reliable and valid instrument for assessing nursing care missed by midwives during labor and birth and the reasons it was missed. Studies with large sample sizes are needed to verify the instrument's applicability in China.

Small Extracellular Vesicles Laden Oxygen-Releasing Thermosensitive Hydrogel for Enhanced Antibacterial Therapy against Anaerobe-Induced Periodontitis Alveolar Bone Defect.

Periodontitis is a bacterially induced chronic destructive inflammatory disease that leads to irreversible destruction of the tooth supporting structure, including connective tissue destruction, bone resorption, and even tooth loss. Until now, there has been no effective treatment to repair inflammatory bone loss in periodontitis. Recently, small extracellular vesicles (sEVs) emerged as the essential paracrine factors of mesenchymal stem cells (MSCs) that mediated tissue regeneration. However, limitations of antimicrobial activity associated with the use of sEVs have led to the urgency of new alternative strategies. Currently, we investigated the potential of a biocompatible oxygen-releasing thermosensitive hydrogel laded with sEVs secreted by bone marrow MSCs (BMMSCs) for the alveolar bone defect in periodontitis. The hydrogel composed of different polymers such as chitosan (CS), poloxamer 407 (P407), and cross-linked hyaluronic acid (c-HA) conglomerating is a kind of nanoporous structure material. Then, the gel matrix further encapsulated sEVs and calcium peroxide nanoparticles to realize the control of sEVs and oxygen release. Furthermore, ascorbic acid was added to achieve the REDOX equilibrium and acid-base equilibrium. The experiments in vivo and in vitro proved its good biocompatibility and effectively inhibited the growth of the periodontal main anaerobe, relieved periodontal pocket anaerobic infections, and promoted the periodontal defect regeneration. Therefore, this finding demonstrated that it was a promising approach for combating anaerobic pathogens with enhanced and selective properties in periodontal diseases, even in other bacteria-induced infections, for future clinical application.

Clinical Characteristics, Drug Resistance, and Risk Factors for Death of Klebsiella pneumoniae Infection in Patients with Acute Pancreatitis: A Single-Center Retrospective Study from China.

Objective: Infection is a common complication of acute pancreatitis (AP). Klebsiella pneumoniae (KP) is one of the most common pathogens associated with nosocomial infections. Our study focuses on investigating the clinical characteristics and risk factors for death of Klebsiella pneumoniae infections in AP patients, further to quantify the prognosis of the patients, and provide evidence for guiding antibiotic use and improving prognosis. Methods: The data of epidemiology, clinical manifestations and drug resistance rate with K. pneumoniae infections in AP patients from January 1, 2012 to August 30, 2022 were retrospectively collected. Logistic regression model and Cox regression model were, respectively, used to determine the risk factors for carbapenem-resistant Klebsiella pneumoniae (CRKP) acquisition and death. The nomogram prediction model was built by RMS software package to predict the 90-day survival rate. Results: One hundred and twenty-six AP patients combined with K. pneumoniae infections, with a mortality rate of 34.9%. The most common infection sites were pancreas and peri-pancreas (54.8%), followed by lung (20.6%) and blood stream (18.3%). The resistance rate of K. pneumoniae to commonly used antibiotics in clinical practice was high, especially CRKP, which was only sensitive to sulfamethoxazole-trimethoprim (SMZ-TMP) and tigecycline (TGC) (resistance rates were 37.57% and 17.57%, respectively). Independent risk factors for CPKP acquisition were male (OR = 1.655, 95% CI 0.642-4.265, P = 0.017) and PICC/CVC implantation (OR = 3.157, 95% CI 1.223-8.147, P = 0.021). Independent risk factors for mortality included carbapenem resistance (HR = 2.556, 95% CI 1.011-6.462, P = 0.047), hemorrhage (HR = 2.392, 95% CI 1.104-5.182, P = 0.027), septic shock (HR = 3.022, 95% CI 1.312-6.959, P = 0.009), age >60 years (HR = 2.977, 95% CI 1.303-6.799, P = 0.01), creatinine >177µmol/L (HR = 2.815, 95% CI 1.075-7.369, P = 0.035). Conclusion: K. pneumoniae infection has become a serious threat for AP patients, which recommends us more attention and active new strategies seeking.

