Assessing the Influence of B-US, CDFI, SE, and Patient Age on Predicting Molecular Subtypes in Breast Lesions Using Deep Learning Algorithms.

OBJECTIVES: Our study aims to investigate the impact of B-mode ultrasound (B-US) imaging, color Doppler flow imaging (CDFI), strain elastography (SE), and patient age on the prediction of molecular subtypes in breast lesions. METHODS: Totally 2272 multimodal ultrasound imaging was collected from 198 patients. The ResNet-18 network was employed to predict four molecular subtypes from B-US imaging, CDFI, and SE of patients with different ages. All the images were split into training and testing datasets by the ratio of 80%:20%. The predictive performance on testing dataset was evaluated through 5 metrics including mean accuracy, precision, recall, F1-scores, and confusion matrix. RESULTS: Based on B-US imaging, the test mean accuracy is 74.50%, the precision is 74.84%, the recall is 72.48%, and the F1-scores is 0.73. By combining B-US imaging with CDFI, the results were increased to 85.41%, 85.03%, 85.05%, and 0.84, respectively. With the integration of B-US imaging and SE, the results were changed to 75.64%, 74.69%, 73.86%, and 0.74, respectively. Using images from patients under 40 years old, the results were 90.48%, 90.88%, 88.47%, and 0.89. When images from patients who are above 40 years old, they were changed to 81.96%, 83.12%, 80.5%, and 0.81, respectively. CONCLUSION: Multimodal ultrasound imaging can be used to accurately predict the molecular subtypes of breast lesions. In addition to B-US imaging, CDFI rather than SE contribute further to improve predictive performance. The predictive performance is notably better for patients under 40 years old compared with those who are 40 years old and above.

[Transperineal versus transrectal ultrasound-guided prostate biopsy in detection of clinically significant and insignificant prostate cancer: A prospective randomized controlled trial].

OBJECTIVE: To compare transperineal prostate biopsy (TPB) with transrectal ultrasound-guided prostate biopsy (TRUSB) in detection of clinically significant prostate cancer (csPCa) and insignificant PCa (insPCa). METHODS: We conducted a prospective randomized clinical study on 279 patients receiving TPB (n = 144) or TRUSB (n = 135) from January 2022 to January 2023, and compared the detection rates of csPCa and insPCa between the two groups. RESULTS: The detection rate of PCa was significantly higher in the TPB than in the TRUSB group (37.50% vs 28.15%, P = 0.026). There were no statistically significant differences between the TPB and TRUSB groups in the detection rates of insPCa (6.94% ï¼»n = 10ï¼½ vs 4.45% ï¼»n = 6ï¼½, P > 0.05) and csPCa (30.56% ï¼»n = 44ï¼½ vs 23.70% ï¼»n = 32ï¼½, P > 0.05), nor in the detection rate of csPCa between different groups of age, PSA concentration and prostate volume (P > 0.05). No statistically significant differences were observed between the TPB and TRUSB groups either in the positive rate of biopsy punctures (ï¼»16.44 ± 2.86ï¼½% vs ï¼»12.48 ± 2.39ï¼½%, P > 0.05) or in the biopsy-related complications of urinary retention, urinary tract infection, hematuria and rectal bleeding (P > 0.05). CONCLUSION: TPB is more effective than TRUSB in detection of PCa, but there is no statistically significant difference between the two approaches in the detection rates of csPCa and insPCa.

Kinetics and prognostic significance of laboratory markers in patients with severe fever with thrombocytopenia syndrome: insight from a comprehensive analysis.

