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.

Effects of ß-mannanase supplementation on productive performance, inflammation, energy metabolism, and cecum microbiota composition of laying hens fed with reduced-energy diets.

The objective of this study is to investigate the beneficial effects and underlying mechanism of dietary ß-mannanase supplementation on the productive performance of laying hens fed with metabolic energy (ME)-reduced diets. A total of 448 Hy-Line gray laying hens were randomly assigned to seven groups. Each group had 8 replicates with 8 hens. The groups included a control diet (CON) with a ME of 2750 kcal/Kg, diets reduced by 100 kcal/Kg or 200 kcal/Kg ME (ME_100 or ME_200), and diets with 0.15 g/Kg or 0.2 g/Kg ß-mannanase (ME_100+ß-M_0.15, ME_100+ß-M_0.2, ME_200+ß-M_0.15, and ME_200+ß-M_0.2). The productive performance, egg quality, intestinal morphology, inflammatory response, mRNA expression related to the Nuclear factor kappa B (NF-κB) and AMPK pathway, and cecum microbiome were evaluated in this study. ME-reduced diets negatively impacted the productive performance of laying hens. However, supplementation with ß-mannanase improved FCR, decreased ADFI, and restored average egg weight to the level of the CON group. ME-reduced diets increased the levels of interleukin-1ß (IL-1ß) and IL-6 while decreasing the levels of IL-4 and IL-10 in the jejunum of laying hens. However, dietary ß-mannanase supplementation improved jejunum morphology, reduced pro-inflammatory cytokine concentrations, and increased levels of anti-inflammatory factors in laying hens fed with ME-reduced diets. The mRNA levels of IL-6, IFN-γ, TLR4, MyD88, and NF-κB in the jejunum of ME-reduced diets were significantly higher than that in CON, dietary ß-mannanase supplementation decreased these genes expression in laying hens fed with ME-reduced diets. Moreover, dietary ß-mannanase supplementation also decreased the mRNA levels of AMPKα and AMPKγ, and increased the abundance of mTOR in the jejunum of laying hens fed with ME-reduced diets. Cecum microbiota analysis revealed that dietary ß-mannanase increased the abundance of various beneficial bacteria (e.g., g_Pseudoflavonifractor, g_Butyricicoccus, and f_Lactobacillaceae) in laying hens fed with ME-reduced diets. In conclusion, dietary ß-mannanase supplementation could improve the productive performance of laying hens fed with a ME-reduced diet by improving intestinal morphology, alleviating intestinal inflammation, changing energy metabolism-related signaling pathways, and increasing cecum-beneficial microbiota.

Effects of Lactobacillus plantarum HW1 on Growth Performance, Intestinal Immune Response, Barrier Function, and Cecal Microflora of Broilers with Necrotic Enteritis.

The purpose of the study was to investigate the effects of Lactobacillus plantarum HW1 on growth performance, intestinal immune response, barrier function, and cecal microflora of broilers with necrotic enteritis. In total, 180 one-day-old male Cobb 500 broilers were randomly allocated into three groups comprising a non-infected control (NC) group, basal diet + necrotic enteritis challenge (NE) group, and basal diet + 4 × 106 CFU/g Lactobacillus plantarum HW1 + necrotic enteritis challenge (HW1) group. Broilers in the NE and HW1 groups were orally given sporulated coccidian oocysts at day 14 and Clostridium perfringens from days 19 to 21. The results showed that the HW1 treatment increased (p < 0.05) the average daily gain of broilers from days 15 to 28 and from days 0 to 28 compared with the NE group. Moreover, the HW1 treatment decreased (p < 0.05) the oocysts per gram of excreta, intestinal lesion scores, ileal interleukin (IL) 1ß and tumor necrosis factor α levels, and serum D-lactic acid and diamine oxidase levels, while increasing (p < 0.05) the ileal IL-10 level, thymus index, and protein expressions of ileal occludin and ZO-1. Additionally, the HW1 treatment decreased (p < 0.05) the jejunal and ileal villus height, jejunal villus height/crypt depth value, and cecal harmful bacterial counts (Clostridium perfringens, Salmonella, Escherichia coli, and Staphylococcus aureus), and increased (p < 0.05) the cecal Lactobacillus count. In conclusion, dietary supplementation with 4 × 106 CFU/g Lactobacillus plantarum HW1 could relieve necrotic enteritis infection-induced intestinal injury and improve growth performance in broilers by improving intestinal barrier function and regulating intestinal microbiology.

