An exosomal strategy for targeting cancer-associated fibroblasts mediated tumors desmoplastic microenvironments.

Tumors desmoplastic microenvironments are characterized by abundant stromal cells and extracellular matrix (ECM) deposition. Cancer-associated fibroblasts (CAFs), as the most abundant of all stromal cells, play significant role in mediating microenvironments, which not only remodel ECM to establish unique pathological barriers to hinder drug delivery in desmoplastic tumors, but also talk with immune cells and cancer cells to promote immunosuppression and cancer stem cells-mediated drug resistance. Thus, CAFs mediated desmoplastic microenvironments will be emerging as promising strategy to treat desmoplastic tumors. However, due to the complexity of microenvironments and the heterogeneity of CAFs in such tumors, an effective deliver system should be fully considered when designing the strategy of targeting CAFs mediated microenvironments. Engineered exosomes own powerful intercellular communication, cargoes delivery, penetration and targeted property of desired sites, which endow them with powerful theranostic potential in desmoplastic tumors. Here, we illustrate the significance of CAFs in tumors desmoplastic microenvironments and the theranostic potential of engineered exosomes targeting CAFs mediated desmoplastic microenvironments in next generation personalized nano-drugs development.

MTX-PEG-modified CG/DMMA polymeric micelles for targeted delivery of doxorubicin to induce synergistic autophagic death against triple-negative breast cancer.

The chemotherapy of triple-negative breast cancer based on doxorubicin (DOX) regimens suffers from great challenges on toxicity and autophagy raised off-target. In this study, a conjugate methotrexate-polyethylene glycol (shorten as MTX-PEG)-modified CG/DMMA polymeric micelles were prepared to endue DOX tumor selectivity and synergistic autophagic flux interference to reduce systematic toxicity and to improve anti-tumor capacity. The micelles could effectively promote the accumulation of autophagosomes in tumor cells and interfere with the degradation process of autophagic flux, collectively inducing autophagic death of tumor cells. In vivo and in vitro experiments showed that the micelles could exert improved anti-tumor effect and specificity, as well as reduced accumulation and damage of chemotherapeutic drugs in normal organs. The potential mechanism of synergistic autophagic death exerted by the synthesized micelles in MDA-MB-231 cells has been performed by autophagic flux-related pathway.

Clinical study of multifactorial diagnosis in prostate biopsy.

PURPOSE: To study the feasibility of using an artificial intelligence (AI) algorithm for the diagnosis of clinically significant prostate cancer (csPCa) on multiparametric MRI (mpMRI) in combination with conventional clinical information. METHODS: A retrospective study cohort with 505 patients was collected, with complete information on age (≤60, 60-80, and >80 years), PSA (≤4, 4-10, and >10 ng/dL), and pathology results. The patients with ISUP group >2 were classified as csPCa, and the patients with ISUP = 1 or no evidence of prostate cancer were classified as non-csPCa. The diagnosis of mpMRI was made by experienced radiologists following the prostate imaging reporting and data system (PIRADS ≤ 2, PIRADS = 3, and PIRADS > 3). The mpMRI images were processed by a homemade AI algorithm, and the AI results were obtained as positive or negative for csPCa. Two logistic regression models were fitted, with pathological findings as the dependent variable, that is, a conventional model and an AI model. The conventional model used age, PSA, and PIRADS as the independent variables. The AI model took the AI result and the abovementioned clinical information as the independent variables. The predicted probability of the patients from the conventional model and the AI model were used to test the prediction efficacy of the models. The DeLong test was performed to compare differences in the area under the receiver operating characteristic (ROC) area under the curve (AUC) between the conventional model and the AI model. RESULTS: In total, 505 patients were included in the study; 280 were diagnosed with csPCa, and 225 were non-csPCa. The median age was 72.0 (67.0, 76.0) years, with a median PSA value of 13.0 (7.46, 27.5) ng/dL. Statically significant differences were found in age, PSA, PIRADS score and AI results between the csPCa and non-csPCa groups (all p < 0.001). In the multivariable regression models, all the variables were independently associated with csPCa. The conventional model (R2 = 0.361) and the AI model (R2 = 0.474) were compared with analysis of variance (ANOVA) and showed statistically significant differences (χ2 = 63.695, p < 0.001). The AUC of the ROC curve for the conventional model was 0.782 (95% confidence interval [CI]: 0.742-0.823), which was less than the AUC of the AI model with statistical significance (0.849 [95% CI: 0.815-0.883], p < 0.001). CONCLUSION: In combination with routine clinical information, such as age, PSA, and PIRADS category, adding information from the AI algorithm based on mpMRI could improve the diagnosis of csPCa.