Severe Fever with Thrombocytopenia Syndrome (SFTS) is an emerging infectious disease with significant mortality. Identifying prognostic factors that influence patient outcomes is crucial for effective clinical management. In this study, we assessed the dynamic changes of laboratory markers and their association with outcomes in 93 SFTS patients. We found that age and hypertension were significantly associated with poor outcomes in SFTS patients. The deceased group exhibited lower platelet counts, elevated liver and kidney function markers, coagulation profiles, inflammatory markers, and cytokines compared to the survival group. Kinetic analysis showed that these markers gradually normalized in the survival group, while they remained persistently abnormal in the deceased group. Furthermore, hypertension, elevated AST, PCT, and IL-10 were identified as independent risk factors for predicting poor prognosis of SFTS patients. These findings provide valuable insights into the prognostic significance of laboratory markers and highlight the importance of early identification of high-risk SFTS patients.

The clinical and immunological characteristics in fatal severe fever with thrombocytopenia syndrome virus (SFTSV) infection.

OBJECTIVE: This study aimed to make a comprehensive evaluation of peripheral immune profiles for further understanding the immunopathogenesis of severe fever with thrombocytopenia syndrome (SFTS). METHODS: Forty-seven patients with SFTS virus infection were included, of which 24 were deceased. The percentages, absolute numbers, phenotype of lymphocyte subsets were detected by flow cytometry. RESULTS: In patients with SFTS, the numbers of CD3+T, CD4+T, CD8+T and NKT cells were decreased compared with healthy controls (HCs), accompanied with highly active and exhausted phenotypes for T cells, and overproliferating plasmablasts. High inflammatory status, dysregulation of coagulation and host immune response were more obvious in deceased patients than that of survivors. Higher levels of PCT, IL-6, IL-10, TNF-α, APTT, TT and the occurrence of hemophagocytic lymphohistiocytosis were poor prognostic indicators of SFTS. CONCLUSIONS: The evaluation of immunological markers in combination with laboratory tests has critical value for selecting prognostic markers and potential treatment target.

STING promotes NLRP3 localization in ER and facilitates NLRP3 deubiquitination to activate the inflammasome upon HSV-1 infection.

One of the fundamental reactions of the innate immune responses to pathogen infection is the release of pro-inflammatory cytokines, including IL-1ß, processed by the NLRP3 inflammasome. The stimulator of interferon genes (STING) has the essential roles in innate immune response against pathogen infections. Here we reveal a distinct mechanism by which STING regulates the NLRP3 inflammasome activation, IL-1ß secretion, and inflammatory responses in human cell lines, mice primary cells, and mice. Interestingly, upon HSV-1 infection and cytosolic DNA stimulation, STING binds to NLRP3 and promotes the inflammasome activation through two approaches. First, STING recruits NLRP3 and facilitates NLRP3 localization in the endoplasmic reticulum, thereby facilitating the inflammasome formation. Second, STING interacts with NLRP3 and attenuates K48- and K63-linked polyubiquitination of NLRP3, thereby promoting the inflammasome activation. Collectively, we demonstrate that the cGAS-STING-NLRP3 signaling is essential for host defense against HSV-1 infection.

Establishment of an orthotopic prostate cancer xenograft mouse model using microscope-guided orthotopic injection of LNCaP cells into the dorsal lobe of the mouse prostate.

BACKGROUND: Orthotopic LNCaP xenograft mouse models closely mimic the progression of androgen-dependent prostate cancer in humans; however, orthotopic injection of LNCaP cells into the mouse prostate remains a challenge. METHODS: Under the guidance of a stereoscopic microscope, the anatomy of the individual prostate lobes in male Balb/c athymic nude mice was investigated, and LNCaP cells were inoculated into the mouse dorsal prostate (DP) to generate orthotopic tumors that mimicked the pathophysiological process of prostate cancer in humans. Real-time ultrasound imaging was used to monitor orthotopic prostate tumorigenesis, contrast-enhanced ultrasonography (CEUS) was used to characterize tumor angiogenesis, and macroscopic and microscopic characteristics of tumors were described. RESULTS: The DP had a trigonal bipyramid-shape and were located at the base of the seminal vesicles. After orthotopic inoculation, gray scale ultrasound imaging showed progressive changes in tumor echotexture, shape and location, and tumors tended to protrude into the bladder. After 8 weeks, the tumor take rate was 65% (n = 13/20 mice). On CEUS, signal intensity increased rapidly, peaked, and decreased gradually. Observations of gross specimens showed orthotopic prostate tumors were well circumscribed, round, dark brown, and soft, with a smooth outer surface and a glossy appearance. Microscopically, tumor cells were arranged in acini encircled by fibrous septa with variably thickened walls, mimicking human adenocarcinoma. CONCLUSIONS: This study describes a successful approach to establishing an orthotopic LNCaP xenograft Balb/c athymic nude mouse model. The model requires a thorough understanding of mouse prostate anatomy and proper technique. The model represents a valuable tool for the in vivo study of the biological processes involved in angiogenesis in prostate cancer and preclinical evaluations of novel anti-angiogenic therapies.

