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Chemotherapy remains the most common treatment for all types of breast cancer. Chemoresistance in tumors is still a major obstacle for treating late-stage breast cancer. In the process of acquiring resistance, tumor cells dynamically evolve to adapt to the challenge of anti-cancer drugs. Besides the upregulation of drug-pumps, signal pathways related to proliferation and survival undergo adaptive evolution. Thus, these drug-resistant cells are more conducive to proliferation, even in stressful conditions. Nevertheless, the detailed mechanism that drives cancer cells to sustain their proliferation ability is unclear. Herein, we reported that the upregulated C-MET signaling acts as a compensatory mechanism that sustains the proliferation of chemoresistant cells in which EGFR family signaling was attenuated. Both C-MET and EGFR family are essential for cell proliferation due to their activation of the STAT3 signaling. Different from other cell models in which C-MET interacts with and phosphorylates EGFR family members, our cell model showed no direct interaction between C-MET and EGFR family members. Therefore, C-MET and EGFR family signaling pathways function independently to sustain the proliferation of resistant cells. Moreover, chemoresistant cells have evolved a novel, STAT3-C-MET feed-forward loop that plays a vital role in sustaining cell proliferation. The activated STAT3 interacts with the MET gene promoter to upregulate its transcription. Most importantly, the combined inhibition of C-MET and EGFR family synergistically inhibits the proliferation of drug-resistant cells in vitro and in xenograft tumor models. This work provides a new strategy for treating drug-resistant breast cancer.

The coronavirus disease 2019 has infected over 150 million people worldwide and led to over 3 million deaths. Severe acute respiratory syndrome (SARS)-CoV-2 lineages B.1.1.7, B.1.617, B.1.351, and P.1 were reported to have higher infection rates than that of wild one. These mutations were noticed to happen in the receptor-binding domain of spike protein (S-RBD), especially mutations N501Y, E484Q, E484K, K417N, K417T, and L452R. Currently, there is still no specific medicine against the virus; moreover, cytokine storm is also a dangerous factor for severe infected patients. In this study, potential S-RBD-targeted active monomers from traditional Chinese medicine Ephedra sinica Stapf (ephedra) were discovered by virtual screening. NanoBiT assay was performed to confirm blocking activities of the screened compounds against the interaction between SARS-CoV-2 S-RBD and angiotensin-converting enzyme 2 (ACE2). We further analyzed the blocking effect of the active compounds on the interactions of mutated S-RBD and ACE2 by computational studies. Moreover, antiinflammatory activities were evaluated using qRT-PCR, enzyme-linked immune sorbent assay, and Western blot analysis. As a result, pseudoephedrine (MHJ-17) and its derivative (MHJ-11) were found as efficient inhibitors disrupting the interactions between ACE2 and both wild and mutated S-RBDs. In addition, they also have antiinflammatory activities, which can be potential drug candidates or lead compounds for further study.

Background and aims Anti-tuberculosis drugs remain as an important cause of drug-induced liver injury (DILI) worldwide. Adverse drug reactions reduce the effectiveness of treatment. We aimed to determine the incidence and risk factors associated with anti-tuberculosis DILI (ATDILI). Methods Using established criteria and causality assessment methods, risk factors for ATDILI were identified in a contemporary cohort and validated in another cohort prospectively. Independent determinants of ATDILI were identified using Cox regression analysis. Results In the derivation cohort (n = 3155), 170 (5.4%) developed ATDILI of which 27 (15.9%) developed jaundice; 9(5.3%) developed acute liver failure (ALF) and 3 died. Among HBsAg positive patients, 11/27 (40.7%) of ATDILI developed after 3 months of starting treatment. In addition, of 218 (6.9%) who developed raised alanine transferase (ALT) levels ≥3 times upper limit normal, 193 (88.5%) resolved and 25 (11.4%) progressed to DILI. Age (HR = 1.014, 95% CI: 1.005-1.023), baseline ALT (HR = 1.014, 95% CI: 1.003-1.024), haemoglobin (HR = 1.011, 95% CI: 1.002-1.020) and HBsAg positivity (HR = 1.516, 95% CI: 1.004-2.290) were independent risk factors for DILI. In the second cohort (n = 1497) of which 85 (5.7%) developed ATDILI. Age (HR = 1.029, 95% CI: 1.003-1.056), baseline AST (HR = 1.036, 95% CI: 1.010-1.062), previous TB treatment (HR = 3.894, 95% CI: 1.304-11.625) and active drinking (HR = 3.624, 95% CI: 1.147-11.454) were risk factors for developing jaundice. Conclusion Elevation of ALT of ≥3 × ULN during anti-TB treatment resolves in the vast majority without developing serious consequences. In two cohorts involving 4652 patients, incidence of ALF and death because of ATDILI are low. Age, baseline ALT, haemoglobin and HBsAg positivity are risk factors for the development of DILI and these inform monitoring and management of these patients.