Intestinal Ultrasound Combined with Blood Inflammatory Markers Is a More Efficient Tool in Evaluating Severity of Crohn's Disease: A Pilot Study.

Background and Aims: Intestinal ultrasound (IUS) is considered a nonirradiating, noninvasive, well-tolerated, and valuable tool for objectively assessing Crohn's disease (CD) activity. However, there is no widely accepted intestinal ultrasound scoring system. This study is aimed at evaluating the efficacy of IUS key parameters, the International Bowel Ultrasound Activity Score (IBUS-SAS), and IBUS-SAS combined with blood inflammatory markers in assessing CD activity. Methods: 40 CD patients were reviewed in this retrospective study and were divided into the moderate-severe group (n = 25) and nonmoderate-severe group (n = 15) based on a simplified endoscopic score of Crohn's disease (SES-CD). Double-balloon enteroscopy/colonoscopy were reviewed by three gastroenterologists. A transabdominal ultrasound was performed by two ultrasound specialists. Blood inflammatory markers were measured from morning samples. Results: In evaluating moderate to severe CD patients, (1) IBUS-SAS had a good predictive effect with an area-under-the-curve (AUC) of 0.855 (P < 0.001); (2) IUS key parameters (including BWT, CDS, BWS, and I-fat) yielded good predictive effects with AUC of 0.811, 0.731, 0.724, and 0.747, respectively (P < 0.001); (3) blood inflammatory markers (including ESR, CRP, PLR, MLR, and NLR) also had good predictive effects with AUC of 0.771, 0.837, 0.728, 0.743, and 0.775, respectively (P < 0.001); (4) IBUS-SAS combined with ESR and CRP exerted the best predictive effect with the highest AUC of 0.912 (95% CI: 0.823-1.000), and the sensitivity and specificity were 88.0% and 80.0%, respectively (P < 0.001). Conclusion: IBUS-SAS combined with ESR and CRP is a more efficient tool than IBUS-SAS alone or inflammatory markers alone in evaluating CD patients with moderate to severe disease activity.

Deep Learning Ultrasound Computed Tomography Under Sparse Sampling.

Ultrasound computed tomography (USCT) is a fast-emerging imaging modality that is expected to help detect and characterize breast tumors by quantifying the distribution of the speed of sound (SOS) and acoustic attenuation in breast tissue. High-quality quantitative SOS reconstruction in USCT requires a large number of transducers, which incurs high system costs and slow computation. In contrast, sparsely distributed arrays are low-cost and fast but significantly degrade image quality. Thus, we propose a framework to achieve high-quality SOS reconstruction under sparse sampling based on a convolutional neural network (SRSS-Net) with faster computation. We first apply the bent-ray algorithm to sparsely sampled data and then apply the SRSS-Net to efficiently improve the image quality. Experimental results on synthetic and real datasets demonstrate that the proposed SRSS-Net provides reconstructions that are superior to those of state-of-the-art methods in terms of artifact suppression, structural preservation, quantitative restoration, and computational speed. As demonstrated in our experiments, the fine-tuning training strategy is suggested when applying SRSS-Net to real-world circumstances. The imaging and computational performance of SRSS-Net on the inhomogeneous breast phantom further demonstrates that SRSS-Net has great potential in real-time breast cancer detection.

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.

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.

Sox4 represses host innate immunity to facilitate pathogen infection by hijacking the TLR signaling networks.