Optimization of loop-mediated isothermal amplification (LAMP) assay for robust visualization in SARS-CoV-2 and emerging variants diagnosis.

Loop-mediated isothermal amplification (LAMP) is widely used in detection of pathogenic microorganisms including SARS-CoV-2. However, the performance of LAMP assay needs further exploration in the emerging SARS-CoV-2 variants test. Here, we design serials of primers and select an optimal set for LAMP-based on SARS-CoV-2 N gene for a robust and visual assay in SARS-CoV-2 diagnosis. The limit of detectable template reaches 10 copies of N gene per 25 µL reaction at isothermal 58℃ within 40 min. Importantly, the primers for LAMP assay locate at 12 to 213 nt of N gene, a highly conservative region, which serves as a compatible test in emerging SARS-CoV-2 variants. Comparison to a commercial qPCR assay, this LAMP assay exerts the high viability in diagnosis of 41 clinical samples. Our study optimizes an advantageous LAMP assay for colorimetric detection of SARS-CoV-2 and emerging variants, which is hopeful to be a promising test in COVID-19 surveillance.

Osteopetrosis-Associated Transmembrane Protein 1 Recruits RNA Exosome To Restrict Hepatitis B Virus Replication.

Hepatitis B virus (HBV) chronically infects approximately 350 million people worldwide, and 600,000 deaths are caused by HBV-related hepatic failure, liver cirrhosis, and hepatocellular carcinoma annually. It is important to reveal the mechanism underlying the regulation of HBV replication. This study demonstrated that osteopetrosis-associated transmembrane protein 1 (Ostm1) plays an inhibitory role in HBV replication. Ostm1 represses the levels of HBeAg and HBsAg proteins, HBV 3.5-kb and 2.4/2.1-kb RNAs, and core-associated DNA in HepG2, Huh7, and NTCP-HepG2 cells. Notably, Ostm1 has no direct effect on the activity of HBV promoters or the transcription of HBV RNAs; instead, Ostm1 binds to HBV RNA to facilitate RNA decay. Detailed studies further demonstrated that Ostm1 binds to and recruits the RNA exosome complex to promote the degradation of HBV RNAs, and knockdown of the RNA exosome component exonuclease 3 (Exosc3) leads to the elimination of Ostm1-mediated repression of HBV replication. Mutant analyses revealed that the N-terminal domain, the transmembrane domain, and the C-terminal domain are responsible for the repression of HBV replication, and the C-terminal domain is required for interaction with the RNA exosome complex. Moreover, Ostm1 production is not regulated by interferon-α (IFN-α) or IFN-γ, and the expression of IFN signaling components is not affected by Ostm1, suggesting that Ostm1 anti-HBV activity is independent of the IFN signaling pathway. In conclusion, this study revealed a distinct mechanism underlying the repression of HBV replication, in which Ostm1 binds to HBV RNA and recruits RNA exosomes to degrade viral RNA, thereby restricting HBV replication.IMPORTANCE Hepatitis B virus (HBV) is a human pathogen infecting the liver to cause a variety of diseases ranging from acute hepatitis to advanced liver diseases, fulminate hepatitis, liver cirrhosis, and hepatocellular carcinoma, thereby causing a major health problem worldwide. In this study, we demonstrated that Ostm1 plays an inhibitory role in HBV protein production, RNA expression, and DNA replication. However, Ostm1 has no effect on the activities of the four HBV promoters; instead, it binds to HBV RNA and recruits RNA exosomes to promote HBV RNA degradation. We further demonstrated that the anti-HBV activity of Ostm1 is independent of the interferon signaling pathway. In conclusion, this study reveals a distinct mechanism underlying the repression of HBV replication and suggests that Ostm1 is a potential therapeutic agent for HBV infection.

