A genome-wide CRISPR screening uncovers that TOB1 acts as a key host factor for FMDV infection via both IFN and EGFR mediated pathways.

The interaction between foot-and-mouth disease virus (FMDV) and the host is extremely important for virus infection, but there are few researches on it, which is not conducive to vaccine development and FMD control. In this study, we designed a porcine genome-scale CRISPR/Cas9 knockout library containing 93,859 single guide RNAs targeting 16,886 protein-coding genes, 25 long ncRNAs, and 463 microRNAs. Using this library, several previously unreported genes required for FMDV infection are highly enriched post-FMDV selection in IBRS-2 cells. Follow-up studies confirmed the dependency of FMDV on these genes, and we identified a functional role for one of the FMDV-related host genes: TOB1 (Transducer of ERBB2.1). TOB1-knockout significantly inhibits FMDV infection by positively regulating the expression of RIG-I and MDA5. We further found that TOB1-knockout led to more accumulation of mRNA transcripts of transcription factor CEBPA, and thus its protein, which further enhanced transcription of RIG-I and MDA5 genes. In addition, TOB1-knockout was shown to inhibit FMDV adsorption and internalization mediated by EGFR/ERBB2 pathway. Finally, the FMDV lethal challenge on TOB1-knockout mice confirmed that the deletion of TOB1 inhibited FMDV infection in vivo. These results identify TOB1 as a key host factor involved in FMDV infection in pigs.

Plasminogen activator urokinase interacts with the fusion protein and antagonizes the growth of Peste des petits ruminants virus.

Peste des petits ruminants is an acute and highly contagious disease caused by the Peste des petits ruminants virus (PPRV). Host proteins play a crucial role in viral replication. However, the effect of fusion (F) protein-interacting partners on PPRV infection is poorly understood. In this study, we found that the expression of goat plasminogen activator urokinase (PLAU) gradually decreased in a time- and dose-dependent manner in PPRV-infected goat alveolar macrophages (GAMs). Goat PLAU was subsequently identified using co-immunoprecipitation and confocal microscopy as an F protein binding partner. The overexpression of goat PLAU inhibited PPRV growth and replication, whereas silencing goat PLAU promoted viral growth and replication. Additionally, we confirmed that goat PLAU interacted with a virus-induced signaling adapter (VISA) to antagonize F-mediated VISA degradation, increasing the production of type I interferon. We also found that goat PLAU reduced the inhibition of PPRV replication in VISA-knockdown GAMs. Our results show that the host protein PLAU inhibits the growth and replication of PPRV by VISA-triggering RIG-I-like receptors and provides insight into the host protein that antagonizes PPRV immunosuppression.IMPORTANCEThe role of host proteins that interact with Peste des petits ruminants virus (PPRV) fusion (F) protein in PPRV replication is poorly understood. This study confirmed that goat plasminogen activator urokinase (PLAU) interacts with the PPRV F protein. We further discovered that goat PLAU inhibited PPRV replication by enhancing virus-induced signaling adapter (VISA) expression and reducing the ability of the F protein to degrade VISA. These findings offer insights into host resistance to viral invasion and suggest new strategies and directions for developing PPR vaccines.

Deletions of MGF110-9L and MGF360-9L from African swine fever virus are highly attenuated in swine and confer protection against homologous challenge.