Toll-like receptors (TLRs) are essential for the protection of the host from pathogen infections by initiating the integration of contextual cues to regulate inflammation and immunity. However, without tightly controlled immune responses, the host will be subjected to detrimental outcomes. Therefore, it is important to balance the positive and negative regulations of TLRs to eliminate pathogen infection, yet avert harmful immunological consequences. This study revealed a distinct mechanism underlying the regulation of the TLR network. The expression of sex-determining region Y-box 4 (Sox4) is induced by virus infection in viral infected patients and cultured cells, which subsequently represses the TLR signaling network to facilitate viral replication at multiple levels by a distinct mechanism. Briefly, Sox4 inhibits the production of myeloid differentiation primary response gene 88 (MyD88) and most of the TLRs by binding to their promoters to attenuate gene transcription. In addition, Sox4 blocks the activities of the TLR/MyD88/IRAK4/TAK1 and TLR/TRIF/TRAF3/TBK1 pathways by repressing their key components. Moreover, Sox4 represses the activation of the nuclear factor kappa-B (NF-κB) through interacting with IKKα/α, and attenuates NF-kB and IFN regulatory factors 3/7 (IRF3/7) abundances by promoting protein degradation. All these contributed to the down-regulation of interferons (IFNs) and IFN-stimulated gene (ISG) expression, leading to facilitate the viral replications. Therefore, we reveal a distinct mechanism by which viral pathogens evade host innate immunity and discover a key regulator in host defense.

Value of ultrasound elastography combined with contrast-enhanced ultrasound and micro-flow imaging in differential diagnosis of benign and malignant breast lesions.

OBJECTIVE: Breast cancer is one of the most common malignant tumors in women and shows a rising incidence at younger ages. Therefore, early diagnosis is of great significance for treatment and prognosis. This study aimed to compare the value of ultrasound elastography (UE) combined with contrast-enhanced ultrasound (CEUS) and micro-flow imaging (MFI) in differential diagnosis of benign and malignant lesions of the breast. METHODS: The sonographic characteristics of UE and CEUS as well as the vascular characteristics of MFI of 109 breast lesions categorized as Breast Imaging Reporting and Data System (BI-RADS) category 4, confirmed by surgical or biopsy pathology were retrospectively analyzed. Receiver operating characteristic (ROC) curves were used to compare the diagnostic efficacy of the three examination modalities, either alone or in combination. RESULTS: Of the 109 breast lesions, 78 lesions were pathologically diagnosed as malignant and 31 as benign. At diagnosis, the area under the ROC curve (AUC), sensitivity, specificity, and accuracy of UE were 0.8495, 65.38%, 83.87% and 83.34%, respectively. The AUC, sensitivity, specificity and accuracy of MFI were 86.29%, 70.51%, 87.10% and 85.56%, respectively. The AUC, sensitivity, specificity and accuracy of CEUS were 90.84%, 88.46%, 74.19% and 89.16%, respectively. The AUC, sensitivity, specificity and accuracy of the combined diagnosis of UE, MFI, and CEUS were 93.90%, 85.90%, 90.32%, and 92.07%, respectively. CONCLUSIONS: The combination of UE, CEUS and MFI has the highest specificity and accuracy in the differential diagnosis of benign and malignant breast lesions compared to any one used singly.

Comparison of tumor angiogenesis in subcutaneous and orthotopic LNCaP mouse models using contrast-enhanced ultrasound imaging.

