Search

The main defense response to Soybean mosaic virus (SMV) infection in soybean [Glycine max (L.) Merr.] is thought to be blockage of intercellular virus transport by callose deposition on plasmodesmata. But the specific regulatory mechanism remains largely unknown. In this study, we found that hydrogen peroxide (H2O2) signal downstream of NO was associated with the regulation of callose accumulation. Abundant H2O2 was produced on the cell membrane and cell wall in the incompatible combination of soybean cultivar Jidou 7 and SMV strain N3, whereas no obvious H2O2 was observed in the compatible combination of Jidou 7 and strain SC-8. When H2O2 production was inhibited, callose accumulation induced by SMV infection decreased to a level insufficient to restrict virus transport in the incompatible combination. The H2O2-associated transcriptome dynamics of soybean during SMV infection was investigated. Transcriptome and functional analysis using virus-induced gene silencing showed that GmSEOB and GmPAP27, two genes regulated by H2O2, functioned in resistance by positively regulating the accumulation of callose in response to SMV infection. These results lay a foundation for further research on the signal transduction and molecular regulation of callose deposition during soybean resistance to SMV infection.

Objectives The aim of this study was to investigate the genomic epidemiology of methicillin-resistant Staphylococcus aureus (MRSA) in China to identify predominant lineages and their associations with clinical data and antimicrobial resistance profiles. Methods We performed a national prevalence study of patients with S. aureus infections in 22 tertiary hospitals in China from 2015 to 2017. Clinical data from patients and the antimicrobial phenotypes were collected for each isolate. Genome sequencing was performed on a proportion of isolates and a phylogenetic analysis was undertaken. Genotypic and phenotypic β-lactam susceptibilities were compared. Results A total of 1900 patients with S. aureus infections were included, of which 40% involved MRSA. Community-associated MRSA (CA-MRSA) infections were 24% of the total isolates. Genomic data showed that more than three-quarters of the MRSA were from three dominant lineages CC239 (25%, 116/471), CC5 (21%, 96/471) and CC59 (33%, 154/471) with CC59 accounting for more than half of the CA-MRSA isolates. Penicillin susceptibility genomic features were observed in 53% (251/470) of MRSA, including almost all of the CC59 (152/154) lineage, and 96% (242/251) of these isolates demonstrated in vitro susceptibility to penicillin or amoxicillin combined with clavulanic acid. Phylogenetic analysis indicated that the CC59 lineage can be divided into six lineages with all Asian CC59 isolates likely arising from an ancestral Mainland China lineage. Conclusions This study showed a high prevalence of CA-MRSA in China, largely due to the widespread presence of CC59. As almost all isolates in this lineage possess genetic variants leading to increased β-lactam susceptibility, we suggest that to improve antibiotic stewardship combinations of penicillins and β-lactamase inhibitors should be included in the antibiotic susceptibility testing panels used to inform treatment decisions and research undertaken on this combination therapy.

Corn dried distiller’s grain with solubles (cDDGS) is a feeding ingredient for monogastric animals but with limited inclusion rate due to its imbalanced amino acids, high fiber content, and anti-nutritional compounds. Moreover, production of cDDGS is costly and energy intensive. This study investigated fungal fermentation of corn stillage mixing with other dry agro-industrial residues which could by-pass the energy-intensive drying process while improving nutritional value of the mixed substrates. Rhizopus oryzae was used to ferment WDGS blended with canola meal (CM), cottonseed meal (CSM), sugar beet pulp (SP) and soybean hull (SH) at different ratio at 28 ℃ for 12 days. Results suggested that short incubation period (4 days) was favorable for improvement of protein and key amino acids profile. Substrate mixture with C/N ratio above 3 effectively reduced ammonia generation. Significant reduction (p