African swine fever, caused by a large icosahedral DNA virus (African swine fever virus, ASFV), is a highly contagious disease in domestic and feral swine, thus posing a significant economic threat to the global swine industry. Currently, there are no effective vaccines or the available methods to control ASFV infection. Attenuated live viruses with deleted virulence factors are considered to be the most promising vaccine candidates; however, the mechanism by which these attenuated viruses confer protection is unclear. Here, we used the Chinese ASFV CN/GS/2018 as a backbone and used homologous recombination to generate a virus in which MGF110-9L and MGF360-9L, two genes antagonize host innate antiviral immune response, were deleted (ASFV-ΔMGF110/360-9L). This genetically modified virus was highly attenuated in pigs and provided effective protection of pigs against parental ASFV challenge. Importantly, we found ASFV-ΔMGF110/360-9L infection induced higher expression of Toll-like receptor 2 (TLR2) mRNA compared with parental ASFV as determined by RNA-Seq and RT-PCR analysis. Further immunoblotting results showed that parental ASFV and ASFV-ΔMGF110/360-9L infection inhibited Pam3CSK4-triggered activating phosphorylation of proinflammatory transcription factor NF-κB subunit p65 and phosphorylation of NF-κB inhibitor IκBα levels, although NF-κB activation was higher in ASFV-ΔMGF110/360-9L-infected cells compared with parental ASFV-infected cells. Additionally, we show overexpression of TLR2 inhibited ASFV replication and the expression of ASFV p72 protein, whereas knockdown of TLR2 had the opposite effect. Our findings suggest that the attenuated virulence of ASFV-ΔMGF110/360-9L might be mediated by increased NF-κB and TLR2 signaling.

Combinational Deletions of MGF110-9L and MGF505-7R Genes from the African Swine Fever Virus Inhibit TBK1 Degradation by an Autophagy Activator PIK3C2B To Promote Type I Interferon Production.

African swine fever (ASF), caused by the African swine fever virus (ASFV), is a transboundary infectious disease of domestic pigs and wild boars, resulting in significant swine production losses. Currently, no effective commercial ASF vaccines or therapeutic options are available. A previous study has shown that deletions of ASFV MGF110-9L and MGF505-7R genes (ASFV-Δ110-9L/505-7R) attenuated virulence in pigs and provided complete protection against parental lethal ASFV CN/GS/2018 (wild-type ASFV [ASFV-WT]) challenge, but the underlying mechanism is unclear. This study found that ASFV-Δ110-9L/505-7R weakened TBK1 degradation compared with ASFV-WT through RNA sequencing (RNA-seq) and Western blotting analyses. Furthermore, we confirmed that ASFV-Δ110-9L/505-7R blocked the degradation of TBK1 through the autophagy pathway. We also identified that the downregulation of an autophagy-related protein PIK3C2B was involved in the inhibition of TBK1 degradation induced by ASFV-Δ110-9L/505-7R. Additionally, we also confirmed that PIK3C2B promoted ASFV-Δ110-9L/505-7R replication in vitro. Together, this study elucidated a novel mechanism of virulence change of ASFV-Δ110-9L/505-7R, revealing a new mechanism of ASF live attenuated vaccines (LAVs) and providing theoretical guidance for the development of ASF vaccines. IMPORTANCE African swine fever (ASF) is a contagious and lethal hemorrhagic disease of pigs caused by the African swine fever virus (ASFV), leading to significant economic consequences for the global pig industry. The development of an effective and safe ASF vaccine has been unsuccessful. Previous studies have shown that live attenuated vaccines (LAVs) of ASFV are the most effective vaccine candidates to prevent ASF. Understanding the host responses caused by LAVs of ASFV is important in optimizing vaccine design and diversifying the resources available to control ASF. Recently, our laboratory found that the live attenuated ASFV-Δ110-9L/505-7R provided complete protection against parental ASFV-WT challenge. This study further demonstrated that ASFV-Δ110-9L/505-7R inhibits TBK1 degradation mediated by an autophagy activator PIK3C2B to increase type I interferon production. These results revealed an important mechanism for candidate vaccine ASFV-Δ110-9L/505-7R, providing strategies for exploring the virulence of multigene-deleted live attenuated ASFV strains and the development of vaccines.

Integrated analysis of RNA methylation regulators crosstalk and immune infiltration for predictive and personalized therapy of diabetic nephropathy.