Cryo-electron microscopy structures of capsids and in situ portals of DNA-devoid capsids of human cytomegalovirus.

The portal-scaffold complex is believed to nucleate the assembly of herpesvirus procapsids. During capsid maturation, two events occur: scaffold expulsion and DNA incorporation. The portal-scaffold interaction and the conformational changes that occur to the portal during the different stages of capsid formation have yet to be elucidated structurally. Here we present high-resolution structures of the A- and B-capsids and in-situ portals of human cytomegalovirus. We show that scaffolds bind to the hydrophobic cavities formed by the dimerization and Johnson-fold domains of the major capsid proteins. We further show that 12 loop-helix-loop fragments-presumably from the scaffold domain-insert into the hydrophobic pocket of the portal crown domain. The portal also undergoes significant changes both positionally and conformationally as it accompanies DNA packaging. These findings unravel the mechanism by which the portal interacts with the scaffold to nucleate capsid assembly and further our understanding of scaffold expulsion and DNA incorporation.

Long-term nitrogen fertilization-induced enhancements of acid hydrolyzable nitrogen are mainly regulated by the most vital microbial taxa of keystone species and enzyme activities.

It is well known that nitrogen (N) fertilizer input is required to improve crop productivity, but we lack a comprehensive understanding of how elevated N input changes the formation of soil acid hydrolyzable nitrogen (AHN) by adjusting the most vital microbial taxa of keystone species of microbial communities and enzyme activities. A 15-year field experiment comprising four levels of inorganic N fertilization was conducted to identify the most important bacterial and fungal taxa of the keystone species derived from cooccurrence networks as well as the vital enzyme activities at the bell mouth and maturity stages. Long-term N fertilization significantly increased the levels of AHN along with its four fractions, including amino acid N (AAN), ammonium N (AN), amino sugar N (ASN), and hydrolysable unidentified N (HUN), by 30.1-118.6 %, regardless of growth stage. Some most vital microbial taxa of keystone species and enzyme activities, which changed in response to N fertilization, mainly regulated each ANH fraction, that is, AHN and AN were mainly controlled by the enrichment of Nocardioides and ß-1,4-N-acetyl-glucosaminidase (NAG), as well as by the reduction of Anaerolinea and urease (UR), AAN was determined by the enrichment of Hannaella and depletion of Penicillium, ASN was regulated by the enrichment of Hannaella and Arthrobacter, and HUN was influenced by the reduction of Penicillium and enrichment of Nitrosospira. These microbial genera have been found to be involved in dissimilatory nitrate reduction to ammonium (DNRA) and nitrification/denitrification processes and the two enzyme activities involved in organic N degradation and N-releasing processes, suggesting that the formation of AHN fractions was closely associated with specific functional microbial taxa and enzyme activities induced by N fertilization. Our results provide new insights into the associations among increased N input, altered formation of soil organic N, and shifts in microbial communities and enzyme activities.

Discovery and Biosynthesis of Glycosylated Cycloheximide from a Millipede-Associated Actinomycete.

Chemical redundancy of microbial natural products (NPs) underscores the importance to exploit new resources of microorganisms. Insect-associated microbes are prolific but largely underexplored sources of diverse NPs. Herein, we discovered the new compound α-l-rhamnosyl-actiphenol (1) from a millipede-associated Streptomyces sp. ML6, which is the first glycosylated cycloheximide-class natural product. Interestingly, bioinformatics analysis of the ML6 genome revealed that the biosynthesis of 1 involves a cooperation between two gene clusters (chx and rml) located distantly on the genome of ML6. We also carried out in vitro enzymatic glycosylation of cycloheximide using an exotic promiscuous glycosyltransferase BsGT-1, which resulted in the production of an additional cycloheximide glycoside cycloheximide 7-O-ß-d-glucoside (5). Although the antifungal and cytotoxic activities of the new compounds 1 and 5 were attenuated relative to those of cycloheximide, our work not only enriches the chemical repertoire of the cycloheximide family but also provides new insights into the structure-activity relationship optimization and ecological roles of cycloheximide.