Seroepidemiology study of rubella virus antibodies among neonates and pregnant women at hospitals in Henan province, China.

Rubella virus infection can cause vertical transmission to the fetus during pregnancy. In China's Henan province, rubella surveillance needs to be well-established. In this research, a total of 1933 neonates and 2502 pregnant women were enrolled, and their sera for IgG and IgM antibodies against rubella were tested by chemiluminescence assay. Of 1933 neonates' sera tested, the seropositive of rubella IgG was 68.7%. The seroprevalence of rubella IgM in neonates was 0.4%. 30.9% of neonates had negative results for IgG and IgM antibodies. Two thousand five hundred and two pregnant women participated in the serosurvey, and 79.3% were rubella IgG positive. Rubella IgG seropositivity in pregnant women differed by age and number of births. 0.8% of the pregnant women had positive results for IgM against the rubella virus. The seronegative of rubella IgG and IgM antibodies in pregnant women was 19.8%. Due to the negative rubella-specific IgG antibody, many neonates remain at risk of rubella virus infection. Rubella virus continues to spread since some neonates and pregnant women with rubella-specific IgM antibody positive have been detected. Rubella vaccination may be introduced for childbearing-age women to increase immunity levels against rubella with periodic sero-surveillance.

Withdrawal of MTX in rheumatoid arthritis patients on bDMARD/tsDMARD plus methotrexate at target: a systematic review and meta-analysis.

OBJECTIVES: To evaluate the effect of MTX withdrawal on disease activity and remission rate in patients at target after treatment with biologic DMARDs (bDMARDs)/targeted synthetic DMARDs (tsDMARDs) plus MTX. MATERIAL AND METHODS: We searched the PubMed, EMBASE and Cochrane Central Register of Controlled Trials (CENTRAL) databases for all randomized controlled trials (RCTs) on MTX withdrawal in patients with RA at target after combination therapy from inception to 7 March 2022 in order to extract data, including: the change from withdrawal in DAS28 at the endpoint; proportion of low disease activity (LDA) assessed by DAS28, Simplified Disease Activity Index (SDAI) or Clinical Disease Activity Index (CDAI); proportion of remission assessed by DAS28, SDAI CDAI or ACR/EULAR Boolean remission. The Cochrane Q test and I2 test were used to assess heterogeneity, and random-effects models were used for data synthesis. This study is registered with PROSPERO (CRD42022303891). RESULTS: Six articles were included for qualitative and quantitative analysis, all of which were noninferior RCTs involving 1430 patients (734 in the withdrawal group and 696 in the continuation group). Compared with continuing combination therapy, tapering off or discontinuing MTX increased DAS28 by 0.20 (95% CI 0.09, 0.32, I2 = 0%) and decreased the percentage of patients with LDA assessed by DAS28 to <3.2 [risk ratio (RR) 0.88 (0.80, 0.97), I2 = 0%]. However, MTX withdrawal did not decrease remission rates assessed by DAS28, SDAI, CDAI or ACR/EULAR Boolean remission [RR 0.90 (0.81, 1.01), 0.93 (0.77, 1.11), 0.90 (0.74, 1.11), 0.95 (0.70, 1.29), respectively]. CONCLUSIONS: Withdrawing MTX slightly increases the RA disease activity in patients treated at target with bDMARDs/tsDMARDs plus MTX and has limited effects for patients with deep remission.

[Cangxi Tongbi Capsules promote chondrocyte autophagy by regulating circRNA＿0008365/miR-1271/p38 MAPK pathway to inhibit development of knee osteoarthritis].