BACKGROUND: RNA methylation is a widely known post-transcriptional regulation which exists in many cancer and immune system diseases. However, the potential role and crosstalk of five types RNA methylation regulators in diabetic nephropathy (DN) and immune microenvironment remain unclear. METHODS: The mRNA expression of 37 RNA modification regulators and RNA modification regulators related genes were identified in 112 samples from 5 Gene Expression Omnibus datasets. Nonnegative Matrix Factorization clustering method was performed to determine RNA modification patterns. The ssGSEA algorithms and the expression of human leukocyte antigen were employed to assess the immune microenvironment characteristics. Risk model based on differentially expression genes responsible for the modification regulators was constructed to evaluate its predictive capability in DN patients. Furthermore, the results were validated by using immunofluorescence co-localizations and protein experiments in vitro. RESULTS: We found 24 RNA methylation regulators were significant differently expressed in glomeruli in DN group compared with control group. Four methylation-related genes and six RNA regulators were introduced into riskScore model using univariate Logistic regression and integrated LASSO regression, which could precisely distinguish the DN and healthy individuals. Group with high-risk score was associated with high immune infiltration. Three distinct RNA modification patterns were identified, which has significant differences in immune microenvironment, biological pathway and eGFR. Validation analyses showed the METTL3, ADAR1, DNMT1 were upregulated whereas YTHDC1 was downregulated in DN podocyte cell lines comparing with cells cultured by the normal glucose. CONCLUSION: Our study reveals that RNA methylation regulators and immune infiltration regulation play critical roles in the pathogenesis of DN. The bioinformatic analyses combine with verification in vitro could provide robust evidence for identification of predictive RNA methylation regulators in DN.

Deletion of MGF-110-9L gene from African swine fever virus weakens autophagic degradation of TBK1 as a mechanism for enhancing type I interferon production.

African swine fever (ASF) caused by African swine fever virus (ASFV) is a devastating disease for the global pig industry and economic benefit. The limited knowledge on the pathogenesis and infection mechanisms of ASF restricts progress toward vaccine development and ASF control. Previously, we illustrated that deletion of the MGF-110-9L gene from highly virulent ASFV CN/GS/2018 strains (ASFV∆9L) results in attenuated virulence in swine, but the underlying mechanism remains unclear. In this study, we found that the difference in virulence between wild-type ASFV (wt-ASFV) and ASFV∆9L strains was mainly caused by the difference in TANK Binding Kinase 1 (TBK1) reduction. TBK1 reduction was further identified to be mediated by the autophagy pathway and this degradative process requires the up-regulation of a positive autophagy regulation molecule- Phosphatidylinositol-4-Phosphate 3-Kinase Catalytic Subunit Type 2 Beta (PIK3C2B). Moreover, TBK1 over-expression was confirmed to inhibit ASFV replication in vitro. In summary, these results indicate that wt-ASFV counteracts type I interferon (IFN) production by degrading TBK1, while ASFVΔ9L enhanced type I IFN production by weakening TBK1 reduction, clarifying the mechanism that ASFVΔ9L present the attenuated virulence in vitro.

Building gender-specific sexually transmitted infection risk prediction models using CatBoost algorithm and NHANES data.