BACKGROUND: Understanding angiogenesis in prostate cancer is essential. LNCaP prostate xenograft tumors are androgen responsive and closely mimic clinical disease. Orthotopic animal models replicate aspects of the cancer microenvironment and are more clinically relevant than subcutaneous models. Comparative studies investigating angiogenesis using contrast-enhanced ultrasound (CEUS) imaging in subcutaneous and orthotopic mouse models of prostate cancer have not been performed. METHODS: Tumor microcirculation and perfusion in subcutaneous and orthotopic LNCaP xenograft Balb/c athymic nude mice models were compared by investigating microbubble wash-in with CEUS. RESULTS: The take rate of subcutaneous and orthotopic tumors were 58.3% and 68.2%, respectively. On CEUS, orthotopic prostate tumors enhanced more rapidly than subcutaneous tumors. Mean arrival-time (Atm) for subcutaneous tumors, orthotopic prostate tumors, and kidney were 4.21±1.86, 1.72±0.79, and 0.73±0.12 s, respectively. Mean Atm was significantly longer for subcutaneous tumors compared to orthotopic prostate tumors or kidney (P<0.01). Mean time to peak enhancement (TtoPk) for subcutaneous tumors, orthotopic prostate tumors, and kidney were 38.56±13.23, 12.39±7.17, and 3.74±1.41 s, respectively. Mean TtoPk were significantly shorter for orthotopic prostate tumors and kidney compared to subcutaneous tumors (P<0.01). Mean wash-in area under the curve (WiAuC) for subcutaneous tumors, orthotopic prostate tumors, and kidney were 611.11±247.52, 1,800.57±623.11, and 1,887.51±103.68 dB, respectively. Mean AUC was significantly higher for orthotopic prostate tumors and kidney compared to subcutaneous tumors (P<0.01). Parametric imaging confirmed these findings. The density of CD31-positive vessels was significantly higher in orthotopic prostate tumors (43.98±6.14 vessels/field) compared to subcutaneous tumors (15.44±3.74 vessels/field, P<0.01). CONCLUSIONS: These findings demonstrate that orthotopic LNCaP xenografts better recreate a pro-angiogenic microenvironment than subcutaneous LNCaP xenografts.

Construction and Validation of a Clinical Predictive Nomogram for Improving the Cancer Detection of Prostate Naive Biopsy Based on Chinese Multicenter Clinical Data.

OBJECTIVES: Prostate biopsy is a common approach for the diagnosis of prostate cancer (PCa) in patients with suspicious PCa. In order to increase the detection rate of prostate naive biopsy, we constructed two effective nomograms for predicting the diagnosis of PCa and clinically significant PCa (csPCa) prior to biopsy. MATERIALS AND METHODS: The data of 1,428 patients who underwent prostate biopsy in three Chinese medical centers from January 2018 to June 2021 were used to conduct this retrospective study. The KD cohort, which consisted of 701 patients, was used for model construction and internal validation; the DF cohort, which consisted of 385 patients, and the ZD cohort, which consisted of 342 patients, were used for external validation. Independent predictors were selected by univariate and multivariate binary logistic regression analysis and adopted for establishing the predictive nomogram. The apparent performance of the model was evaluated via internal validation and geographically external validation. For assessing the clinical utility of our model, decision curve analysis was also performed. RESULTS: The results of univariate and multivariate logistic regression analysis showed prostate-specific antigen density (PSAD) (P<0.001, OR:2.102, 95%CI:1.687-2.620) and prostate imaging-reporting and data system (PI-RADS) grade (P<0.001, OR:4.528, 95%CI:2.752-7.453) were independent predictors of PCa before biopsy. Therefore, a nomogram composed of PSAD and PI-RADS grade was constructed. Internal validation in the developed cohort showed that the nomogram had good discrimination (AUC=0.804), and the calibration curve indicated that the predicted incidence was consistent with the observed incidence of PCa; the brier score was 0.172. External validation was performed in the DF and ZD cohorts. The AUC values were 0.884 and 0.882, in the DF and ZD cohorts, respectively. Calibration curves elucidated greatly predicted the accuracy of PCa in the two validation cohorts; the brier scores were 0.129 in the DF cohort and 0.131 in the ZD cohort. Decision curve analysis showed that our model can add net benefits for patients. A separated predicted model for csPCa was also established and validated. The apparent performance of our nomogram for PCa was also assessed in three different PSA groups, and the results were as good as we expected. CONCLUSIONS: In this study, we put forward two simple and convenient clinical predictive models comprised of PSAD and PI-RADS grade with excellent reproducibility and generalizability. They provide a novel calculator for the prediction of the diagnosis of an individual patient with suspicious PCa.