Antivirulence therapy by cell membrane coated nanoparticles has shown promise against bacterial infections. However, current approaches remain unsatisfactory when facing Escherichia coli (E. coli) infections, since the E. coli secretes multiple bacterial toxins including endotoxins and exotoxins that are challenging to eliminate simultaneously. What is worse, the absorptive scavengers normally rely on random contact of the diffuse toxins, which is not efficient. For the current cell membrane coated platform, the single type of cell membrane cannot fully meet the detoxing requirement facing multiple toxins. To address these problems, a polymyxin B (PMB)-modified, red blood cell (RBC)-mimetic hybrid liposome (P-RL) was developed. The P-RL was fabricated succinctly through fusion of PMB-modified lipids and the RBC membranes. By the strong interaction between PMB and the E. coli membrane, P-RL could attach and anchor to the E. coli; attributed to the fused RBC membrane and modified PMB, the P-RL could then efficiently neutralize both endotoxins and exotoxins from the toxin fountainhead. In vitro and in vivo results demonstrated the P-RL had a significant anchoring effect to E. coli. Moreover, compared with the existing RBC vesicles or PMB-modified liposomes, P-RL exhibited a superior therapeutic effect against RBC hemolysis, macrophage activation, and a mixed-toxin infection in mice. Potently, P-RL could inhibit E. coli O157:H7-induced skin damage, intestinal infection, and mouse death. Overall, the P-RL could potentially improve the detoxing efficiency and markedly expand the detoxification spectrum of current antivirulence systems, which provides different insights into drug-resistant E. coli treatment.

Emerging evidence suggests that the dysregulation of autophagy-related genes (ARGs) is coupled with the carcinogenesis and progression of breast cancer (BRCA). We constructed three subtype-specific risk models using differentially expressed ARGs. In Luminal, Her-2, and Basal-like BRCA, four- (BIRC5, PARP1, ATG9B, and TP63), three- (ITPR1, CCL2, and GAPDH), and five-gene (PRKN, FOS, BAX, IFNG, and EIF4EBP1) risk models were identified, which all have a receiver operating characteristic > 0.65 in the training and testing dataset. Multivariable Cox analysis showed that those risk models can accurately and independently predict the overall survival of BRCA patients. Comprehensive analysis showed that the 12 identified ARGs were correlated with the overall survival of BRCA patients; six of the ARGs (PARP1, TP63, CCL2, GAPDH, FOS, and EIF4EBP1) were differentially expressed between BRCA and normal breast tissue at the protein level. In addition, the 12 identified ARGs were highly interconnected and displayed high frequency of copy number variation in BRCA samples. Gene set enrichment analysis suggested that the deactivation of the immune system was the important driving force for the progression of Basal-like BRCA. This study demonstrated that the 12 ARG signatures were potential multi-dimensional biomarkers for the diagnosis, prognosis, and treatment of BRCA.