BACKGROUND AND AIMS: Sexually transmitted infections (STIs) are a significant global public health challenge due to their high incidence rate and potential for severe consequences when early intervention is neglected. Research shows an upward trend in absolute cases and DALY numbers of STIs, with syphilis, chlamydia, trichomoniasis, and genital herpes exhibiting an increasing trend in age-standardized rate (ASR) from 2010 to 2019. Machine learning (ML) presents significant advantages in disease prediction, with several studies exploring its potential for STI prediction. The objective of this study is to build males-based and females-based STI risk prediction models based on the CatBoost algorithm using data from the National Health and Nutrition Examination Survey (NHANES) for training and validation, with sub-group analysis performed on each STI. The female sub-group also includes human papilloma virus (HPV) infection. METHODS: The study utilized data from the National Health and Nutrition Examination Survey (NHANES) program to build males-based and females-based STI risk prediction models using the CatBoost algorithm. Data was collected from 12,053 participants aged 18 to 59 years old, with general demographic characteristics and sexual behavior questionnaire responses included as features. The Adaptive Synthetic Sampling Approach (ADASYN) algorithm was used to address data imbalance, and 15 machine learning algorithms were evaluated before ultimately selecting the CatBoost algorithm. The SHAP method was employed to enhance interpretability by identifying feature importance in the model's STIs risk prediction. RESULTS: The CatBoost classifier achieved AUC values of 0.9995, 0.9948, 0.9923, and 0.9996 and 0.9769 for predicting chlamydia, genital herpes, genital warts, gonorrhea, and overall STIs infections among males. The CatBoost classifier achieved AUC values of 0.9971, 0.972, 0.9765, 1, 0.9485 and 0.8819 for predicting chlamydia, genital herpes, genital warts, gonorrhea, HPV and overall STIs infections among females. The characteristics of having sex with new partner/year, times having sex without condom/year, and the number of female vaginal sex partners/lifetime have been identified as the top three significant predictors for the overall risk of male STIs. Similarly, ever having anal sex with a man, age and the number of male vaginal sex partners/lifetime have been identified as the top three significant predictors for the overall risk of female STIs. CONCLUSIONS: This study demonstrated the effectiveness of the CatBoost classifier in predicting STI risks among both male and female populations. The SHAP algorithm revealed key predictors for each infection, highlighting consistent demographic characteristics and sexual behaviors across different STIs. These insights can guide targeted prevention strategies and interventions to alleviate the impact of STIs on public health.

Picornavirus 3C - a protease ensuring virus replication and subverting host responses.

The protease 3C is encoded by all known picornaviruses, and the structural features related to its protease and RNA-binding activities are conserved; these contribute to the cleavage of viral polyproteins and the assembly of the viral RNA replication complex during virus replication. Furthermore, 3C performs functions in the host cell through its interaction with host proteins. For instance, 3C has been shown to selectively 'hijack' host factors involved in gene expression, promoting picornavirus replication, and to inactivate key factors in innate immunity signaling pathways, inhibiting the production of interferon and inflammatory cytokines. Importantly, 3C maintains virus infection by subtly subverting host cell death and modifying critical molecules in host organelles. This Review focuses on the molecular mechanisms through which 3C mediates physiological processes involved in virus-host interaction, thus highlighting the picornavirus-mediated pathogenesis caused by 3C.

An Arabidopsis Retention and Splicing complex regulates root and embryo development through pre-mRNA splicing.

Pre-mRNA splicing is an important step in the posttranscriptional processing of transcripts and a key regulator of development. The heterotrimeric retention and splicing (RES) complex plays vital roles in the growth and development of yeast, zebrafish, and humans by mediating pre-mRNA splicing of multiple genes. However, whether the RES complex is conserved in plants and what specific functions it has remain unknown. In this study, we identified Arabidopsis (Arabidopsis thaliana) BUD13 (AtBUD13), GROWTH, DEVELOPMENT AND SPLICING 1 (GDS1), and DAWDLE (DDL) as the counterparts of the yeast RES complex subunits Bud site selection protein 13 (Bud13), U2 snRNP component Snu17 (Snu17), and Pre-mRNA leakage protein 1, respectively. Moreover, we showed that RES is an ancient complex evolutionarily conserved in eukaryotes. GDS1 directly interacts with both AtBUD13 and DDL in nuclear speckles. The BUD13 domain of AtBUD13 and the RNA recognition motif domain of GDS1 are necessary and sufficient for AtBUD13-GDS1 interaction. Mutants of AtBUD13, GDS1, and DDL failed to properly splice multiple genes involved in cell proliferation and showed defects in early embryogenesis and root development. In addition, we found that GDS1 and DDL interact, respectively, with the U2 small nuclear ribonucleoproteins auxiliary factor AtU2AF65B and the NineTeen Complex-related splicing factor SKIP, which are essential for early steps of spliceosome assembly and recognition of splice sites. Altogether, our work reveals that the Arabidopsis RES complex is important for root and early embryo development by modulating pre-mRNA splicing.

African Swine Fever Virus MGF-505-7R Negatively Regulates cGAS-STING-Mediated Signaling Pathway.