Mouse α-Defensins: Structural and Functional Analysis of the 17 Cryptdin Isoforms Identified from a Single Jejunal Crypt.

Mouse α-defensins, better known as cryptdins, are host protective antimicrobial peptides produced in the intestinal crypt by Paneth cells. To date, more than 20 cryptdin mRNAs have been identified from mouse small intestine, of which the first six cryptdins (Crp1 to Crp6) have been isolated and characterized at the peptide level. We quantified bactericidal activities against Escherichia coli and Staphylococcus aureus of the 17 cryptdin isoforms identified by Ouellette and colleagues from a single jejunal crypt (A. J. Ouellette et al., Infect Immun 62:5040-5047, 1994), along with linearized analogs of Crp1, Crp4, and Crp14. In addition, we analyzed the most potent and weakest cryptdins in the panel with respect to their ability to self-associate in solution. Finally, we solved, for the first time, the high-resolution crystal structure of a cryptdin, Crp14, and performed molecular dynamics simulation on Crp14 and a hypothetical mutant, T14K-Crp14. Our results indicate that mutational effects are highly dependent on cryptdin sequence, residue position, and bacterial strain. Crp14 adopts a disulfide-stabilized, three-stranded ß-sheet core structure and forms a noncanonical dimer stabilized by asymmetrical interactions between the two ß1 strands in parallel. The killing of E. coli by cryptdins is generally independent of their tertiary and quaternary structures that are important for the killing of S. aureus, which is indicative of two distinct mechanisms of action. Importantly, sequence variations impact the bactericidal activity of cryptdins by influencing their ability to self-associate in solution. This study expands our current understanding of how cryptdins function at the molecular level.

Structural insights into a shared mechanism of human STING activation by a potent agonist and an autoimmune disease-associated mutation.

Stimulator of interferon gene (STING) is increasingly exploited for the potential in cancer immunotherapy, yet its mechanism of activation remains not fully understood. Herein, we designed a novel STING agonist, designated as HB3089 that exhibits robust and durable anti-tumor activity in tumor models across various cancer types. Cryo-EM analysis reveals that HB3089-bound human STING has structural changes similar to that of the STING mutant V147L, a constitutively activated mutant identified in patients with STING-associated vasculopathy with onset in infancy (SAVI). Both structures highlight the conformational changes of the transmembrane domain (TMD), but without the 180°-rotation of the ligand binding domain (LBD) previously shown to be required for STING activation. Further structure-based functional analysis confirmed a new STING activation mode shared by the agonist and the SAVI-related mutation, in which the connector linking the LBD and the TMD senses the activation signal and controls the conformational changes of the LBD and the TMD for STING activation. Together, our findings lead to a new working model for STING activation and open a new avenue for the rationale design of STING-targeted therapies either for cancer or autoimmune disorders.

Experiences and needs of front-line nurses during the COVID-19 pandemic: A systematic review and qualitative meta-synthesis.