Clubroot disease, caused by Plasmodiophora brassicae, is a serious soil-borne disease of Brassica crops worldwide. Pakchoi is one of the most important cruciferous vegetable crops and commonly infected by P. brassicae. To date, the physiological changes and mechanism of pakchoi in response to P. brassicae are largely unknown. In this study, seedlings of two pakchoi cultivars, cv. Xinxiaqing (a clubroot-susceptible cultivar) and Yanlong (a less susceptible cultivar than Xinxiaqing), were inoculated with P. brassicae. Results showed that infected roots were enlarged and changed into club shape galls. Fresh root weight, relative electrical conductivity, the activity of lactate dehydrogenase (LDH) and alcohol dehydrogenase (ADH) in infected roots were significantly induced. In contrast, a significant reduction of root length, root function, and the activity of succinic dehydrogenase (SDH), catalase (CAT), ascorbate peroxidase (APX), and superoxide dismutase (SOD) were observed in diseased roots. Interestingly, activities of malate dehydrogenase (MDH) and peroxidase (POD) in S1 and S2 plant roots were increased and decreased in S3 plant roots. Additionally, infected Xinxiaqing roots showed more serious disease symptoms than Yanlong, and the antioxidant enzyme activities were lowered in Xinxiaqing roots compared with those in infected Yanlong roots, indicating the importance of these enzymes in plant resistance against clubroot disease.

The purpose of the present study was to analyze the clinical and pathological characteristics, treatment, and prognosis of de novo metastatic breast cancer (DnMBC). Information regarding 1,890 patients treated for advanced breast cancer at the Tianjin Medical University Cancer Hospital between January 2008 to December 2017 was collected. Clinicopathological characteristics, treatments and outcomes of these patients were compared using the chi-square test, log-rank test, and Cox regression analysis. A total of 171 patients were diagnosed with DnMBC. The median age at diagnosis was 53 years (range, 23-77). The percentage of T4 staging was higher (37.4%), 69.6% of patients were estrogen receptor (ER) positive, 59.1% were progesterone receptor positive, 29.8% had positive human epidermal growth factor receptor 2 (HER2) status, 68.4% had Ki-67 ≥20%, 55% had oligometastasis at the initial diagnosis, ~87.7% were treated with chemotherapy initially and 24% received palliative surgery for the primary tumor. After a median follow-up time of 26 months, the median progression-free survival (PFS) and overall survival (OS) among patients with DnMBC were 11 (8.7-13.3) months and 34 (27.9-40.1) months, respectively. In the multivariable model, ER status and sites of first metastasis (oligometastasis or polymetastasis) were identified to be independent predictors of PFS (P

Epilepsy is a transient neurological disorder associated with changes in the functional connections of the brain. Abnormal electrical discharges can be observed during an epileptic seizure. However, in the absence of an epileptic seizure, the anatomical structure of the brain and the electrical waves of the brain are not observed, making it difficult to explain the cause. This paper deals with together weighted imaging (DWI) sequence data in functional magnetic resonance imaging (FMRI) of epileptic patients before seizure, using Anatomical Automatic Labeling (AAL) template extracted 116 brain regions and the introduction of time series, a matrix of 116 × 116. Pearson correlation coefficient was calculated to investigate the pathological condition of brain function in epilepsy patients, using of neural network visualization system of innovative visual display and compared with the normal epileptic brain function to connect the image, with 38 cases of epilepsy by 187 cases of normal DWI experiment data, and can confirm the existence of brain function in patients with epilepsy connections. Cerebral neural network visualization system showed partial functional connection loss between frontal lobe and temporal lobe in epileptic group compared with normal control group.