Inducible LGALS3BP/90K activates antiviral innate immune responses by targeting TRAF6 and TRAF3 complex.

The galectin 3 binding protein (LGALS3BP, also known as 90K) is a ubiquitous multifunctional secreted glycoprotein originally identified in cancer progression. It remains unclear how 90K functions in innate immunity during viral infections. In this study, we found that viral infections resulted in elevated levels of 90K. Further studies demonstrated that 90K expression suppressed virus replication by inducing IFN and pro-inflammatory cytokine production. Upon investigating the mechanisms behind this event, we found that 90K functions as a scaffold/adaptor protein to interact with TRAF6, TRAF3, TAK1 and TBK1. Furthermore, 90K enhanced TRAF6 and TRAF3 ubiquitination and served as a specific ubiquitination substrate of TRAF6, leading to transcription factor NF-κB, IRF3 and IRF7 translocation from the cytoplasm to the nucleus. Conclusions: 90K is a virus-induced protein capable of binding with the TRAF6 and TRAF3 complex, leading to IFN and pro-inflammatory production.

Capsular extension at ultrasound is associated with lateral lymph node metastasis in patients with papillary thyroid carcinoma: a retrospective study.

BACKGROUND: In patients with papillary thyroid cancer (PTC), cervical lymph node metastasis (LNM) must be carefully assessed to determine the extent of lymph node dissection required and patient prognosis. Few studies attempted to determine whether the ultrasound (US) appearance of the primary thyroid tumor could be used to predict cervical lymph node involvement. This study aimed to identify the US features of the tumor that could predict cervical LNM in patients with PTC. METHODS: This was a retrospective study of patients with pathologically confirmed PTC. We evaluated the following US characteristics: lobe, isthmus, and tumor size; tumor position; parenchymal echogenicity; the number of lesions (i.e., tumor multifocality); parenchymal and lesional vascularity; tumor margins and shape; calcifications; capsular extension; tumor consistency; and the lymph nodes along the carotid vessels. The patients were grouped as no LNM (NLNM), central LNM (CLNM) alone, and lateral LNM (LLNM) with/without CLNM, according to the postoperative pathological examination. RESULTS: Totally, 247 patients, there were 67 men and 180 women. Tumor size of > 10 mm was significantly more common in the CLNM (70.2%) and LLNM groups (89.6%) than in the NLNM group (45.4%). At US, capsular extension > 50% was most common in the LLNM group (35.4%). The multivariable analysis revealed that age (OR = 0.203, 95%CI: 0.095-0.431, P < 0.001) and tumor size (OR = 2.657, 95%CI: 1.144-6.168, P = 0.023) were independently associated with CLNM compared with NLNM. In addition, age (OR = 0.277, 95%CI: 0.127-0.603, P = 0.001), tumor size (OR = 6.069, 95%CI: 2.075-17.75, P = 0.001), and capsular extension (OR = 2.09, 95%CI: 1.326-3.294, P = 0.001) were independently associated with LLNM compared with NLNM. CONCLUSION: Percentage of capsular extension at ultrasound is associated with LLNM. US-guided puncture cytology and eluent thyroglobulin examination could be performed as appropriate to minimize the missed diagnosis of LNM.

SUMO1 SUMOylates and SENP3 deSUMOylates NLRP3 to orchestrate the inflammasome activation.