Background: Front-line nurses have played a critical role during the coronavirus disease 2019 (COVID-19) pandemic. A number of qualitative studies reported front-line nurses' experiences and needs in caring for patients with COVID-19. However, the application of evidence from a single qualitative study to guide clinical practice has limitations. This study aimed to explore front-line nurses' experiences and needs during the COVID-19 pandemic through a qualitative meta-synthesis. Methods: Seven databases were searched from 1 December 2019 to 20 January 2022, including PubMed, Web of Science, Cochrane COVID-19 study register, CINAHL, PsycINFO, MedRxiv, and bioRxiv. The quality of included studies was appraised using the Critical Appraisal Skills Program (CASP) qualitative research appraisal tool. Meta-synthesis was used to synthesize the data from included studies. Results: A total of 70 studies were included, and five synthesized findings were developed: (1) Although nurses actively devoted themselves to fighting against COVID-19, considering their professional responsibility and historical previous experience with mankind, they were not invulnerable; (2) There were various difficulties and challenges in caring for patients with COVID-19, including fear related to providing patients with care, shortage of protective equipment and manpower, and negative attitude of family members; (3) Facing difficulties and challenges, nurses could only partly cope by using mixed means to overcome those, including media, learning, gaining skills, responding together, and organizational assistance; (4) To better respond to the COVID-19 pandemic, nurses' needs should be paid attention to. Counseling, training, information, resources, and investment are pivotal; (5) Despite the hardships, nurses became stronger and gained gratitude, positivity, mental peace, and confidence. Conclusions: This study reveals that the psychological experiences of front-line nurses varied, and they faced a variety of challenges. Although nurses had some coping strategies, they still needed multifaceted support to meet the challenges. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, PROSPERO: CRD42021255468.

Association Between Metabolic Dysfunction-Associated Fatty Liver Disease and the Risk of Cirrhosis in Patients with Chronic Hepatitis B-A Retrospective Cohort Study.

Background: Metabolic dysfunction-associated fatty liver disease (MAFLD) is a novel proposed concept that is being recognized worldwide. Both chronic hepatitis B (CHB) and MAFLD have been independently attributed to an increased risk of disease development to cirrhosis. However, it is still unclear whether MAFLD is associated with an increased risk of cirrhosis in CHB patients. Aim: This study aimed to analyze the impact of MAFLD on the risk of cirrhosis in CHB patients. Methods: In this retrospective cohort study, consecutive CHB patients with or without MAFLD were enrolled from January 1st, 2007, to May 1st, 2020, in Guangdong Provincial Hospital of Chinese Medicine. Inverse probability treatment weighting (IPTW) was performed to balance the covariates across groups. The weighted Kaplan-Meier analysis and Cox regression analysis were used to compare both groups for the risk of cirrhosis. Results: A total of 1223 CHB patients were included in this study during the median follow-up of 5.25 years; of these patients, 355 were CHB-MAFLD patients. After IPTW, the weighted Kaplan-Meier analysis showed that the weighted cumulative incidence of cirrhosis was significantly higher in patients with MAFLD than that in patients without MAFLD (12.6% versus 7.1%, P=0.015). In the weighted multivariate Cox analysis, coexisting MAFLD was related to an increased risk of cirrhosis [adjusted weighted hazard ratio (HR) 1.790; P =0.020]. Age (>40 years, adjusted weighted HR, 1.950; P=0.015), diabetes mellitus (adjusted weighted HR, 1.883; P=0.041), non-antiviral treatment (adjusted weighted HR, 2.037; P=0.013), and baseline serum HBV DNA levels (>2.4 log10 IU/mL, adjusted weighted HR, 1.756; P=0.045) were significant risk factors for cirrhosis. Conclusion: We found that MAFLD was associated with a higher risk of cirrhosis in CHB patients.

Virulence Factors of Pseudomonas Aeruginosa and Antivirulence Strategies to Combat Its Drug Resistance.

Pseudomonas aeruginosa is an opportunistic pathogen causing nosocomial infections in severely ill and immunocompromised patients. Ubiquitously disseminated in the environment, especially in hospitals, it has become a major threat to human health due to the constant emergence of drug-resistant strains. Multiple resistance mechanisms are exploited by P. aeruginosa, which usually result in chronic infections difficult to eradicate. Diverse virulence factors responsible for bacterial adhesion and colonization, host immune suppression, and immune escape, play important roles in the pathogenic process of P. aeruginosa. As such, antivirulence treatment that aims at reducing virulence while sparing the bacterium for its eventual elimination by the immune system, or combination therapies, has significant advantages over traditional antibiotic therapy, as the former imposes minimal selective pressure on P. aeruginosa, thus less likely to induce drug resistance. In this review, we will discuss the virulence factors of P. aeruginosa, their pathogenic roles, and recent advances in antivirulence drug discovery for the treatment of P. aeruginosa infections.