Objective: The objective of this article is to report a rare case of glucocorticoid hypersensitivity syndrome, which may be associated with an underlying rubella virus infection. Case Report: A 29-year-old man showed progressive weight gain for 16 months accompanied by a moon face, enlarged dorsocervical fat pad, central obesity, and purple striae. His cortisol circadian rhythm was normal, and plasma cortisol levels at 8:00 AM fluctuated between 3.2 and 9.54 μg/dL (reference range, 4.3-22.4 μg/dL). A dexamethasone suppression test with a very low dose (0.25 mg) of dexamethasone showed a marked decrease in plasma cortisol level to 0 μg/dL. Adrenal computed tomography and pituitary magnetic resonance imaging findings were normal. The Z-score of the bone density in the lumbar spine was −4.2. The IgM antibody for the rubella virus was positive. His erythrocyte sedimentation rate was 24 mm/hour (reference range

Drug transportation is impeded by various barriers in the hypoxic solid tumor, resulting in compromised anticancer efficacy. Herein, a solid lipid monostearin (MS)-coated CaO2/MnO2 nanocarrier was designed to optimize doxorubicin (DOX) transportation comprehensively for chemotherapy enhancement. The MS shell of nanoparticles could be destroyed selectively by highly-expressed lipase within cancer cells, exposing water-sensitive cores to release DOX and produce O2. After the cancer cell death, the core-exposed nanoparticles could be further liberated and continue to react with water in the tumor extracellular matrix (ECM) and thoroughly release O2 and DOX, which exhibited cytotoxicity to neighboring cells. Small DOX molecules could readily diffuse through ECM, in which the collagen deposition was decreased by O2-mediated hypoxia-inducible factor-1 inhibition, leading to synergistically improved drug penetration. Concurrently, DOX-efflux-associated P-glycoprotein was also inhibited by O2, prolonging drug retention in cancer cells. Overall, the DOX transporting processes from nanoparticles to deep tumor cells including drug release, penetration, and retention were optimized comprehensively, which significantly boosted antitumor benefits.

OBJECTIVES Constipation and opioid-induced constipation (OIC) are common with limited treatment options. We investigated whether a noninvasive method of auricular vagal nerve stimulation (aVNS) could be used for treating OIC and explored its potential mechanisms and neural pathways in a rodent model of OIC. MATERIALS AND METHODS Sprague-Dawley were chronically implanted with one pair of auricular electrodes for aVNS. Sixteen rats were treated with loperamide for a week while another 16 rats received bilateral vagotomy, then randomly treated with aVNS or sham-aVNS for a week. In addition, eight normal rats were implanted with a polyethylene catheter in the proximal colon for assessing whole colon transit. RESULTS 1) The number of fecal pellets and water content in feces increased after aVNS, compared with sham-aVNS. 2) aVNS accelerated colon transit and whole gut transit, compared with sham-aVNS. 3) In colon tissues, aVNS increased the protein expression of choline acetyltransferase, glial cell line-derived neurotrophic factor and the c-kit expression in myenteric interstitial cells of Cajal but decreased the protein expression of neural nitric oxide synthase (p

Venomous snakebites cause clinical manifestations that range from local to systemic and are considered a significant global health challenge. Persistent or refractory thrombocytopenia has been frequently reported in snakebite patients, especially in cases caused by viperidae snakes. Viper envenomation-induced thrombocytopenia may persist in the absence of significant consumption coagulopathy even after the antivenom treatment, yet the mechanism remains largely unknown. Our study aims to investigate the mechanism and discover novel therapeutic targets for coagulopathy-independent thrombocytopenia caused by viper envenomation. Here we found that patients bitten by Protobothrops mucrosquamatus and Trimeresurus stejnegeri, rather than Naja. atra may develop antivenom-resistant and coagulopathy-independent thrombocytopenia. Crude venoms and the derived C-type lectin-like proteins from these vipers significantly increased platelet surface expression of neuraminidase and platelet desialylation, therefore led to platelet ingestion by both macrophages and hepatocytes in vitro, and drastically decreased peripheral platelet counts in vivo. Our study is the first to demonstrate that desialylation-mediated platelet clearance is a novel mechanism of viper envenomation-induced refractory thrombocytopenia and C-type lectin-like proteins derived from the viper venoms contribute to snake venom-induced thrombocytopenia. The results of this study suggest the inhibition of platelet desialylation as a novel therapeutic strategy against viper venom-induced refractory thrombocytopenia.