The NLRP3 inflammasome regulates innate immune and inflammatory responses by promoting caspase1-dependent induction of pro-inflammatory cytokines. However, aberrant inflammasome activation causes diverse diseases, and thus inflammasome activity must be tightly controlled. Here, we reveal a molecular mechanism underlying the regulation of NLRP3 inflammasome. NLRP3 interacts with SUMO-conjugating enzyme (UBC9), which subsequently promotes small ubiquitin-like modifier 1 (SUMO1) to catalyze NLRP3 SUMOylation at residue Lys204. SUMO1-catalyzed SUMOylation of NLRP3 facilitates ASC oligomerization, inflammasome activation, and interleukin-1ß secretion. Moreover, this study also reveals that SUMO-specific protease 3 (SENP3) is required for the deSUMOylation of NLRP3. Interestingly, SENP3 deSUMOylates NLRP3 to attenuate ASC recruitment and speck formation, the NLRP3 inflammasome activation, as well as IL-1ß cleavage and secretion. In conclusion, we reveal that SUMO1-catalyzed SUMOylation and SENP3-mediated deSUMOylation of NLRP3 orchestrate the inflammasome activation.

Successful treatment of a kidney transplant patient with COVID-19 and late-onset Pneumocystis jirovecii pneumonia.

BACKGROUND: Solid transplant patients are susceptible to Pneumocystis jirovecii pneumonia (PJP). While the vast majority of PJP cases occur within the first 6 months after transplantation, very few PJP cases are seen beyond 1 year post-transplantation (late-onset PJP). PJP and coronavirus disease 2019 (COVID-19, caused by infection with SARS-CoV-2) share quite a few common clinical manifestations and imaging findings, making the diagnosis of PJP often underappreciated during the current COVID-19 pandemic. To date, only 1 case of kidney transplantation who developed COVID-19 and late-onset PJP has been reported, but this patient also suffered from many other infections and died from respiratory failure and multiple organ dysfunction syndrome. A successful treatment of kidney patients with COVID-19 and late-onset PJP has not been reported. CASE PRESENTATION: We present a case of a 55-year-old male kidney transplant patient with COVID-19 who also developed late-onset PJP. He received a combined treatment strategy, including specific anti-pneumocystis therapy, symptomatic supportive therapy, adjusted immunosuppressive therapy, and use of antiviral drugs/antibiotics, ending with a favorable outcome. CONCLUSIONS: This case highlights the importance of prompt and differential diagnosis of PJP in kidney transplant patients with SARS-CoV-2 infection. Further studies are required to clarify if kidney transplant patients with COVID-19 could be prone to develop late-onset PJP and how these patients should be treated.

Paxillin mediates ATP-induced activation of P2X7 receptor and NLRP3 inflammasome.

BACKGROUND: Extracellular adenosine triphosphate (ATP), a key danger-associated molecular pattern (DAMP) molecule, is released to the extracellular medium during inflammation by injured parenchymal cells, dying leukocytes, and activated platelets. ATP directly activates the plasma membrane channel P2X7 receptor (P2X7R), leading to an intracellular influx of K+, a key trigger inducing NLRP3 inflammasome activation. However, the mechanism underlying P2X7R-mediated activation of NLRP3 inflammasome is poorly understood, and additional molecular mediators have not been identified. Here, we demonstrate that Paxillin is the molecule connecting the P2X7 receptor and NLRP3 inflammasome through protein interactions. RESULTS: We show a distinct mechanism by which Paxillin promotes ATP-induced activation of the P2X7 receptor and NLRP3 inflammasome. Extracellular ATP induces Paxillin phosphorylation and then facilitates Paxillin-NLRP3 interaction. Interestingly, Paxillin enhances NLRP3 deubiquitination and activates NLRP3 inflammasome upon ATP treatment and K+ efflux. Moreover, we demonstrated that USP13 is a key enzyme for Paxillin-mediated NLRP3 deubiquitination upon ATP treatment. Notably, extracellular ATP promotes Paxillin and NLRP3 migration from the cytosol to the plasma membrane and facilitates P2X7R-Paxillin interaction and PaxillinNLRP3 association, resulting in the formation of the P2X7R-Paxillin-NLRP3 complex. Functionally, Paxillin is essential for ATP-induced NLRP3 inflammasome activation in mouse BMDMs and BMDCs as well as in human PBMCs and THP-1-differentiated macrophages. CONCLUSIONS: We have identified paxillin as a mediator of NLRP3 inflammasome activation. Paxillin plays key roles in ATP-induced activation of the P2X7 receptor and NLRP3 inflammasome by facilitating the formation of the P2X7R-Paxillin-NLRP3 complex.