Magnetic polymeric nanobubbles with optimized core size for MRI/ultrasound bimodal molecular imaging of prostate cancer.

Aim: To design MRI/ultrasound (US) dual modality imaging probes with optimized size for prostate cancer imaging by targeting prostate-specific membrane antigen (PSMA). Materials & methods: The PSMA-targeting polypeptide-nanobubbles (PP-NBs) with core size of 400 and 700 nm were fabricated and evaluated. Results: With excellent physical property and specificity, PP-NBs of both core size could image PSMA expression in prostate cancer xenografts. Particularly, 400 nm PP-NBs generated higher PSMA-specific MRI/US dual modality contrast enhancement than 700 nm PP-NBs in correlation with histopathologic findings. Conclusion: Benefit from the smaller core size, 400 nm PP-NBs had higher permeability and specificity than 700 nm PP-NBs, hence producing better PSMA-specific MRI/US dual modality imaging.

The TLR3/IRF1/Type III IFN Axis Facilitates Antiviral Responses against Enterovirus Infections in the Intestine.

Enteroviruses infect gastrointestinal epithelium cells, cause multiple human diseases, and present public health risks worldwide. However, the mechanisms underlying host immune responses in intestinal mucosa against the early enterovirus infections remain elusive. Here, we showed that human enteroviruses including enterovirus 71 (EV71), coxsackievirus B3 (CVB3), and poliovirus 1 (PV1) predominantly induce type III interferons (IFN-λ1 and IFN-λ2/3), rather than type I interferons (IFN-α and IFN-ß), in cultured human normal and cancerous intestine epithelial cells (IECs), mouse intestine tissues, and human clinical intestine specimens. Mechanistic studies demonstrated that IFN-λ production is induced upon enterovirus infection through the Toll-like receptor 3/interferon regulatory factor 1 (TLR3/IRF1) signaling pathway in IECs. In turn, the supplementation of IFN-λ subsequently induces intrinsically antiviral responses against enterovirus replication. Notably, intraperitoneal injection in neonatal C57BL/6J mice with mouse recombinant IFN-λ2 protein represses EV71 replication and protects mice from viral lethal effects. Altogether, these results revealed a distinct mechanism by which the host elicited immune responses against enterovirus infections in intestine through activating the TLR3/IRF1/type III IFN axis. The new findings would provide an antiviral strategy for the prevention and treatment of enterovirus infections and associated diseases.IMPORTANCE Enterovirus infections are significant sources of human diseases and public health risks worldwide, but little is known about the mechanism of innate immune response in host intestine epithelial surface during the viral replication. We reported the epithelial immune response in cultured human normal and cancerous cells (IECs), mouse tissues, and human clinical intestine specimens following infection with enterovirus 71. The results mechanistically revealed type III interferons (IFN-λ1 and IFN-λ2/3), rather than type I interferons (IFN-α and IFN-ß), as the dominant production through TLR3/IRF1 signaling upon multiple human enterovirus infection, including enterovirus 71 (EV71), coxsackievirus B3 (CVB3), and poliovirus 1 (PV1). IFN-λ subsequently induced antiviral activity against enterovirus replication in vitro and in vivo. These studies uncovered the role of the novel process of type III IFN production involved in the TLR3/IRF1 pathway in host intestine upon enterovirus infection, which highlighted a regulatory manner of antiviral defense in intestine during enterovirus infection.

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.

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.

MYSM1 Represses Innate Immunity and Autoimmunity through Suppressing the cGAS-STING Pathway.