Liver cancer is the fifth-most common cancer worldwide, with the third-highest rate of cancer-related mortality. Hepatocellular carcinoma (HCC) is the leading pathologic subtype, contributing 85% to 90% of cases of primary liver cancer. Most HCC patients are diagnosed at an advanced stage at which treatment is not curative. This study assessed the performance of a newly developed blood-based assay that utilizes genomic features and protein markers for the early detection of HCC. Two cancer-associated hallmarks, copy-number aberrations (CNA) and fragment size (FS), were characterized by shallow whole-genome sequencing of cell-free DNA and utilized to differentiate cancer patients from healthy subjects. As a clinically implemented biomarker of HCC, plasma α-fetoprotein (AFP) was also used with the genomic surrogates to optimize the detection of HCCs. The sensitivity of AFP ≥20.0 μg/L in detecting HCC was 57.9%. The combined genomic classifier CNA + FS via cell-free DNA shallow whole-genome sequencing identified nearly half of AFP-negative HCC patients (43.8%). By integrating CNA, FS as well as AFP (HCCseek), 75.0% sensitivity was achieved at 98.0% specificity, resulting in 92.6% accuracy, with 58.6% sensitivity in stage I HCC. The quantitative output of HCCseek was correlated with the severity of the disease (tumor size, stage, and recurrence-free survival). In summary, this study describes an efficient, noninvasive, and cost-effective method to detect HCC.

Aconitine, a highly toxic alkaloid derived from Aconitum L., affects the central nervous system and peripheral nervous system. However, the underlying mechanism of aconitine-induced neurotoxicity remains unclear. This study investigates the effects and mechanism of aconitine on mitochondrial energy metabolism in SH-SY5Y cells. Results demonstrated that aconitine exposure suppressed cell proliferation and led to an increase in reactive oxygen species (ROS) and excessive lactate dehydrogenase (LDH) release. Aconitine (400 μmol/L) induced abnormal mitochondrial energy metabolism that quantified by the significant decrease in ATP production, basal respiration, proton leak, maximal respiration, and succinate dehydrogenase (SDH) activity. Phosphorylation of AMPK was significantly reduced in aconitine-treated SH-SY5Y cells. The AMPK activator AIACR pretreatment effectively promoted ATP production to ameliorate mitochondrial energy metabolism disorder caused by aconitine. Mitochondrial biosynthesis was inhibited after treatment with 400 μmol/L aconitine, which was characterized by mitochondria number, TFAM expression, and mtDNA copy number. Moreover, aconitine prompted the down-regulation of mitochondrial fusion proteins OPA1, Mfn1 and Mfn2, and the up-regulation of mitochondrial fission proteins p-Drp1 and p-Mff. These results suggest that aconitine induces mitochondrial energy metabolism dysfunction in SH-SY5Y cells, which may involve the inhibition of AMPK signaling and abnormal mitochondrial dynamics.

Background A growing body of literature suggests that early life circumstances can influence mental health throughout the lifespan. However, how these early life circumstances cumulatively contribute to depression in old age is not completely understood. The aim of this study was to examine the associations of eight factors with depression among community-dwelling older adults. Methods Data were from the China Health and Retirement Longitudinal Study. We included 8,239 community-dwelling individuals who were ≥60 years, completed the life history questionnaire, and had assessment of depression. An early life disadvantage index was established using risk factors that were significantly associated with depression. Logistic regression was used to examine the association of each early life risk factor and the index with depression. Results Of 8239 individuals included, 2,055 (24.9%) had depression. In bivariate analysis, each of eight early life risk factors was significantly associated with depression. Except for maternal and paternal education, all risk factors persisted to be associated with depression after multivariable adjustment. In the multivariable-adjusted model, a one-point higher in the early life disadvantage index (range: 0-6) was associated with a 45% (95% CI: 37%, 53%) higher odds of depression. Limitations Depressive symptoms were measured in our study only by the CES-D scale. Some early life experiences might not be fully reliable due to recall bias. Conclusion There was a strong association between early life environments and depressive symptoms among Chinese community-dwelling older adults. Adverse early life circumstances could contribute cumulatively to depression in old age.