A Case Report of Neonatal 2019 Coronavirus Disease in China.

In December 2019, the coronavirus disease (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in China and now has spread in many countries. Pregnant women are a population susceptible to COVID-19 and are more likely to have complications and even progress to severe illness. We report a case of neonatal COVID-19 in China with pharyngeal swabs testing positive by real-time reverse-transcription polymerase chain reaction assay 36 hours after birth. However, whether the case is a vertical transmission from mother to child remains to be confirmed.

Three Patients with COVID-19 and Pulmonary Tuberculosis, Wuhan, China, January-February 2020.

During January-February 2020, coronavirus disease (COVID-19) and tuberculosis were diagnosed for 3 patients in Wuhan, China. All 3 patients had COVID-19 pneumonia. One severely ill patient died after acute respiratory distress syndrome developed. Clinicians and public health officials should be aware of underlying chronic infections such as tuberculosis in COVID-19 patients.

Dengue Virus M Protein Promotes NLRP3 Inflammasome Activation To Induce Vascular Leakage in Mice.

Dengue virus (DENV) infection causes serious clinical symptoms, including dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Vascular permeability change is the main feature of the diseases, and the abnormal expression of proinflammatory cytokines is the important cause of vascular permeability change. However, the mechanism underlying vascular permeability induced by DENV has not been fully elucidated. Here, we reveal a distinct mechanism by which DENV infection promotes NLRP3 inflammasome activation and interleukin-1 beta (IL-1ß) release to induce endothelial permeability and vascular leakage in mice. DENV M protein interacts with NLRP3 to facilitate NLRP3 inflammasome assembly and activation, which induce proinflammatory cytokine IL-1ß activation and release. Notably, M can induce vascular leakage in mouse tissues by activating the NLRP3 inflammasome and IL-1ß. More importantly, inflammatory cell infiltration and tissue injuries are induced by M in wild-type (WT) mouse tissues, but they are not affected by M in NLRP3 knockout (NLRP3-/-) mouse tissues. Evans blue intensities in WT mouse tissues are significantly higher than in NLRP3-/- mouse tissues, demonstrating an essential role of NLRP3 in M-induced vascular leakages in mice. Therefore, we propose that upon DENV infection, M interacts with NLRP3 to facilitate inflammasome activation and IL-1ß secretion, which lead to the induction of endothelial permeability and vascular leakage in mouse tissues. The important role of the DENV-M-NLRP3-IL-1ß axis in the induction of vascular leakage provides new insights into the mechanisms underlying DENV pathogenesis and DENV-associated DHF and DSS development.IMPORTANCE Dengue virus (DENV) is a mosquito-borne pathogen, and infections by this virus are prevalent in over 100 tropical and subtropical countries or regions, with approximately 2.5 billion people at risk. DENV infection induces a spectrum of clinical symptoms, ranging from classical dengue fever (DF) to severe dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Therefore, it is important to understand the mechanisms underlying DENV pathogenesis. In this study, we reveal that the DENV membrane protein (M) interacts with the host NLRP3 protein to promote NLRP3 inflammasome activation, which leads to the activation and release of a proinflammatory cytokine, interleukin-1 beta (IL-1ß). More importantly, we demonstrate that M protein can induce vascular permeability and vascular leakage and that NLRP3 is required for M-induced vascular leakage in mouse tissues. Collectively, this study reveals a distinct mechanism underlying DENV pathogeneses and provides new insights into the development of therapeutic agents for DENV-associated diseases.