African swine fever virus (ASFV) is a devastating infectious disease in pigs, severely threatening the global pig industry. To efficiently infect animals, ASFV must evade or inhibit fundamental elements of the innate immune system, namely the type I IFN response. In this study, we identified that ASFV MGF-505-7R protein exerts a negative regulatory effect on STING-dependent antiviral responses. MGF-505-7R interacted with STING and inhibited the cGAS-STING signaling pathway at STING level. MGF-505-7R overexpression either degraded STING or STING expression was reduced in ASFV-infected cells via autophagy, whereas STING expression was elevated in MGF-505-7R-deficient ASFV-infected cells. We further found that MGF-505-7R promoted the expression of the autophagy-related protein ULK1 to degrade STING, whereas ULK1 was elevated in MGF-505-7R-deficient ASFV-infected cells. Moreover, MGF-505-7R-deficient ASFV induced more IFN-ß production than wild-type ASFV and was attenuated in replication compared with wild-type ASFV. The replicative ability of MGF-505-7R-deficient ASFV was also attenuated compared with wild-type. Importantly, MGF-505-7R-deficient ASFV was fully attenuated in pigs. Our results showed for the first time, to our knowledge, a relationship involving the cGAS-STING pathway and ASFV MGF-505-7R, contributing to uncover the molecular mechanisms of ASFV virulence and to the rational development of ASFV vaccines.

Follow-up survey of general practitioners in Zhejiang Province post-completion of position transition training in 2017-2020.

BACKGROUND: Position transition training for general practitioners in Zhejiang Province started in 2017 and has since been held once a year. By the beginning of 2022, four training sessions were completed. The purpose of this survey was to establish the current situation of trainees after their graduation and provide reference for the evaluation of the training effect. METHODS: Of the 738 trainees who completed the training, 253 were contacted and followed up. A self-designed questionnaire was used to conduct the survey through online filling in. The content included questions to elucidate the following information: whereabouts after the training, registration as a general practitioner, undertaken general practice teaching and scientific research work, current occupational environment, improvement of post competence after receiving position transition training, willingness to complete survey, willingness to participate in future training programs, etc. RESULTS: A number of 253 valid questionnaires were collected with a recovery rate of 100%. Notably, 93.68% of the participants successfully completed their training and obtained the Training Certificate of General Practitioners. Further, 83.4% were registered as general practitioners, 82.94% of which added on the basis of the original registered scope of practice. Currently, most of them work in primary health care institutions, primarily occupied with medical treatment, chronic disease management, COVID-19 prevention and control, health education, and prevention and health care. Of them, 27.01% were currently undertaking teaching work, and only 3.32% of them were conducting scientific research work related to general practice. The overall satisfaction of the trainees in the three theoretical training bases was above 90%, with no statistically significant difference among them (P > 0.05). Importantly, 84.11% of the followed-up personnel hoped to continue to participate in similar training in the future to improve their general practitioner core competences. CONCLUSION: The position transition training in Zhejiang Province has achieved good results, but the details of training and the implementation of policies in individual regions need to be improved. Most of the graduates were willing to continue their education, especially in general practitioners with special interests.

LINC00963 May Be Associated with a Poor Prognosis in Patients with Cervical Cancer.

BACKGROUND Recently, the upregulation of LINC00963 expression has been reported in various cancer subtypes. LINC00963 expression can promote cancer cell invasion and metastasis. However, the clinical significance of LINC00963 in cervical and endocervical cancer (CESC) has remained relatively unexamined. MATERIAL AND METHODS We assessed the mRNA expression of LINC00963 in patients with CESC based on data acquired from The Cancer Genome Atlas (TCGA) to determine pathways involved in CESC pathogenesis with respect to LINC00963. We included 3 normal and 304 tumor samples in this study. RESULTS The scatter plot and paired plot showed differences in LINC00963 expression between normal and tumor samples (P<0.01). Overall survival (OS) analysis revealed that CESC patients with high expression of LINC00963 demonstrated worse prognosis than CESC patients with low expression of LINC00963 (P<0.01). Multivariate analysis with the Cox proportional hazards model indicated that the expression of LINC00963 (HR 0.297; 95% CI 0.115-0.776; P=0.012) and primary therapy outcome (HR 0.162; 95% CI 0.059-0.446; P=0.001) were independent prognostic factors for patients with CESC. GSEA results showed that reactome biological oxidations, inflammasomes, apoptosis, toll-like receptor signaling pathway, JAK/STAT signaling pathway, and NF-kappaB activation were differentially enriched in CESC samples with the high LINC00963 expression phenotype. CONCLUSIONS Our results confirmed the association of significantly high levels of LINC00963 expression in CESC with several observed clinical features. LINC00963 may be a potentially useful prognostic molecular biomarker associated with poor survival in patients with CESC.