A facile and environmentally-friendly strategy for increasing antioxidant activity is a crucial issue for value-added lignin and lignin-carbohydrate complex (LCC) as alternative antioxidants. However, the antioxidant activities of lignin and LCC by the traditional solid-liquid extraction (SLE) methods were restricted by the relatively lower solubility induced from high molecular weight (Mw), and the less functional groups including, phenolic hydroxyl and carboxyl. To improve the antioxidantion of lignin and LCC, lithium chloride/dimethyl sulfoxide (LiCl/DMSO) solvent fractionation (LDSF) was conducted to increase the functional groups and reduce Mw, in which LiCl/DMSO acted triple roles as solvent, acid, and metal chloride catalyst for the depolymerization reaction synchronously. The β-O-4′ linkages were cleaved to release the phenolic hydroxyl, resulting in decreasing Mw; the hydroxyl of the side-chain of lignin was oxidized into carboxyl. Thus, the lignin (LD-RL) and LCC (LD-LCC) samples from LDSF had a higher syringyl (S)/guaiacyl (G) ratio, phenolic hydroxyl, and carboxyl contents, but less Mw than control groups from SLE. Consequently, they presented more excellent scavenging rates toward DPPH and ABTS radicals, up to 90%. This work provided panoramic perspectives and basics of the green and convenient approach to isolate and modify lignin and LCC for great antioxidantion with LDSF.

Patients with obstructive sleep apnea (OSA) frequently experience apnea-related oxygen desaturation events (ODE) accompanied by striking blood pressure (BP) fluctuations during sleep. We aimed to investigate the effects of characteristics of ODE on nocturnal BP fluctuations in OSA patients.A total of 6199 ODE were obtained from 30 patients with who underwent overnight portable monitoring and beat-to-beat BP monitoring simultaneously. The associations between nocturnal BP parameters and the characteristics of ODE were studied. The mean value of systolic BP (SBP) monitored during ODE was higher than the non-hypoxia SBP value (122.0 ± 15.9 vs. 120.4 ± 15.1 mmHg, P = 0.001) and nighttime SBP value (122.0 ± 15.9 vs. 120.8 ± 15.0 mmHg, P = 0.002). SBP variability (SBPV) during ODE was higher than the values not during ODE (14.0 ± 2.8 vs. 13.2 ± 2.6 mmHg, P = 0.043) and nighttime SBPV (14.0 ± 2.8 vs. 12.9 ± 2.3 mmHg, P 0.001). Hypoxia SBP index, defined as the percentage of SBP surge (△SBP) ≥10 mmHg to all △SBP during ODE, increased with greater respiratory event index (P = 0.01). Both the coefficient of variation for SBP values of an ODE (SBPV') and event-related SBP elevation (△SBP') increased with raised amplitude of ODE (P 0.001 for SBPV' and P 0.001 for △SBP'). Similar results were observed when the duration of events was analyzed (P 0.001 for SBPV' and P 0.001 for △SBP').BP related to ODE may be the main component of increased BP during sleep in OSA patients. In addition to the frequency of respiratory events, the amplitude and duration of ODE may have a role in nocturnal BP fluctuations in OSA patients.