Impact of Metabolic Dysfunction Associated Fatty Liver Disease on the Prognosis of Patients with Hepatitis B Virus-Related Hepatocellular Carcinoma Based on Propensity Score Matching Analysis.

Purpose: Both metabolic dysfunction-associated fatty liver disease (MAFLD) and hepatitis B virus (HBV) are risk factors for hepatocellular carcinoma (HCC). Although concurrent MAFLD is common in patients with HBV-related HCC, whether MAFLD increases the risk of poor prognosis in patients with HBV-related HCC remains unclear. This study aimed to investigate the impact of MAFLD on prognosis in patients with HBV-related HCC. Patients and Methods: In this retrospective cohort study, 549 patients with HBV-related HCC were enrolled from January 2010 to April 2020 in Guangdong Provincial Hospital of Chinese Medicine, including 169 patients with MAFLD (MAFLD group) and 380 patients without MAFLD (Non-MAFLD group). Propensity score matching (PSM) analysis was performed to balance the baseline characteristics. Kaplan-Meier survival curves were performed to compare the prognosis between the two matched groups. A multivariate Cox proportional hazards model was used to determine the risk factors for poor prognosis. Results: The median follow-up time for all patients was 20 (interquartile range 8-40) months. We found concurrent MAFLD was associated with a significantly decreased PFS rate before and after PSM analysis. The 1-year, 2-year, and 3-year PFS rates for the MAFLD and Non-MAFLD groups after PSM were 61.3% and 70.8%, 43.9% and 54.5%, 31.1% and 41.8%, respectively. Cox multivariable analysis showed that concurrent MAFLD was an independent risk factor for poor prognosis (death or progression) (HR = 1.49, P = 0.001). More interestingly, the risk of poor prognosis was significantly higher in the MAFLD subtype with metabolic components ≥2 compared to those with metabolic components <2 (HR = 1.97, P < 0.001). Conclusion: Concurrent MAFLD was associated with a higher risk of poor prognosis in patients with HBV-related HCC, especially MAFLD with metabolic components ≥2.

Structural basis for inhibition of the SARS-CoV-2 RNA polymerase by suramin.

The COVID-19 pandemic caused by nonstop infections of SARS-CoV-2 has continued to ravage many countries worldwide. Here we report that suramin, a 100-year-old drug, is a potent inhibitor of the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) and acts by blocking the binding of RNA to the enzyme. In biochemical assays, suramin and its derivatives are at least 20-fold more potent than remdesivir, the currently approved nucleotide drug for treatment of COVID-19. The 2.6 Å cryo-electron microscopy structure of the viral RdRp bound to suramin reveals two binding sites. One site directly blocks the binding of the RNA template strand and the other site clashes with the RNA primer strand near the RdRp catalytic site, thus inhibiting RdRp activity. Suramin blocks viral replication in Vero E6 cells, although the reasons underlying this effect are likely various. Our results provide a structural mechanism for a nonnucleotide inhibitor of the SARS-CoV-2 RdRp.

Design of a Genetically Programmed Biomimetic Lipase Nanoreactor.

Alternative to the traditionally independent production of lipase, chemical synthesis of nano-carriers, and then preparing nanoimmobilized enzymes, we exploit a yeast genetically programmed virus biomimetic lipase nanoreactor in a sustainable manner. The nanoreactor biogenesis process integrated lipase production, protein component (coat-protein subunit and scaffold protein) production, self-assembly of protein components, and the encapsulation of lipase into protein nanocages using a simple process. It included overexpression of nanocage components, coat-protein subunits, and fused lipase-scaffold proteins and subsequent spontaneous self-assembly and encapsulation based on the specific interaction between the coat-protein subunit and the scaffold protein fused in the target lipase enzyme. The genetically programmable lipase nanoreactor showed improved stability under various harsh conditions, and was validated in fatty acid methyl ester synthesis with 86% yield at a high concentration of waste cooking oil (200 mM), which demonstrates the robustness and feasibility of the lipase nanoreactor in biodiesel production.