Evaluation of the health promotion effect of hepatitis B prevention and treatment in the Zhejiang demonstration area, China.

BACKGROUND: To investigate the health literacy level and health promotion effect of hepatitis B prevention and treatment in the demonstration area of Zhejiang Province. METHODS: The National Science and Technology Major Health Education Group took 6 demonstration areas in Zhejiang Province as the whole research site. After the sample size (N=2160 people) was determined, a multistage stratified cluster sampling method was used to conduct a questionnaire survey in 2018 (before health education) and 2019 (after health education). Stata 12 statistical software was used to analyse the status and improvement rate of hepatitis B health literacy of residents in the demonstration area before and after health education and compare the health promotion effects of different health intervention methods. RESULTS: Before and after health education, there was no significant difference in the basic information of the subjects (P>0.05). After the health education intervention, the level of hepatitis B health literacy of residents in the demonstration area increased by 11.8%, and the difference was statistically significant (P < 0.001). The awareness rate of hepatitis B transmission was low before health education but increased after health education. The form of "Internet +" health education may better improve the residents' health literacy level about hepatitis B prevention and treatment. CONCLUSION: After health education, the level of health literacy of residents in the Zhejiang demonstration area about hepatitis B prevention and control significantly improved, but there is room for further improvement. In the future, targeted health education intervention should be carried out, and the health education mode of "Internet +" can achieve better results to effectively prevent and control hepatitis B.

Administration of Exogenous Progesterone Protects Against Brucella abortus Infection-Induced Inflammation in Pregnant Mice.

Progesterone has been recognized as essential for the establishment and maintenance of pregnancy, and is typically known as an immunosuppressive agent. However, its effects on mediating Brucella infection-induced inflammation have not been evaluated. Here we demonstrated that Brucella abortus infection inhibits progesterone levels in the pregnant mouse by suppressing the production of progesterone by placenta. Progesterone treatment significantly reduced the secretion of inflammatory cytokines in serum, macrophages, and trophoblasts of B. abortus-infected mice, leading to decreased placentitis and enhancing the pup viability. Mechanistically, this decreased inflammatory response results from inhibition of NF-kB activation by progesterone. Moreover, progesterone treatment suppresses B. abortus growth within trophoblasts associated with an inability of bacteria to escape the late endosome compartment in vitro. Collectively, our data illustrate that progesterone treatment might be useful therapeutically in protection against placentitis or abortion caused by B. abortus infection.

Thioredoxin 2 Negatively Regulates Innate Immunity to RNA Viruses by Disrupting the Assembly of the Virus-Induced Signaling Adaptor Complex.