Recent evidence suggests that splicing factors (SFs) and alternative splicing (AS) play important roles in cancer progression. We constructed four SF-risk-models using 12 survival-related SFs. In Luminal-A, Luminal-B, Her-2, and Basal-Like BRCA, SF-risk-models for three genes (PAXBP1, NKAP, and NCBP2), four genes (RBM15B, PNN, ACIN1, and SRSF8), three genes (LSM3, SNRNP200, and SNU13), and three genes (SRPK3, PUF60, and PNN) were constructed. These models have a promising prognosis-predicting power. The co-expression and protein-protein interaction analysis suggest that the 12 SFs are highly functional-connected. Pathway analysis and gene set enrichment analysis suggests that the functional role of the selected 12 SFs is highly context-dependent among different BRCA subtypes. We further constructed four AS-risk-models with good prognosis predicting ability in four BRCA subtypes by integrating the four SF-risk-models and 21 survival-related AS-events. This study proposed that SFs and ASs were potential multidimensional biomarkers for the diagnosis, prognosis, and treatment of BRCA.

Vascular remodeling and neuroprotection are two major adaptable methods for treating ischemic stroke. Edaravone is a protective agent for the treatment of stroke and was used as a positive control in the present study. Sodium tanshinone IIA sulfonate (STS) has demonstrated therapeutic clinical effects in cerebral infarction in China, while its mechanisms of action in ischemic stroke have remained elusive. The angiogenesis and neuroprotective effects of STS were evaluated in a rat model induced by middle cerebral artery occlusion and 3 days of reperfusion. When used at the same dose, the magnitude of the therapeutic effect of STS was similar to that of edaravone in terms of decreased blood-brain barrier damage as indicated by reduced Evans blue leakage, improved neurological deficits, alleviated cerebral edema and inhibition of histopathological changes caused by ischemia/reperfusion. The TUNEL assay demonstrated that the ability of STS to inhibit neuronal apoptosis was equivalent to that of edaravone. Immunofluorescence detection of CD31 and α-smooth muscle actin indicated that the vascular density was significantly reduced in the vehicle group compared with that in the sham operation group, STS increased the microvessel density in the ischemic area. Furthermore, in the vehicle group the protein expression of vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR) as determined by fluorescence microscopy and immunohistochemistry was significantly reduced compared with that in the sham group. However, STS promoted their expression compared to the vehicle group respectively, and increaed the mRNA expression of VEGF, VEGFR, CD31 and angiopoietin-1 as determined by reverse transcription-quantitative PCR, but these changes were not significant or not present for edaravone apart from Ang-1. In conclusion, STS protected against ischemic brain injury by promoting angiogenesis in ischemic areas and inhibiting neuronal apoptosis. These results provide a potential treatment for stroke recovery.

Purpose Previous studies have focused on global cerebral alterations observed in cirrhosis. However, little was known about the specific abnormalities of vision-related brain regions in cirrhotic patients. In this study, we sought to explore neurological alterations of vision-related regions by measuring brain resting-state network connectivity, based on the structural investigation in cirrhotic patients without clinical sign of hepatic encephalopathy (HE). Methods Structural and functional magnetic resonance image (MRI) data were collected from 20 hepatitis B virus (HBV)-related cirrhotic patients without clinical sign of HE and from 20 healthy controls (HC). Voxel-based morphometric (VBM) analysis and brain functional network analysis were performed to detect abnormalities in cerebral structure and function. Results Cirrhotic patients showed regions with the most significant gray matter reduction primarily in vision-related brain regions, including the bilateral lingual gyri, left putamen, right fusiform gyrus, and right calcarine gyrus, and other significant gray matter reductions were distributed in bilateral hippocampus. Based on structural investigation focused on vision-related regions, brain functional network analysis revealed decreased functional connectivity between brain functional networks within vision-related regions (primary visual network (PVN), higher visual network (HVN), visuospatial network (VSN)) in the patient group compared with HC group. Conclusion These results indicate that structural and functional impairment were evident in the vision-related brain regions in cirrhotic patients without clinical sign of hepatic encephalopathy. The physiopathology and clinical relevance of these changes could not be ascertained from the present study, which provided a basis for further evolution of the disease.