Correction: Oncogenic KSHV-encoded interferon regulatory factor upregulates HMGB2 and CMPK1 expression to promote cell invasion by disrupting a complex lncRNA-OIP5-AS1/miR-218-5p network.

[This corrects the article DOI: 10.1371/journal.ppat.1007578.].

[Investigation of anxiety and depression in patients from the emergency department during COVID-19 epidemic].

OBJECTIVE: To investigate the status of anxiety and depression in patients requiring emergency treatment during the epidemic of COVID-19 to identify the patients with acute psychological stress disorder. METHODS: During the COVID-19 epidemic, the medical staff divided the patients visiting the emergency department into suspected group, fever group and control group through interview of the patients at triage. Self-rating anxiety scale (SAS) and self-rating depression scale (SDS) were distributed to each patient, and a trained medical staff was responsible for assisting the patient to complete the scales. RESULTS: A total of 557 sets of scales were distributed, including 211 in suspected COVID-19 case group, 167 in fever group and 179 in the control group. A total of 516 scales were retrieved, including 197 in suspected case group, 151 in fever group and 168 in control group. In the 3 groups, the incidence rates of anxiety and depression were 57.87% and 58.88%, 48.34% and 43.71%, and 18.31% and 18.99%, respectively, and the rates were significantly higher in suspected group and fever group than in the control group (P < 0.01), and significantly higher in suspected group than in fever group (P < 0.05). The standardized anxiety and depression scale scores in suspected case group, fever group and control group were 57.38±16.25 and 42.58±14.27, 51.23±15.29 and 38.32±15.39, and 32.58±17.8 and 12.25±12.94, respectively. Compared with the control group, both suspected case group and fever group had significantly higher standard scores for anxiety and depression (P < 0.01), and suspected case group had significantly higher standardized scores than fever group (P < 0.01). CONCLUSIONS: Among the patients visiting the emergency treatment, the patients with suspected COVID-19 and common fever are more likely to develop anxiety and depressive symptoms.

An oncogenic viral interferon regulatory factor upregulates CUB domain-containing protein 1 to promote angiogenesis by hijacking transcription factor lymphoid enhancer-binding factor 1 and metastasis suppressor CD82.

Kaposi's sarcoma (KS), a highly angiogenic and invasive vascular tumor, is the most common AIDS-associated cancer caused by KS-associated herpesvirus (KSHV) infection. We have recently shown that KSHV-encoded viral interferon regulatory factor 1 (vIRF1) contributes to KSHV-induced cell motility (PLoS Pathog. 15:e1007578, 2019). However, the role of vIRF1 in KSHV-induced angiogenesis remains unknown. Here, using two in vivo angiogenesis models including the chick chorioallantoic membrane assay (CAM) and the matrigel plug angiogenesis assay in mice, we show that vIRF1 promotes angiogenesis by upregulating CUB domain (for complement C1r/C1s, Uegf, Bmp1) containing protein 1 (CDCP1). Mechanistically, vIRF1 enhances the expression of transcription factor lymphoid enhancer-binding factor 1 (Lef1) and binds to Lef1 to promote CDCP1 transcription. Meanwhile, vIRF1 degrades metastasis suppressor CD82 through an ubiquitin-proteasome pathway by recruiting E3 ubiquitin ligase AMFR to CD82, which protects CDCP1 from CD82-mediated, palmitoylation-dependent degradation. CDCP1 activates AKT signaling, which is required for vIRF1-induced cell motility but not angiogenesis. Our results illustrate that, by hijacking Lef1 and CD82, vIRF1 upregulates CDCP1 to promote angiogenesis and cell invasion. These novel findings demonstrate the vIRF1 targets multiple cellular proteins and pathways to promote the pathogenesis of KS, which could be attractive therapeutic targets for KSHV-induced malignancies.