The virus-induced signaling adaptor (VISA) complex plays a critical role in the innate immune response to RNA viruses. However, the mechanism of VISA complex formation remains unclear. Here, we demonstrate that thioredoxin 2 (TRX2) interacts with VISA at mitochondria both in vivo and in vitro Knockdown and knockout of TRX2 enhanced the formation of the VISA-associated complex, as well as virus-triggered activation of interferon regulatory factor 3 (IRF3) and transcription of the interferon beta 1 (IFNB1) gene. TRX2 inhibits the formation of VISA aggregates by repressing reactive oxygen species (ROS) production, thereby disrupting the assembly of the VISA complex. Furthermore, our data suggest that the C93 residue of TRX2 is essential for inhibition of VISA aggregation, whereas the C283 residue of VISA is required for VISA aggregation. Collectively, these findings uncover a novel mechanism of TRX2 that negatively regulates VISA complex formation.IMPORTANCE The VISA-associated complex plays pivotal roles in inducing type I interferons (IFNs) and eliciting the innate antiviral response. Many host proteins are identified as VISA-associated-complex proteins, but how VISA complex formation is regulated by host proteins remains enigmatic. We identified the TRX2 protein as an important regulator of VISA complex formation. Knockout of TRX2 increases virus- or poly(I·C)-triggered induction of type I IFNs at the VISA level. Mechanistically, TRX2 inhibits the production of ROS at its C93 site, which impairs VISA aggregates at its C283 site, and subsequently impedes the assembly of the VISA complex. Our findings suggest that TRX2 plays an important role in the regulation of VISA complex assembly.

Foot-and-Mouth Disease Virus 3A Protein Causes Upregulation of Autophagy-Related Protein LRRC25 To Inhibit the G3BP1-Mediated RIG-Like Helicase-Signaling Pathway.

Foot-and-mouth disease virus (FMDV) is one of the most notorious pathogens in the global livestock industry. To establish an infection, FMDV needs to counteract host antiviral responses. Several studies have shown how FMDV suppresses the type I interferon (IFN) response; however, whether FMDV modulates the integrated autophagy and innate immunity remains largely unknown. Here, the porcine Ras-GAP SH3-binding protein 1 (G3BP1) was shown to promote the retinoic acid-inducible gene I (RIG-I)-like helicase (RLH) signaling by upregulating the expression of RIG-I and melanoma differentiation-associated gene 5 (MDA5). FMDV nonstructural protein 3A interacted with G3BP1 to inhibit G3BP1 expression and G3BP1-mediated RLH signaling by upregulating the expression of autophagy-related protein LRRC25. In addition, 3A proteins of other picornaviruses, including Seneca Valley virus (SVV) 3A, enterovirus 71 (EV71) 3A, and encephalomyocarditis virus (EMCV) 3A, also showed similar actions. Taking the data together, we elucidated, for the first time, a novel mechanism by which FMDV has evolved to inhibit IFN signaling and counteract host innate antiviral responses by autophagy.IMPORTANCE We show that foot-and-mouth disease virus (FMDV) 3A inhibits retinoic acid-inducible gene I (RIG-I)-like helicase signaling by degrading G3BP1 protein. Furthermore, FMDV 3A reduces G3BP1 by upregulating the expression of autophagy-related protein LRRC25. Additionally, other picornavirus 3A proteins, such as Seneca Valley virus (SVV) 3A, enterovirus 71 (EV71) 3A, and encephalomyocarditis virus (EMCV) 3A, also degrade G3BP1 by upregulating LRRC25 expression. This study will help us improve the design of current vaccines and aid the development of novel control strategies to combat FMD.

Adsorption behavior of Cd (II) on TEMPO-oxidized cellulose in inorganic/ organic complex systems.

2,2,6,6-Tetramethylpiperidine-1-oxyl (TEMPO) was oxidized to produce TEMPO-oxidized cellulose (TOCS) with a nanofunctionalized surface and abundant carboxyl groups. In a batch experiment, three pH values (2, 5 and 7), three modes (single, binary and multiple systems), and systems with inorganic and organic materials were applied to explore the adsorption of coexisting metals and antibiotics on TOCS. The adsorption capacity of TOCS was substantially influenced by these factors, and the adsorption behaviors were also different in these systems. In general, the coordination behaviors and electrostatic attraction between Cd(II) and carboxyl groups were identified as the mechanism employed by the single system, while hydrophobic interactions, π interactions, hydrogen bonding and pore filling contributed to the adsorption of sulfonamides (SAs) on TOCS in the binary system. The bridging effect was determined to be the key mechanism; i.e., most Cd(II) and SAs in the form of [SA-Cd] complexes interacted with carboxyl groups, especially in the presence of high concentrations of Cd(II) and SAs. These adsorption behaviors were determined quantitatively by performing density functional theory (DFT) calculations. In addition, TOCS showed excellent adsorption capacity in a more complex interference system, and the maximum adsorption capacity was 5.83 mg/g.