Background Microcalcification is a very important diagnostic information in breast cancer. The purpose of this study was to determine the relationship of clinicopathological features and prognosis of breast cancer with microcalcification and to detect biomarkers related to the possible mechanisms of microcalcifications. Patients and methods All 529 subjects with microcalcifications were selected from patients who had been examined using breast mammography. The control group did not have detectable microcalcifications, and was matched in a ratio of 1:3. The clinicopathological factors, progression-free survival (PFS), and overall survival were evaluated by SPSS. Results There was a significant difference in tumor size between the two groups, with larger tumors in the calcification group than the control group, and the proportion of patients in the calcification group with tumors of >5 cm was 20.4% vs 17.2% in the control group (P=0.041). The proportion of patients with lymph node metastasis in the calcification group was higher than that of the control group (35% vs 27.9%, P=0.027). The recurrence rate in ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC) patients with microcalcification was higher than that in the control group (P=0.035 and 0.044). BMP-2 expression was higher in breast cancer tissues, especially in breast cancer tissues with microcalcifications. The recurrence rate in the BMP-2(+) group was higher than that in the BMP-2(-) group both in DCIS and IDC (P=0.044 and 0.049). Microcalcifications and the positive expression of BMP-2 were independent factors affecting the PFS of the breast cancer patients. Conclusion Through the analysis of this study, it was found that the prognosis of the patients with microcalcification was relatively poor. BMP-2 was highly expressed in the breast cancer with microcalcification and was associated with poor prognosis.

DL-3-n-butylphthalide (NBP) is commonly used to treat ischemic strokes due to its antioxidative and anti-inflammatory effects. The present study aimed to examine the protective effects of NBP on myocardial ischemia-reperfusion injury (MIRI) by establishing a MIRI model in H9c2 cells. Cell viability assay using Cell Counting Kit-8, lactate dehydrogenase (LDH) cytotoxicity and lipid peroxidation malondialdehyde (MDA) content were assessed to detect cell activity, degree of cell injury and oxidative stress reaction. Reverse transcription-quantitative PCR was used to quantify the expression of inflammatory factors in H9c2 cells. Western blotting and immunofluorescence staining were used to detect the protein expression of PI3K/AKT and heat shock protein 70 (HSP70). The present results indicated that NBP significantly increased cell viability during ischemia-reperfusion. Moreover, NBP inhibited the release of LDH and the production of MDA. NBP treatment also significantly decreased the expression of inflammatory factors at the mRNA level. Additionally, NBP activated the PI3K/AKT pathway and upregulated the expression of HSP70 compared with cells in the MIRI model. LY294002, a PI3K inhibitor, reversed the protective effects of NBP and suppressed the expression of HSP70. The present study demonstrated that NBP protected H9c2 cells from MIRI by regulating HSP70 expression via PI3K/AKT pathway activation.

Background: The failure of chemotherapy is accompanied by the emergence of drug resistance and tumor relapse. Tumor metastasis induced by drug resistance is a major challenge in successful cancer treatment. Nevertheless, the mechanisms underlying the pro-invasive and metastatic ability of drug resistance remain elusive. Exosome-mediated intercellular communications between cancer cells and stromal cells in tumor microenvironment are required for cancer initiation and progression. Recent reports have shown that communications between cancer cells also promote tumor aggression. However, little attention has been regarded on this aspect. In this study, we aimed to investigate the mechanisms of exosomes derived from drug-resistant cells in regulating the invasion and metastasis of sensitive breast cancer cells.Methods: Exosomes isolated from drug-resistant breast cancer cells and their parental cells were used to treat breast cancer cells, and then the migration and invasion abilities were examined. The tandem mass tag (TMT)-based quantitative proteomic method was carried out to identify key molecules that regulate cancer aggressiveness. Lentivirus-mediated shRNAs, overexpression, point mutation, truncation mutation, Western blotting, tumor xenograft mice models, and in vivo breast cancer metastatic models were used to investigate the functional role of EphA2 on the invasion and metastatic potential of breast cancer cells.Results: We demonstrated that drug-resistant cell-derived exosomes promoted the migration and invasion of sensitive breast cancer cells. Quantitative proteomic analysis showed that EphA2 was rich in exosomes from drug-resistant cells. Exosomal EphA2 conferred the invasive/metastatic phenotype transfer from drug-resistant cells to sensitive cells. In addition, we provided considerable evidence that exosomal EphA2 activated ERK1/2 signaling through the ligand Ephrin A1-dependent reverse pathway rather than the forward pathway, thereby promoting breast cancer progression. Conclusions: Our findings indicate the key functional role of exosomal EphA2 in the transmission of aggressive phenotype between cancer cells that do not rely on direct cell–cell contact. Our study also suggests that the increase of EphA2 in drug-resistant cell-derived exosomes may be an important mechanism of chemotherapy/drug resistance-induced breast cancer progression.