To investigate the mechanism by which Cangxi Tongbi Capsules promote chondrocyte autophagy to inhibit knee osteoarthritis(KOA) progression by regulating the circRNA＿0008365/miR-1271/p38 mitogen-activated protein kinase(MAPK) pathway. The cell and animal models of KOA were established and intervened with Cangxi Tongbi Capsules, si-circRNA＿0008365, si-NC, and Cangxi Tongbi Capsules combined with si-circRNA＿0008365. Flow cytometry and transmission electron microscopy were employed to determine the level of apoptosis and observe autophagosomes, respectively. Western blot was employed to reveal the changes in the protein levels of microtubule-associated protein light chain 3(LC3)Ⅱ/Ⅰ, Beclin-1, selective autophagy junction protein p62/sequestosome 1, collagen Ⅱ, a disintegrin and metalloproteinase with thrombospondin motifs 5(ADAMTS-5), and p38 MAPK. The mRNA levels of circRNA＿0008365, miR-1271, collagen Ⅱ, and ADAMTS-5 were determined by qRT-PCR. Hematoxylin-eosin staining was employed to reveal the pathological changes of the cartilage tissue of the knee, and enzyme-linked immunosorbent assay to measure the levels of interleukin-1ß(IL-1ß) and tumor necrosis factor-alpha(TNF-α). The chondrocytes treated with IL-1ß showed down-regulated expression of circRNA＿0008365, up-regulated expression of miR-1271 and p38 MAPK, lowered autophagy level, increased apoptosis rate, and accelerated catabolism of extracellular matrix. The intervention with Cangxi Tongbi Capsules up-regulated the expression of circRNA＿0008365, down-regulated the expression of miR-1271 and p38 MAPK, increased the autophagy level, decreased the apoptosis rate, and weakened the catabolism of extracellular matrix. However, the effect of Cangxi Tongbi Capsules was suppressed after interfering with circRNA＿0008365. The in vivo experiments showed that Cangxi Tongbi Capsules dose-dependently inhibited the p38 MAPK pathway, enhanced chondrocyte autophagy, and mitigated articular cartilage damage and inflammatory response, thereby inhibiting the progression of KOA in rats. This study indicated that Cangxi Tongbi Capsules promoted chondrocyte autophagy by regulating the circRNA＿0008365/miR-1271/p38 MAPK pathway to inhibit the development of KOA.

Automatic segmentation of hepatic metastases on DWI images based on a deep learning method: assessment of tumor treatment response according to the RECIST 1.1 criteria.

BACKGROUND: Evaluation of treated tumors according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria is an important but time-consuming task in medical imaging. Deep learning methods are expected to automate the evaluation process and improve the efficiency of imaging interpretation. OBJECTIVE: To develop an automated algorithm for segmentation of liver metastases based on a deep learning method and assess its efficacy for treatment response assessment according to the RECIST 1.1 criteria. METHODS: One hundred and sixteen treated patients with clinically confirmed liver metastases were enrolled. All patients had baseline and post-treatment MR images. They were divided into an initial (n = 86) and validation cohort (n = 30) according to the examined time. The metastatic foci on DWI images were annotated by two researchers in consensus. Then the treatment responses were assessed by the two researchers according to RECIST 1.1 criteria. A 3D U-Net algorithm was trained for automated liver metastases segmentation using the initial cohort. Based on the segmentation of liver metastases, the treatment response was assessed automatically with a rule-based program according to the RECIST 1.1 criteria. The segmentation performance was evaluated using the Dice similarity coefficient (DSC), volumetric similarity (VS), and Hausdorff distance (HD). The area under the curve (AUC) and Kappa statistics were used to assess the accuracy and consistency of the treatment response assessment by the deep learning model and compared with two radiologists [attending radiologist (R1) and fellow radiologist (R2)] in the validation cohort. RESULTS: In the validation cohort, the mean DSC, VS, and HD were 0.85 ± 0.08, 0.89 ± 0.09, and 25.53 ± 12.11 mm for the liver metastases segmentation. The accuracies of R1, R2 and automated segmentation-based assessment were 0.77, 0.65, and 0.74, respectively, and the AUC values were 0.81, 0.73, and 0.83, respectively. The consistency of treatment response assessment based on automated segmentation and manual annotation was moderate [K value: 0.60 (0.34-0.84)]. CONCLUSION: The deep learning-based liver metastases segmentation was capable of evaluating treatment response according to RECIST 1.1 criteria, with comparable results to the junior radiologist and superior to that of the fellow radiologist.