Running an Internet Hospital in China: Perspective Based on a Case Study.

Internet hospitals, as a new forum for doctors to conduct diagnosis and treatment activities based on the internet, are emerging in China and have become integral to the development of the medical field in conjunction with increasing reforms and policies in China's medical and health system. Here, we take the Internet Hospital of the First Affiliated Hospital, Zhejiang University (FAHZU Internet Hospital) as an example to discuss the operations and functional positioning of developing internet hospital medical services in relation to physical hospitals. This viewpoint considers the platform operation, management, and network security of FAHZU Internet Hospital, and summarizes the advantages and limitations in the operation to provide a reference for other areas with interest in developing internet hospitals.

Normotensive and hypertensive Immunoglobulin a nephropathy with ischemic renal injury: clinicopathological characteristics and prognosis.

OBJECTIVES: This study aimed to investigate the clinicopathological characteristics and prognosis of normotensive and hypertensive IgAN patients with ischemic renal injury. METHODS: A total of 344 cases of IgAN with ischemic renal injury were included in the study, including 99 normotensive IgAN patients (28.8%) and 245 hypertensive IgAN patients (71.2%). In addition, 467 IgAN patients without ischemic renal injury were included as controls, including 205 normotensive patients and 262 hypertensive patients. Clinicopathological and prognostic data were collected and analyzed. RESULTS: Compared with patients without ischemic renal injury, IgAN patients with ischemic renal injury displayed a higher proportion of hypertention, a higher proportion of ischemic glomerulosclerosis, tubular atrophy/interstitial fibrosis and vascular lesions (all p < .05). There was no significant difference in cumulative survival between the normotensive IgAN patients groups (Log-rank χ2 = 0.479; p = .489). Furthermore, ischemic renal injury was not a risk factor for end-point events in normotensive IgAN patients (HR = 1.103; 95% CI: 0.279-4.365; p = .889). There was lower cumulative survival in hypertensive IgAN patients with ischemic renal injury (Log-rank χ2 = 11.352, p = .001). Moreover, ischemic renal injury was a risk factor for end-point events in hypertensive IgAN patients (HR = 1.889; 95% CI: 1.124-3.178; p = .016). CONCLUSIONS: Ischemic renal injury can occur in normotensive IgAN patients. Although the pathological changes may not affect the long-term prognosis of normotensive IgAN patients, the prognosis for hypertensive IgAN patients remains poor. Therefore, increased attention should be paid to the clinical management of ischemic lesions in hypertensive IgAN patients.

AtBUD13 affects pre-mRNA splicing and is essential for embryo development in Arabidopsis.

Pre-mRNA splicing is an important step for gene expression regulation. Yeast Bud13p (bud-site selection protein 13) regulates the budding pattern and pre-mRNA splicing in yeast cells; however, no Bud13p homologs have been identified in plants. Here, we isolated two mutants that carry T-DNA insertions at the At1g31870 locus and shows early embryo lethality and seed abortion. At1g31870 encodes an Arabidopsis homolog of yeast Bud13p, AtBUD13. Although AtBUD13 homologs are widely distributed in eukaryotic organisms, phylogenetic analysis revealed that their protein domain organization is more complex in multicellular species. AtBUD13 is expressed throughout plant development including embryogenesis and AtBUD13 proteins is localized in the nucleus in Arabidopsis. RNA-seq analysis revealed that AtBUD13 mutation predominantly results in the intron retention, especially for shorter introns (≤100 bases). Within this group of genes, we identified 52 genes involved in embryogenesis, out of which 22 are involved in nucleic acid metabolism. Our results demonstrate that AtBUD13 plays critical roles in early embryo development by effecting pre-mRNA splicing.