The immune system is not only required for preventing threats exerted by pathogens but also essential for developing immune tolerance to avoid tissue damage. This study identifies a distinct mechanism by which MYSM1 suppresses innate immunity and autoimmunity. The expression of MYSM1 is induced upon DNA virus infection and by intracellular DNA stimulation. MYSM1 subsequently interacts with STING and cleaves STING K63-linked ubiquitination to suppress cGAS-STING signaling. Notably, Mysm1-deficient mice exhibit a hyper-inflammatory response, acute tissue damage, and high mortality upon virus infection. Moreover, in the PBMCs of patients with systemic lupus erythematosus (SLE), MYSM1 production decreases, while type I interferons and pro-inflammatory cytokine expressions increase. Importantly, MYSM1 treatment represses the production of IFNs and pro-inflammatory cytokines in the PBMCs of SLE patients. Thus, MYSM1 is a critical repressor of innate immunity and autoimmunity and is thus a potential therapeutic agent for infectious, inflammatory, and autoimmune diseases.

A measurement method of knee joint space width by ultrasound: a large multicenter study.

BACKGROUND: Although plain radiology is the primary method for assessing joint space width (JSW), it has poor sensitivity to change over time in regards to determining longitudinal progression. We, therefore, developed a new ultrasound (US) measurement method of knee JSW and aimed to provide a monitoring method for the change of JSW in the future. METHODS: A multicenter study was promoted by the Professional Committee of Musculoskeletal Ultrasound, the Ultrasound Society, and the Chinese Medical Doctor Association. US study of knee specimens determined the landmarks for ultrasonic measurement of knee JSW. The US of 1,272 participants from 27 centers was performed to discuss the feasibility and possible influencing factors of knee JSW. The landmarks for US measurement of knee JS, the inflection point of medial femoral epicondyle and the proximal end of the tibia, were determined. RESULTS: The mean knee JSW1 (medial knee JSW) was 8.57±1.95 mm in females and 9.52±2.31 mm in males. The mean knee JSW2 (the near medial knee JSW) was 9.07±2.24 mm in females and 10.17±2.35 mm in males. The JSW values of males were significantly higher than those of females, with a statistical difference. JSW values were negatively correlated with age and body mass index (BMI) to different degrees and positively correlated with height. CONCLUSIONS: The novel US measurement method can be used to measure knee JSW.

Enterovirus 71 induces neural cell apoptosis and autophagy through promoting ACOX1 downregulation and ROS generation.

Enterovirus 71 (EV71) infection causes hand, foot, and mouth disease (HFMD), and even fatal neurological complications. However, the mechanisms underlying EV71 neurological pathogeneses are largely unknown. This study reveals a distinct mechanism by which EV71 induces apoptosis and autophagy in neural cells. EV71 non-structure protein 3D (also known as RNA-dependent RNA polymerase, RdRp) interacts with the peroxisomal protein acyl-CoA oxidase 1 (ACOX1), and contributes to ACOX1 downregulation. Further studies demonstrate that EV71 reduces peroxisome numbers. Additionally, knockdown of ACOX1 or peroxin 19 (PEX19) induces apoptosis and autophagy in neural cells including human neuroblastoma (SK-N-SH) cells and human astrocytoma (U251) cells, and EV71 infection induces neural cell death through attenuating ACOX1 production. Moreover, EV71 infection and ACOX1 knockdown facilitate reactive oxygen species (ROS) production and attenuate the cytoprotective protein deglycase (DJ-1)/Nuclear factor erythroid 2-related factor 2 (NRF2)/Heme oxygenase 1 (HO-1) pathway (DJ-1/NRF2/HO-1), which collectively result in ROS accumulation in neural cells. In conclusion, EV71 downregulates ACOX1 protein expression, reduces peroxisome numbers, enhances ROS generation, and attenuates the DJ-1/NRF2/HO-1 pathway, thereby inducing apoptosis and autophagy in neural cells. These findings provide new insights into the mechanism underlying EV71-induced neural pathogenesis, and suggest potential treatments for EV71-associated diseases.