Prevalence and distribution of human papillomavirus genotypes among women attending gynecology clinics in northern Henan Province of China.

BACKGROUND: Human papillomavirus (HPV) infection can cause cervical and other cancers, including vulva, vagina, penis, anus, or oropharynx. However, in China's northern Henan Province, data on the prevalence and genotype distribution of HPV among women attending gynecology clinics is limited. This study aimed to investigate the current prevalence and genotype distribution of HPV among women attending gynecology clinics in northern Henan Province. METHODS: This study included 15,616 women aged 16-81 years old who visited the Xinxiang central hospital's gynecology department between January 2018 and December 2019. HPV DNA was detected by a conventional PCR method followed by HPV type-specific hybridization, which was designed to detect 17 high-risk HPV (HR-HPV) genotypes and 20 low-risk HPV (LR-HPV) genotypes. HPV prevalence and corresponding 95% confidence intervals (95% CI) were calculated using SPSS 18.0. RESULTS: The overall HPV prevalence was 19.7% among women in northern Henan Province. Single, double, and multiple HPV infections accounted for 13.7%, 4.3%, and 1.8% of the total cases. Most infections were caused by HR-HPV (71.8%), and single genotype HPV infection (13.7%) was the most common pattern. The most common HR-HPV genotype was HPV16 (4.3%), followed by HPV52 (3.5%) and HPV58 (2.0%). The most common LR-HPV genotype was HPV6 (1.4%), followed by HPV61 (1.1%) and HPV81 (1.1%). CONCLUSIONS: HPV infection is high among women attending gynecology clinics in northern Henan Province. The highest prevalence was found in women less than 20 years old. In northern Henan Province, the 9-valent HPV vaccine is strongly recommended for regular immunization.

Utility of diffusion weighted imaging-based radiomics nomogram to predict pelvic lymph nodes metastasis in prostate cancer.

BACKGROUND: Preoperative pelvic lymph node metastasis (PLNM) prediction can help clinicians determine whether to perform pelvic lymph node dissection (PLND). The purpose of this research is to explore the feasibility of diffusion-weighted imaging (DWI)-based radiomics for preoperative PLNM prediction in PCa patients at the nodal level. METHODS: The preoperative MR images of 1116 pathologically confirmed lymph nodes (LNs) from 84 PCa patients were enrolled. The subjects were divided into a primary cohort (67 patients with 192 positive and 716 negative LNs) and a held-out cohort (17 patients with 43 positive and 165 negative LNs) at a 4:1 ratio. Two preoperative pelvic lymph node metastasis (PLNM) prediction models were constructed based on automatic LN segmentation with quantitative radiological LN features alone (Model 1) and combining radiological and radiomics features (Model 2) via multiple logistic regression. The visual assessments of junior (Model 3) and senior (Model 4) radiologists were compared. RESULTS: No significant difference was found between the area under the curve (AUCs) of Models 1 and 2 (0.89 vs. 0.90; P = 0.573) in the held-out cohort. Model 2 showed the highest AUC (0.83, 95% CI 0.76, 0.89) for PLNM prediction in the LN subgroup with a short diameter ≤ 10 mm compared with Model 1 (0.78, 95% CI 0.70, 0.84), Model 3 (0.66, 95% CI 0.52, 0.77), and Model 4 (0.74, 95% CI 0.66, 0.88). The nomograms of Models 1 and 2 yielded C-index values of 0.804 and 0.910, respectively, in the held-out cohort. The C-index of the nomogram analysis (0.91) and decision curve analysis (DCA) curves confirmed the clinical usefulness and benefit of Model 2. CONCLUSIONS: A DWI-based radiomics nomogram incorporating the LN radiomics signature with quantitative radiological features is promising for PLNM prediction in PCa patients, particularly for normal-sized LNM.