Previously our laboratory first reported that dropping of freeze-dried monoclonal antibody (mAb) formulations could cause protein degradation and aggregation (J Pharm Sci, 2021, 1625). In this manuscript, we evaluated effects of secondary package on stability of several freeze-dried biopharmaceutical formulations during dropping. The degradation of mAb-Y during dropping with different secondary packages was determined by the sensitive particle analyzing techniques micro-flow imaging (MFI) and dynamic light scattering (DLS). Electron paramagnetic resonance (EPR) was used to detect free radicals after repeated dropping in different secondary packages. The amount of free radicals and SbVPs was correlated to the sample temperature as well as the secondary package during dropping. Our observations suggest that secondary packaging has significant effect on freeze-dried biopharmaceutical stability during dropping and therefore should be thoroughly screened and optimized to assure high product quality even for the presumed highly stable freeze-dried biopharmaceuticals.

In order to study the analysis of blood flow field characteristics of cerebral aneurysm patients before and after stent implantation based on CT images of ART-TV-PI, this paper firstly improved the ART-TV algorithm of algebraic reconstruction technology and obtained the ART-TV-PI algorithm, which was compared with the ART algorithm and ART-TV algorithm. Afterwards, the CT images based on the above three algorithms were used to analyze the changes of average blood flow velocity, average wall pressure, average wall deformation, and average shear force of 48 cases of cerebral aneurysm patients before and after stent implantation. The results showed that the mean square error and radiation dose of the ART-TV-PI algorithm (0.00012 and 1.65 mSv) were significantly lower than those of the ART algorithm (0.0031 and 3.09 mSv) and ART-TV algorithm (0.00082 and 2.52 mSv), and the signal-to-noise ratio (23.94) was significantly higher than those of the ART algorithm (11.32) and ART-TV algorithm (16.89), with statistically significant differences ( P < 0.05 ). The differences of mean blood flow velocity, mean wall pressure, mean wall deformation, and mean shear force before and after stent implantation among the three algorithms were not statistically significant ( P > 0.05 ), and the average index of the ART-TV-PI algorithm was the highest. Under the ART-TV-PI algorithm, the mean blood flow velocity (0.044 m/s), the mean wall pressure (71.7 Pa), the mean wall deformation (0.057 mm), and the mean shear force (889 Pa) after stent implantation were significantly lower than those before stent implantation (0.165 m/s, 160.8 Pa, 0.721 mm, and 2690 Pa), with average decreases of 73.3%, 55.4%, 92.1%, and 64.3%, respectively, and the differences were statistically significant ( P < 0.05 ). In conclusion, the images reconstructed by the ART-TV-PI algorithm have good image quality, which provides great convenience for surgical examination of cerebral aneurysm stent implantation and is worthy of clinical application.

This work was aimed to study the risk factors and prognostic treatment for acute ischemic stroke (AIS) patients with early neurological deterioration (END) after intravenous thrombolytic therapy via compressed sensing algorithm-based magnetic resonance imaging (CS-MRI). 231 patients who were diagnosed with AIS were selected, and the final involved number of patients was 182. Patients with AIS were treated with intravenous thrombolysis with alteplase within 4.5 hours of onset. After treatment, patients with early neurological deterioration were defined as the deteriorating group and those without early neurological impairment were defined as the nondeteriorating group. In univariate analysis, hypertension, white blood cell count, and National Institutes of Health Stroke Scale (NIHSS) score were correlated with the occurrence of END. Under the CS-MRI theory, the two groups of patients were evaluated for middle cerebral artery basal ganglia infarction and internal watershed infarction. After univariate analysis, the P < 0.1 variables were taken as the independent variable, and the binary logistic regression model was adopted for multivariate regression analysis. It was disclosed that NIHSS score was not correlated with the occurrence of early neurological function deterioration, while homocysteine was. Hypertension, white blood cell count, homocysteine, and NIHSS score were risk factors for END. The image analysis revealed that the incidence of deteriorating basal ganglia infarction group was lower relative to the nondeteriorating group, and the incidence of watershed infarction was higher in the deteriorating group versus the nondeteriorating group. The image analysis suggested that predicting the occurrence of END through risk factors can actively provide endovascular treatment for patients with AIS.