HoxA10 Facilitates SHP-1-Catalyzed Dephosphorylation of p38 MAPK/STAT3 To Repress Hepatitis B Virus Replication by a Feedback Regulatory Mechanism.

Hepatitis B virus (HBV) infection is the leading cause of chronic hepatitis B (CHB), liver cirrhosis (LC), and hepatocellular carcinoma (HCC). This study reveals a distinct mechanism underlying the regulation of HBV replication. HBV activates homeobox A10 (HoxA10) in human hepatocytes, leukocytes, peripheral blood mononuclear cells (PBMCs), HepG2-NTCP cells, leukocytes isolated from CHB patients, and HBV-associated HCC tissues. HoxA10 in turn represses HBV replication in human hepatocytes, HepG2-NTCP cells, and BALB/c mice. Interestingly, we show that during early HBV infection, p38 mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3) were activated to facilitate HBV replication; however, during late HBV infection, HoxA10 was induced to attenuate HBV replication. Detailed studies reveal that HoxA10 binds to p38 MAPK, recruits SH2-containing protein tyrosine phosphatase 1 (SHP-1) to facilitate SHP-1 in catalyzing dephosphorylation of p38 MAPK/STAT3, and thereby attenuates p38 MAPK/STAT3 activation and HBV replication. Furthermore, HoxA10 binds to the HBV enhancer element I (EnhI)/X promoter, competes with STAT3 for binding of the promoter, and thereby represses HBV transcription. Taken together, these results show that HoxA10 attenuates HBV replication through repressing the p38 MAPK/STAT3 pathway by two approaches: HoxA10 interacts with p38 MAPK and recruits SHP-1 to repress HBV replication, and HoxA10 binds to the EnhI/X promoter and competes with STAT3 to attenuate HBV transcription. Thus, the function of HoxA10 is similar to the action of interferon (IFN) in terms of inhibition of HBV infection; however, the mechanism of HoxA10-mediated repression of HBV replication is different from the mechanism underlying IFN-induced inhibition of HBV infection.IMPORTANCE Two billion people have been infected with HBV worldwide; about 240 million infected patients developed chronic hepatitis B (CHB), and 650,000 die each year from liver cirrhosis (LC) or hepatocellular carcinoma (HCC). This work elucidates a mechanism underlying the control of HBV replication. HBV infection activates HoxA10, a regulator of cell differentiation and cancer progression, in human cells and patients with CHB and HCC. HoxA10 subsequently inhibits HBV replication in human tissue culture cells and mice. Additionally, HoxA10 interacts with p38 MAPK to repress the activation of p38 MAPK and STAT3 and recruits and facilitates SHP-1 to catalyze the dephosphorylation of p38 MAPK and STAT3. Moreover, HoxA10 competes with STAT3 for binding of the HBV X promoter to repress HBV transcription. Thus, this work reveals a negative regulatory mechanism underlying the control of HBV replication and provides new insights into the development of potential agents to control HBV infection.

Zika virus circumvents host innate immunity by targeting the adaptor proteins MAVS and MITA.