Osthole Suppresses Knee Osteoarthritis Development by Enhancing Autophagy Activated via the AMPK/ULK1 Pathway.

Knee osteoarthritis (KOA) is an increasingly prevalent heterogeneous disease characterized by cartilage erosion and inflammation. As the main chemical constituent of Angelicae Pubescentis Radix (APR), an anti-inflammatory herbal medicine, the potential biological effects and underlying mechanism of osthole on chondrocytes and KOA progression remain elusive. In this study, the potential effect and mechanism of osthole on KOA were investigated in vitro and in vivo. We found that osthole inhibited IL-1ß-induced apoptosis and cartilage matrix degeneration by activating autophagy in rat chondrocytes. In addition, osthole could activate autophagy through phosphorylation of AMPK/ULK1, and AMPK serves as a positive upstream regulator of ULK1. Furthermore, KOA rats treated with osthole showed phosphorylation of the AMPK/ULK1 pathway and autophagy activation, as well as cartilage protection. Collectively, the AMPK/ULK1 signaling pathway can be activated by osthole to enhance autophagy, thereby suppressing KOA development. Osthole may be a novel and effective therapeutic agent for the clinical treatment of KOA.

Prediction of pelvic lymph node metastasis in prostate cancer using radiomics based on T2-weighted imaging. / 基于T2åŠ æƒæˆåƒçš„å½±åƒç»„å­¦åˆ—çº¿å›¾æ¨¡åž‹é¢„æµ‹å‰åˆ—è ºç™Œç›†è ”æ·‹å·´ç»“è½¬ç§».

OBJECTIVES: Pelvic lymph node metastasis (PLNM) is an important factor that affects the stage and prognosis of prostate cancer. Invasive extended pelvic lymph node dissection (ePLND) is the most effective method for clinically diagnosing PLNM. Accurate preoperative prediction of PLNM can reduce unnecessary ePLND. This study aims to investigate the clinical value of radiomics nomogram in predicting PLNM of prostate cancer based on T2-weighted imaging (T2WI). METHODS: Magnetic resonance (MR) data of 71 patients with prostate cancer who underwent ePLND from January 2017 to June 2021 in Peking University First Hospital were collected retrospectively. All patients were assigned into a training set (January 2017 to December 2020, n=56, containing 186 lymph nodes) and a test set (January 2021 to June 2021, n=15, containing 45 lymph nodes) according to the examination time of multiparametric magnetic resonance imaging (mpMRI). Two radiologists matched the dissected lymph nodes on MRI images, and manually annotated the region of interest (ROI). Based on the outlined ROI, 3 metastatic lymph node prediction models were established: Model 1 (only image features of T2WI), Model 2 (radiomics features based on random forest), and Model 3 (combination of the image and radiomics features). A nomogram was also established. The clinicopathologic characteristics of the patients were obtained from the medical records, including age, the Gleason score, the level of prostate-specific antigen (PSA), and clinical and pathological T stage. The preoperative radiological features of the pelvic lymph nodes (LNs) include size of LNs (the short and long diameters) and volume of LNs. Receiver operating characteristic (ROC) curve was used to evaluate the diagnostic efficacy of the 3 models and decision curve analysis (DCA) was used to evaluate the clinical benefits of the models. RESULTS: No significant differences were found between the training set and test set regarding age, Gleason scores, PSA level, and clinical and pathological T stage (all P>0.05). The differences in volume, short diameter and long diameter between metastatic and non-metastatic LNs were statistically significant in both training set and test set (all P<0.05). In multivariate regression analysis, the short diameter and marginal status of LNs were included in Model 1. Eighteen omics features were selected to construct Model 2. The signal distribution of LNs and Rad score were the significant risk factors for predicting metastasis of pelvic LNs in Model 3. The C-index of nomogram based on Model 3 reached 0.964, and the calibration curve showed that the model had high calibration degree. In the test set, the area under the curves of Model 1, 2, and 3 were 0.78, 0.93, and 0.96 respectively, Model 2 and Model 3 showed significantly higher diagnostic efficiency than Model 1 (Model 1 vs Model 2, P=0.019; Model 1 vs Model 3, P=0.020). There was no significant difference in the area under the curve between Model 2 and Model 3 (P=0.649). The DCA results of the 3 models showed that all models obtained higher net benefits than the PLNM-all or PLNM-none protocol in different ranges of threshold probabilities and Model 3 had the highest clinical benefit. CONCLUSIONS: The radiomics nomogram based on T2WI shows a good predictive efficacy for preoperative PLNM in patients with prostate cancer, which could be served as an imaging biomarker to optimize decision-making and adjust adjuvant treatments.