Glioblastomas (GBM) is the most common primary malignant brain tumor, and radiotherapy plays a critical role in its therapeutic management. Unfortunately, the development of radioresistance is universal. Here, we identified calcium-regulated heat-stable protein 1 (CARHSP1) as a critical driver for radioresistance utilizing genome-wide CRISPR activation screening. This is a protein with a cold-shock domain (CSD)-containing that is highly similar to cold-shock proteins. CARHSP1 mRNA level was upregulated in irradiation-resistant GBM cells and knockdown of CARHSP1 sensitized GBM cells to radiotherapy. The high expression of CARHSP1 upon radiation might mediate radioresistance by activating the inflammatory signaling pathway. More importantly, patients with high levels of CARHSP1 had poorer survival when treated with radiotherapy. Collectively, our findings suggested that targeting the CARHSP1/TNF-α inflammatory signaling activation induced by radiotherapy might directly affect radioresistance and present an attractive therapeutic target for GBM, particularly for patients with high levels of CARHSP1.

Purpose Previous studies usually examine the associations between psychological distresses and quality of life (QOL) with a variable-centred approach, while little is known about the effect of the individual variance in time-varying changes of psychological distresses on QOL. Therefore, this study aimed to examine whether individual variance in psychological distresses during the early phases post-earthquake would develop different QOL’s levels among adolescent survivors 10-year after the Wenchuan earthquake. Methods Data were extracted from the Wenchuan Earthquake Adolescent Health Cohort Study. The current study included 744 adolescent survivors who effectively completed surveys at 6 months, 24 months, and 10 years after the earthquake. Self-report questionnaires were administered to collect information on socio-demographic characteristics, earthquake exposure, life events, anxiety symptoms, depressive symptoms, posttraumatic stress symptoms (PTSS), and QOL. Data were analysed using hierarchical multiple regression. Results Trajectories of psychological distresses were classified as follow: resistance (anxiety 40.73%; depression 54.70%; PTSS 74.46%), recovery (anxiety 17.20%; depression 9.27%; PTSS 10.35%), delayed dysfunction (anxiety 10.35%; depression 18.15%; PTSS 6.18%), and chronicity (anxiety 31.72%; depression 17.88%; PTSS 9.01%). After controlling covariates, hierarchical multiple regression only revealed that the anxiety trajectory with delayed dysfunction remained significantly predictive for four domains of QOL (physical health, psychological health, social relationships, and environment). Conclusion The current study highlights the importance of focusing on the variations in trajectories of anxiety symptoms among disaster survivors and providing individualized mental health services to improve survivors’ QOL.

Ribonucleotide reductase (RNR) is the key enzyme that catalyzes the production of deoxyribonucleotides (dNTPs) for DNA replication and it is also essential for cancer cell proliferation. As the RNR inhibitor, Gemcitabine is widely used in cancer therapies, however, resistance limits its therapeutic efficacy and curative potential. Here, we identified that mTORC2 is a main driver of gemcitabine resistance in non-small cell lung cancers (NSCLC). Pharmacological or genetic inhibition of mTORC2 greatly enhanced gemcitabine induced cytotoxicity and DNA damage. Mechanistically, mTORC2 directly interacted and phosphorylated RNR large subunit RRM1 at Ser 631. Ser631 phosphorylation of RRM1 enhanced its interaction with small subunit RRM2 to maintain sufficient RNR enzymatic activity for efficient DNA replication. Targeting mTORC2 retarded DNA replication fork progression and improved therapeutic efficacy of gemcitabine in NSCLC xenograft model in vivo. Thus, these results identified a mechanism through mTORC2 regulating RNR activity and DNA replication, conferring gemcitabine resistance to cancer cells.