Recently, Zika virus (ZIKV) has generated extraordinary concern because of its severe neurotoxicity. Disturbingly, there is no vaccine or specific drug to prevent or treat the diseases caused by ZIKV infection. Thus, it is extremely urgent to characterize the pathogenesis of ZIKV. It has been documented that ZIKV can evade antiviral responses of host cells. Here, we demonstrate that ZIKV strain SZ-WIV01 down-regulates the production of type I IFN and IFN-stimulated genes along with the expression of mitochondrial antiviral signaling protein (MAVS) and mediator of IFN regulatory factor 3 activation (MITA). In the mechanism, ZIKV nonstructural (NS) 3 and NS2B3 negatively regulate IFN-related retinoic acid-inducible gene I-like receptor signaling pathway by targeting MAVS and MITA, respectively. Overexpression of ZIKV NS3 and NS2B3 dramatically inhibits expression of IFN-ß. ZIKV NS3 interacts with MAVS, and NS2B3 interacts with MITA, which catalyzes K48-linked polyubiquitination of MAVS and MITA for degradation. Further investigations suggest that ZIKV NS2B3 impairs polyinosinic:polycytidylic acid-triggered K63-linked polyubiquitination of MITA, thereby subverting the activation of downstream sensors. Our study reveals an undiscovered mechanism for ZIKV to escape the innate immune response, providing new insights into clinical study of vaccines or effective drugs.-Li, W., Li, N., Dai, S., Hou, G., Guo, K., Chen, X., Yi, C., Liu, W., Deng, F., Wu, Y., Cao, X. Zika virus circumvents host innate immunity by targeting the adaptor proteins MAVS and MITA.

Cullin1 binds and promotes NLRP3 ubiquitination to repress systematic inflammasome activation.

Activation of the NACHT, leucine-rich repeat, and pyrin domains-containing protein 3 (collectively known as NLRP3) inflammasome plays a key role in host immune response, which is the first line of defense against cellular stresses and pathogen infections. However, excessive inflammasome activation damages host cells, and therefore it must be precisely controlled. Here, we discover that Cullin1 (CUL1), a key component of the Skp1-Cullin1-F-box E3 ligase, plays a critical role in controlling the NLRP3 inflammasome. CUL1 represses inflammasome assembly in cultured cells, suppresses NLRP3 function in human monocytic cell line macrophages, and attenuates inflammatory responses in mouse model. Detailed studies demonstrate that CUL1 interacts with NLRP3 and promotes NLRP3 ubiquitination, but not protein degradation, to repress the NLRP3 inflammasome activation. Moreover, upon inflammatory stimuli, including ATP and nigericin treatments, CUL1 disassociates from NLRP3 to release the repression of the NLRP3 inflammasome. Thus, this study reveals a distinct and unique mechanism underlying the control of systematic activation of the NLRP3 inflammasome.-Wan, P., Zhang, Q., Liu, W., Jia, Y., Ai, S., Wang, T., Wang, W., Pan, P., Yang, G., Xiang, Q., Huang, S., Yang, Q., Zhang, W., Liu, F., Tan, Q., Zhang, W., Wu, K., Liu, Y., Wu, J. Cullin1 binds and promotes NLRP3 ubiquitination to repress systematic inflammasome activation.

Clinical and pathological findings of SARS-CoV-2 infection and concurrent IgA nephropathy: a case report.

BACKGROUND: Since the Coronavirus Disease 2019 (COVID-19) outbreak, there is accumulating data on the clinical characteristics, treatment strategies and prognosis of COVID-19 in patients with concurrent renal disease. Postmortem investigations reveal renal involvement in COVID-19, and most recently, several biopsy researches reveal that acute tubular injury, as well as glomerular nephropathy such as collapsing glomerulopathy were common histological findings. However, to our best knowledge, there is limited data regarding IgA nephropathy in the setting of COVID-19. CASE PRESENTATION: In the present case, we report a 65-year old Chinese woman who presented with dark-colored urine, worsening proteinuria and decreased renal function after COVID-19 infection. She received a renal biopsy during COVID-19 infection. The renal biopsy revealed IgA nephropathy without any evidence for SARS-Cov-2. The findings suggest that the renal abnormalities were a consequence of exacerbation of this patient's underlying glomerular disease after COVID-19 infection. After a regimen of 3-day course of glucocorticoid and angiotensin II receptor blocker therapy, the patient recovered and remained stable upon follow-up. CONCLUSIONS: It is important to consider the underlying glomerular disease exacerbation as well as virus induced injury when dealing with renal abnormalities in patients with COVID-19. A kidney biopsy may be indicated to exclude a rapidly progressive glomerular disease.