Cox15 is a novel oncogene that required for lung cancer cell proliferation.

Lung cancer is one of the most malignant and prevalent tumors and accounts for the vast majority of cancer death worldwide. However, the molecular mechanisms underlying lung cancer progression are poorly understood. Here, we reveal that both transcription and protein expression levels of Cox15 were increased in lung cancer. Nrf2 specifically binds to the Cox15 promoter and triggers Cox15 expression at the transcriptional level. Cox15 functions as a novel oncogene that facilitates lung cancer cell proliferation. Additionally, Aripiprazole, a potent inhibitor of Cox15, executives profoundly suppressive effects on lung cancers cells growth and tumor progression in vivo and in vitro through exerting therapeutic effects. Taken together, our results unravel that Cox15 holds great potential to act as a prognostic molecule for lung cancer patients' prognosis in the future.

SH3GL3 acts as a novel tumor suppressor in glioblastoma tumorigenesis by inhibiting STAT3 signaling.

Glioblastoma (GBM) is the most severe malignant tumors of the central nervous system. Glioblastoma stem cells (GSCs) are considered to account for tumor initiation, therapeutic resistance, and tumor relapse. Yet the underlying mechanisms of GSC stemness maintenance remain largely unknown. Abnormal activation of STAT3 signaling is required for GBM tumorigenesis and GSC self-renewal. In this study, we provide evidence that SH3GL3 was weakly expressed in GBM and its high expression correlated with a favorable prognosis for GBM patients. Ectopic of SH3GL3 expression considerably inhibits GBM cell malignant behaviors, including GBM cell proliferation, migration as well as GSCs self-renewal ability. Mechanistically, we first found that SH3GL3 interacts with STAT3, which thereby inhibiting STAT3 nuclear localization. Overexpression of constitutively activated (STAT3-C) restored the growth, migration and self-renewal ability impaired by overexpression of SH3GL3. Together, our work shed insight on a critical regulatory mechanism mediated by SH3GL3 to decrease the stem cell-like property and tumorigenic potential.

Development and validation of the 3D U-Net algorithm for segmentation of pelvic lymph nodes on diffusion-weighted images.

BACKGROUND: The 3D U-Net model has been proved to perform well in the automatic organ segmentation. The aim of this study is to evaluate the feasibility of the 3D U-Net algorithm for the automated detection and segmentation of lymph nodes (LNs) on pelvic diffusion-weighted imaging (DWI) images. METHODS: A total of 393 DWI images of patients suspected of having prostate cancer (PCa) between January 2019 and December 2020 were collected for model development. Seventy-seven DWI images from another group of PCa patients imaged between January 2021 and April 2021 were collected for temporal validation. Segmentation performance was assessed using the Dice score, positive predictive value (PPV), true positive rate (TPR), and volumetric similarity (VS), Hausdorff distance (HD), the Average distance (AVD), and the Mahalanobis distance (MHD) with manual annotation of pelvic LNs as the reference. The accuracy with which the suspicious metastatic LNs (short diameter > 0.8 cm) were detected was evaluated using the area under the curve (AUC) at the patient level, and the precision, recall, and F1-score were determined at the lesion level. The consistency of LN staging on an hold-out test dataset between the model and radiologist was assessed using Cohen's kappa coefficient. RESULTS: In the testing set used for model development, the Dice score, TPR, PPV, VS, HD, AVD and MHD values for the segmentation of suspicious LNs were 0.85, 0.82, 0.80, 0.86, 2.02 (mm), 2.01 (mm), and 1.54 (mm) respectively. The precision, recall, and F1-score for the detection of suspicious LNs were 0.97, 0.98 and 0.97, respectively. In the temporal validation dataset, the AUC of the model for identifying PCa patients with suspicious LNs was 0.963 (95% CI: 0.892-0.993). High consistency of LN staging (Kappa = 0.922) was achieved between the model and expert radiologist. CONCLUSION: The 3D U-Net algorithm can accurately detect and segment pelvic LNs based on DWI images.