Clubroot is one of the most serious diseases affecting Brassicaceae plants worldwide. However, there is no effective control method for clubroot. Salicylic acid (SA) is a plant hormone that plays a critical role in plant defense. In our study, we found the disease severity of a clubroot-sensitive cultivar of pakchoi, Xinxiaqing, was reduced with 0.6mM exogenous SA after the infection of P. brassicae. To investigate the mechanism of SA-reduced disease severity against clubroot, then we analyzed the plant growth, alteration of antioxidant enzyme system, and related gene expression of Xinxiaqing. Results showed that the clubroot incidence rate and disease index were decreased after being treated with 0.6 mM exogenous SA. Furthermore, plant growth, reactive oxygen species (ROS) contents, and membrane lipid peroxidation were changed. The activities of antioxidant enzymes, including superoxide dismutase (SOD), ascorbic acid-peroxidase (APX), catalase (CAT), and glutathione reductase (GR), were increased. Additionally, the production rates of malondialdehyde (MDA), hydrogen peroxide (H2O2), and superoxide anion (O2·–) were also inhibited. The expression levels of genes, encoding SOD, APX, CAT, and GR, were increased. By summering all results, we conclude that 0.6 mM SA contributes to the reduction of disease severity to clubroot by increasing the activities of antioxidant enzymes, abilities of osmotic regulation, and ROS scavenging to reduce the clubroot-induced damage in pakchoi.

The aim of this study is to investigate the association between maternal gestational weight gain (GWG) and preterm birth according to pre-pregnancy body mass index (BMI) and maternal age. We did a cohort, hospital-based study in Quzhou, South China, from 1 Jan 2018 to 30 June 2019. We selected 4274 singleton live births in our analysis, 315 (7.4%) of which were preterm births. In the overall population, excess GWG was significantly associated with a decreased risk of preterm birth compared with adequate GWG (adjusted OR 0.81 [95% CI 0.72–0.91]), and the risk varied by increasing maternal age and pre-pregnancy BMI. Interestingly, underweight women who older than 35 years with excess GWG had significantly increased odds of preterm birth compared with adequate GWG in underweight women aged 20–29 years (2.26 [1.06–4.85]) and normal weight women older than 35 years (2.23 [1.13–4.39]). Additionally, low GWG was positively and significantly associated with preterm birth overall (1.92 [1.47–2.50]). Among normal weight women category, compared with adequate GWG women aged 20–29 years did, those older than 20 years with low GWG, had significantly higher odds of preterm birth, which increased with maternal age (1.80 [1.16–2.79] in 20–29 years, 2.19 [1.23–3.91] in 30–34 years, 3.30 [1.68–6.46] in ≫ 35 years). In conclusion, maternal GWG was significantly associated with the risk of preterm birth, but the risk varied by pre-pregnancy BMI and maternal age.