Background Neoadjuvant chemoradiotherapy (nCRT) followed by surgery is a currently widely used strategy for locally advanced esophageal cancer (EC). However, the conventional imaging methods have certain deficiencies in the evaluation and prediction of the efficacy of nCRT. This study aimed to explore the value of functional imaging in predicting the response to neoadjuvant chemoradiotherapy (nCRT) in locally advanced esophageal squamous cell carcinoma (ESCC). Methods Fifty-four patients diagnosed with locally advanced ESCC from August 2017 to September 2019 and treated with nCRT were retrospectively analyzed. DW-MRI scanning was performed before nCRT, at 10–15 fractions of radiotherapy, and 4–6 weeks after the completion of nCRT. 18F-FDG PET/CT scans were performed before nCRT and 4–6 weeks after the completion of nCRT. These 18F-FDG PET/CT and DW-MRI parameters and relative changes were compared between patients with pathological complete response (pCR) and non-pCR. Results A total of 8 of 54 patients (14.8%) were evaluated as disease progression in the preoperative assessment. The remaining forty-six patients underwent operations, and the pathological assessments of the surgical resection specimens demonstrated pathological complete response (pCR) in 10 patients (21.7%) and complete response of primary tumor (pCR-T) in 16 patients (34.8%). The change of metabolic tumor volume (∆MTV) and change of total lesion glycolysis (∆TLG) were significantly different between patients with pCR and non-pCR. The SUVmax-Tpost, MTV-Tpost, and TLG-Tpost of esophageal tumors in 18F-FDG PET/CT scans after neoadjuvant chemoradiotherapy and the ∆ SUVmax-T and ∆MTV-T were significantly different between pCR-T versus non-pCR-T patients. The esophageal tumor apparent diffusion coefficient (ADC) increased after nCRT; the ADCduring, ADCpost and ∆ADCduring were significantly different between pCR-T and non-pCR-T groups. ROC analyses showed that the model that combined ADCduring with TLG-Tpost had the highest AUC (0.914) for pCR-T prediction, with 90.0% and 86.4% sensitivity and specificity, respectively. Conclusion 18F-FDG PET/CT is useful for re-staging after nCRT and for surgical decision. Integrating parameters of 18F-FDG PET/CT and DW-MRI can identify pathological response of primary tumor to nCRT more accurately in ESCC.

Through searching the literature on the mechanism of acupuncture for primary dysmenorrhea in the last 15 years, this paper summarizes systematically the current study progress on the analgesic mechanism of acupuncture for primary dysmenorrhea, from the perspectives of animal experiment and human trials. In terms of research methods, the behavioral observation, evaluation of central and peripheral biochemical indexes, and molecular biological techniques were mainly used in the animal experiments; whilst the clinical symptoms and evaluation of peripheral serum biochemical indexes were focused on in human trials. As for the research results, the animal experiments showed that acupuncture may play an analgesic role by regulating endocrine, promoting the release of central and peripheral neurotransmitters, regulating immune function, and relieving uterine smooth muscle spasm. However, the human trials have found that acupuncture can produce analgesic effects by regulating serum prostaglandin and ovarian hormone levels, promoting the release of peripheral β-endorphin, improving the uterine artery flow status, and relieving uterine smooth muscle spasm. Although different research methods were used in animal and human studies, the similar results were obtained in acupuncture regulating endocrine levels, promoting release of peripheral neurotransmitters, and alleviating uterine smooth muscle spasms. In addition, at present stage, animal experiments are more than human trials in numbers, and there are relatively few studies on the central mechanism of acupuncture analgesia in human trials. Therefore, in view of this phenomenon, this paper proposes to use functional magnetic resonance imaging (fMRI) technology to explore the central mechanism of acupuncture analgesia in human body, so as to provide a new idea for further exploring the mechanism of acupuncture analgesia in treating primary dysmenorrhea.