Mast cells contribute to Enterovirus 71 infection-induced pulmonary edema in neonatal mice.

Enterovirus (EV) 71 infection has been widely acknowledged as the leading cause of severe hand, foot and mouth disease (HFMD), which may rapidly lead to fatal pulmonary edema. In this study, we established a mouse model for EV71 infection exhibiting high incidence of severe symptoms with pulmonary edema. Mast cells (MCs) accumulation, activation and allergic inflammation were found in the brains, lungs and skeletal muscle of mice after EV71 infection, especially in the lungs of mice. Levels of histamine, platelet-activating factor (PAF), interleukin (IL)-4, IL-5, IL-13, tumor necrosis factor-α (TNF-α), nitric oxide (NO), endocrine gland-derived vascular endothelial growth factor (EG-VEGF) and noradrenaline (NA) were increased in EV71-infected lungs. In addition, EV71 infection reduced the number of pulmonary T cells, dendritic cells (DCs) and monocytes, and increased the number of lung eosinophils, Tregs and MCs. MCs number and tryptase expression in target organs or tissues posed a trend towards an increase from control to severe mice. There were positive correlations between MCs number in the brains (r = 0.701, P = 0.003), lungs (r = 0.802, P < 0.0001), skeletal muscles (r = 0.737, P = 0.001) and mean clinical score. Thus, our results suggested that MCs contributed to the pulmonary edema during EV71 infection.

Breakdown of Nonrelativistic QCD Factorization in Processes Involving Two Quarkonia and its Cure.

We study inclusive processes involving two heavy quarkonia in nonrelativistic QCD (NRQCD) and demonstrate that, in the presence of two P-wave Fock states, NRQCD factorization breaks down, leaving uncanceled infrared singularities. As phenomenologically important examples, we consider the decay ϒ→χ_{cJ}+X via bb[over ¯](^{3}P_{J_{b}}^{[8]})→cc[over ¯](^{3}P_{J}^{[1]})+gg and the production process e^{+}e^{-}→J/ψ+χ_{cJ}+X via e^{+}e^{-}→cc[over ¯](^{3}P_{J_{1}}^{[8]})+cc[over ¯](^{3}P_{J}^{[1]})+g. We infer that such singularities will appear for double quarkonium hadroproduction at next-to-leading order. As a solution to this problem, we introduce to NRQCD effective field theory new types of operators whose quantum corrections absorb these singularities.

Neural interactions mediating conflict control and its training-induced plasticity.

Cognitive control is of great plasticity. Training programs targeted on improving it have been suggested to yield neural changes in the brain. However, until recently, the relationship between training-induced brain changes and improvements in cognitive control is still an open issue. Besides, although the literature has attributed the operation of cognitive control to interactions between large-scale networks, the neural pathways directly associated with it remain unclear. The current study aimed to examine these issues by focusing on conflict processing. In particular, we employed a training program with a randomized controlled design. The main findings were as follows: 1) In behavior, the training group showed reduced conflict effect after training, relative to the control group; 2) In the pretest stage, the behavioral conflict effect was negatively correlated with a number of neural pathways, including the connectivity from the cingulo-opercular network (CON) to the cerebellum and to sub-regions of the dorsal visual network; 3) increase in the connectivity strength of several network interactions, such as the connectivity from the CON to the cerebellum and to the primary visual network, was associated with behavioral gains; 4) there were also nonlinear correlations between behavioral and neural changes. These findings highlighted a critical role of the modulation of CON on other networks in mediating conflict processing and its plasticity, and raised the significance of investigating nonlinear relationship in the field of cognitive training.