Objective: To study the efficacy of Professor Zhiqiang Guo's unique sequential herbal therapy in the treatment of premature ovarian insufficiency (POI) of the kidney deficiency and liver constraint pattern. Methods: Ninety patients with POI who consulted with Professor Guo at Dongzimen Hospital, Beijing University of Chinese Medicine from January 2012 to December 2015 were enrolled. Treatment consisted of sequential therapy using traditional Chinese medicine formulae with the actions of nourishing the liver and kidney. Course of treatment was 3 consecutive menstrual cycles for each participant except for those who became pregnant during treatment. Baseline data including age, course of disease, past medical history, lifestyle, pregnancy outcome, menstrual status (cycle length, menstrual flow duration and volume), as well as gonadal hormone levels before and after treatment were recorded and analyzed. Results: During treatment, 18 (20.0%) participants became pregnant. Symptoms including scanty menstrual flow, irritability, low libido, insomnia and excessive dreaming at night, nightsweats, hot flashes, and depression were markedly alleviated. Changes in follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels at early follicular stage were observed (P = .009 and P = .002, respectively), and FSH/LH differed significantly pre- and posttreatment (P = .044). Conclusion: Professor Guo's sequential Chinese herbal therapy with the actions of nourishing the liver and kidney to treat POI can enhance ovarian function, promote pregnancy, and improve quality of life. Keywords: Premature ovarian insufficiency, Infertility, Traditional Chinese herbal medicinals, Sequential therapy, Nourish the liver and kidney

Autism spectrum disorder (ASD) is a general neurodevelopmental disorder associated with altered brain connectivity. However, most connectivity analyses in ASD focus on static functional connectivity, largely neglecting brain activity dynamics that have been reported to provide deeper insight into the underlying mechanisms of brain functions. Therefore, we anticipate that the use of dynamic functional connectivity (DFC) with interaction of clustering measures could help characterize ASD severity and reveal more information. In this study, we applied the sliding-window and k-means clustering methods to perform DFC and clustering analyses in ASD and typically developing (TD) groups. Data from 62 ASD and 63 TD children were acquired from the open-access data set Autism Brain Imaging Data Exchange. Our findings revealed higher DFC variability between the posterior cingulate gyrus (PCC) and middle temporal pole (TPOmid) in subjects with ASD. The connection between the PCC and pars opercularis of inferior frontal gyrus (IFGoper) also presented greater variability in ASD, with the increase depending on ASD symptom severity. Furthermore, clustering analysis showed higher averaged dwell time and probability of transition for globally hyper-connected state in the ASD group, which could be related to connection variability between the PCC and IFGoper. Our results demonstrate that both the PCC and IFGoper play crucial roles in characterizing symptom severity and state configuration in ASD, and brain connectivity dynamics may serve as potential indicators of ASD in future studies. Autism Res 2020, 13: 230-243. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Dynamic functional connectivity (DFC) refers to functional connectivity that changes over a short time. This study found that DFC instability between the posterior cingulate gyrus and pars opercularis of inferior frontal gyrus is associated with abnormal brain pattern configurations and dysfunction of social cognitive processes in autism spectrum disorder (ASD). These findings could contribute to a deeper understanding of the neural mechanisms of ASD and help characterize ASD severity.

HuR (human antigen R), an mRNA-binding protein responsible for poor prognosis in nearly all kinds of malignancies, is a potential anti-tumor target for drug development. While screening HuR inhibitors with a fluorescence polarization (FP) based high-throughput screening (HTS) system, the clinically used drug eltrombopag was identified. Activity of eltrombopag on molecular level was verified with FP, electrophoretic mobility shift assay (EMSA), simulation docking and surface plasmon resonance (SPR). Further, we showed that eltrombopag inhibited in vitro cell proliferation of multiple cancer cell lines and macrophages, and the in vivo anti-tumor activity was also demonstrated in a 4T1 tumor-bearing mouse model. The in vivo data showed that eltrombopag was efficient in reducing microvessels in tumor tissues. We then confirmed the HuR-dependent anti-angiogenesis effect of eltrombopag in 4T1 cells and RAW264.7 macrophages with qRT-PCR, HuR-overexpression and HuR-silencing assays, RNA stability assays, RNA immunoprecipitation and luciferase assays. Finally, we analyzed the in vitro anti-angiogenesis effect of eltrombopag on human umbilical vein endothelial cells (HUVECs) mediated by macrophages with cell scratch assay and in vitro Matrigel angiogenesis assay. With these data, we revealed the HuR-dependent anti-angiogenesis effect of eltrombopag in breast tumor, suggesting that the existing drug eltrombopag may be used as an anti-cancer drug., Graphical abstract This study elucidated the anti-tumor effect and new mechanism of the clinical drug eltrombopag, where eltrombopag exhibited anti-tumor angiogenesis effect through targeting HuR protein in cancer cells and macrophages. With these data, we emphasize the efficiency of HuR inhibitor for tumor angiogenesis inhibition.Image 1