Region-specific expression of precursor and mature brain-derived neurotrophic factors after chronic alcohol exposure.

BACKGROUND: Alcohol abuse is a serious health problem worldwide that causes a variety of physical and mental disorders. Research has shown that the brain-derived neurotrophic factor (BDNF) plays an important role in alcohol addiction. The BDNF precursor (proBDNF) exhibits different actions than BDNF through separate receptors and pathways in the central nervous system. However, the effects of proBDNF and BDNF in alcohol addiction are not fully known. OBJECTIVES: The objective was to identify the expression patterns and effects of proBDNF and BDNF after chronic alcohol exposure. METHODS: A total of 40 male adult mice were studied. A mouse psychomotor sensitization (PS) model was established to explore the effects of BDNF and proBDNF treatment following chronic alcohol exposure. Reverse transcription PCR (RT-PCR) was performed to measure mRNA levels for BDNF, TrkB, P75NTR, and sortilin in the prefrontal cortex, hippocampus, and dorsal striatum of Kunming mice after chronic alcohol exposure. RESULTS: In Kunming mice, chronic alcohol exposure up-regulated BDNF and TrkB mRNA levels in the prefrontal cortex, but decreased sortilin and P75 mRNA levels in the dorsal striatum. No changes in mRNA levels were found in other measured brain regions in the alcohol and control groups. CONCLUSION: Chronic alcohol exposure induced the region-specific expression of BDNF and proBDNF and their respective receptors in the brain. These results suggest that BDNF and proBDNF signaling pathways may play major roles in alcohol preference and addiction.

Alertness function of thalamus in conflict adaptation.

Conflict adaptation reflects the ability to improve current conflict resolution based on previously experienced conflict, which is crucial for our goal-directed behaviors. In recent years, the roles of alertness are attracting increasing attention when discussing the generation of conflict adaptation. However, due to the difficulty of manipulating alertness, very limited progress has been made in this line. Inspired by that color may affect alertness, we manipulated background color of experimental task and found that conflict adaptation significantly presented in gray and red backgrounds but did not in blue background. Furthermore, behavioral and functional magnetic resonance imaging results revealed that the modulation of color on conflict adaptation was implemented through changing alertness level. In particular, blue background eliminated conflict adaptation by damping the alertness regulating function of thalamus and the functional connectivity between thalamus and inferior frontal gyrus (IFG). In contrast, in gray and red backgrounds where alertness levels are typically high, the thalamus and the right IFG functioned normally and conflict adaptations were significant. Therefore, the alertness function of thalamus is determinant to conflict adaptation, and thalamus and right IFG are crucial nodes of the neural circuit subserving this ability. Present findings provide new insights into the neural mechanisms of conflict adaptation.

Intracellularly expressed nanobodies against non-structural protein 4 of porcine reproductive and respiratory syndrome virus inhibit virus replication.

OBJECTIVE: To isolate specific nanobodies to porcine reproductive and respiratory syndrome virus (PRRSV) non-structural protein 4 (Nsp4) and investigate their potential antiviral activities. RESULTS: Three PRRSV Nsp4-specific nanobodies were isolated from a phage display library of the variable domains of camelid heavy chain-only antibodies. Nanobody genes were introduced into MARC-145 cells using lentivirus vectors to establish cell lines stably expressing nanobodies. These intracellularly expressed nanobodies were tested for interaction with PRRSV-encoded Nsp4 within PRRSV-infected MARC-145 cells. Nb41 and Nb43 intrabodies each potently inhibited PRRSV replication, protected MARC-145 cells from PRRSV-induced cytopathic effect and fully blocked PRRSV replication at an MOI of 0.001 or lower. CONCLUSION: Intracellularly expressed Nb41 and Nb43 potently suppressed PRRSV replication in MARC-145 cells. Nanobodies hold great potential for development as novel antiviral treatments for PRRSV infection.