Salvianolate has been widely used for the treatment of cerebrovascular diseases. However, the detailed molecular mechanism of how it alleviates cerebral ischaemia-reperfusion injury is not well understood. In the present study, we investigated the neuroprotective effects of salvianolate in acute cerebral infarction using the PC12 cell oxygen-glucose deprivation (OGD) model in vitro and the rat transient middle cerebral artery occlusion (MCAO) model in vivo. The results showed that the salvianolate significantly reduced the level of reactive oxygen species and inhibited the Caspase-3 signalling pathway in vitro; at the same time, in vivo experiments showed that salvianolate obviously reduced the infarct area (12.9%) and repaired cognitive function compared with the model group (28.28%). In conclusion, our data demonstrated that the salvianolate effectively alleviated cerebral ischaemia-reperfusion injury via suppressing the Caspase-3 signalling pathway.

Clubroot, caused by Plasmodiophora Brassicae, is a serious soil-borne disease in worldwide. In recent years, progression of clubroot is rapid and serious in Shanghai, China. In this study, The inheritance of clubroot resistance (CR) were determined in pakchoi using F2 segregation population that were developed by crossing highly resistant line ‘CR38’ and susceptible line ‘CS22’. Two novel QTLs, qBrCR38-1 and qBrCR38-2, was identified by BSA-seq (Bulked Segregant Sequencing) resistant to P. brassicae physiological race 7. Two significant peak qBrCR38-1 and qBrCR38-2 were observed by three statistical methods between interval of 19.7–20.6 Mb in chromosome A07 and 20.0–20.6 Mb in chromosome A08, respectively. In addition, Polymorphic SNPs identified within target regions were converted to kompetitive allele-specific PCR (KASP) assays. In target regions of qBrCR38-1 and qBrCR38-2, there were twenty SNP sites identified, eleven KASP markers of which are significantly associated to CR (P B.rapa, and the associated SNPs can be effectively used for marker-assisted breeding.

Among selected study populations, myocardial perfusion scintigraphy (MPS) in patients with left bundle branch block (LBBB) has been reported to show a low specificity for the diagnosis of coronary disease. However, the stress electrocardiogram (ECG) is nondiagnostic in this setting. To place this method in its appropriate clinical context, we evaluated MPS in all 69 consecutive patients with LBBB studied with scintigraphy for clinical reasons during a 4-year period. Among 32 patients who underwent coronary angiography for clinical indications, per patient sensitivity, 96%; per vessel sensitivity, 84%, 50%, and 100% for left anterior descending (LAD), left circumflex (LCX), and right coronary artery (RCA) involvement, respectively; and per vessel specificity, 95% and 68% for LCX and RCA disease, respectively, were not significantly different from those previously published for the method in patients without LBBB. Although per patient specificity, 38%, and specificity, 39%, for LAD disease were low, the predictive value of a positive test remained relatively high (83%) owing to the small number of patients selected for angiography, in part based on scintigraphic findings, with normal coronary anatomy. In addition to a possible specific pathophysiologic cause related to LBBB, apparent perfusion abnormalities in the LAD distribution may relate to generic conditions that can make scintigraphic interpretation ambiguous, often in the anterior distribution, regardless of the clinical setting. Additionally, the apparent lack of scintigraphic specificity in the LAD distribution could relate in part to a selection bias toward catheterization of patients with induced scintigraphic abnormalities, especially in the LAD distribution.(ABSTRACT TRUNCATED AT 250 WORDS)