Breast cancer was the leading cause of newly diagnosed cases of tumors in 2020, ranking as the second highest cause of female death. Chemotherapy remains the conventional treatment of choice for breast tumors in most clinical cases. However, it is often accompanied by a poor prognosis and severe side effects, resulting from an insufficient accumulation of the drug at tumor sites and an unsystematic distribution of the drug across the body. Inspired by the fact that breast tumor cells overexpress integrin α2β1 on the surface, we designed and constructed an integrin α2β1 targeting DGEA-modified liposomal doxorubicin (DGEA-Lipo-DOX) platform for application in breast cancer therapy. The DGEA-Lipo-DOX was stable with a uniform particle size of 121.1 ± 3.8 nm and satisfactory drug encapsulation. Demonstrated in vitro and in vivo, the constructed platform exhibited improved antitumor ability. The DGEA-Lipo-DOX showed 4-fold enhanced blood circulation and 6-fold increased accumulation of DOX at the tumor sites compared to those of free DOX, resulting in a significantly enhanced antitumor efficacy in tumor-bearing mice. A preliminary safety evaluation suggested that the systemic toxicity of DOX was relieved by DGEA-Lipo delivery. Collectively, binding integrin α2β1 by DGEA may represent an alternative therapeutic strategy for potentially safer breast cancer treatment.

Objectives To compare early and long-term outcomes of redo-isolated tricuspid surgery (RITS) after left-sided valve surgery. Methods We retrospectively reviewed 173 patients who underwent RITS for severe tricuspid regurgitation after previous left-sided valve surgery from January 1999 to December 2019. Patients were divided into two groups: RITS by median sternotomy (m-RITS; n = 78) and totally endoscopic approach (e-RITS; n = 95). Perioperative outcomes and follow-up results were analyzed. Results There were 19 (11%) in-hospital deaths (14.1% in m-RITS and 8.4% in e-RITS, p = .234) that decreased from 16.7% (1999-2014) to 6.9% (2015-2019) (p = .044). Tricuspid valve replacement (odds ratio [OR] = 4.989, 95% confidence interval [CI]: 1.133-29.790, p = .041) and NYHA function class IV (OR = 9.611, 95% CI: 2.102-43.954, p = .004) were independent risk factors for in-hospital mortality. The overall 1-, 5-, 10-, and 15-year survival rates were 97.2% (95% CI: 94.5%-99.9%), 80.3% (95% CI: 71.7%-88.9%), 59.2% (95% CI: 43.5%-75.5%), and 49.3% (95% CI: 27.2%-71.4%), respectively. Conclusion Patients undergoing RITS carry a high risk of early mortality. There was no significant difference in early mortality or long-term survival between the endoscopy and median sternotomy, whereas the endoscopy approach was associated with shorter intensive care unit stays and fewer reoperations. Repair resulted in lower surgical mortality than replacement with acceptable residual tricuspid regurgitation.

Traditionally B3 breast lesions are treated surgically, but overtreatment is a concern, as the majority have a final benign diagnosis. A national screening program introduced vacuum-assisted excision (VAE) for managing B3 lesions in late 2016. This retrospective study aimed to assess the outcomes associated with this approach.All B3 lesions diagnosed between 01/2017 and 12/2019 were identified at two centres. Information was obtained on the initial biopsy and final histology, and method of VAE image guidance, needle size and number of cores. Lesions were excluded if there was cancer elsewhere in the breast at the time of diagnosis; the lesion was not suitable for VAE due to position in the breast or had B3 pathology for which open biopsy was still required. The final decision to offer VAE was always made at a multidisciplinary meeting (MDM). Risk difference was used to test the significance at p ≤ .05.In total, 258 B3 lesions were diagnosed, 105 (40.7%) met the inclusion criteria and underwent VAE. VAE was performed under X-ray (89/105) or ultrasound guidance (16/105), taking an average of 18.5 cores with the 10-G needle or 10.8 cores with the 7-G needle. Nine cases (8.6%) were upgraded to a malignant diagnosis following VAE. Malignancy was found in 15.5% (9/58) of B3 lesions with epithelial atypia, but in none without atypia (0/47) (p = .004). No new lesions or malignancy has occurred at the site of the VAE with an average mammographic follow-up of 2.2 years.Upgrade to malignancy following VAE was uncommon (8.6%) and associated with atypia in the initial biopsy. VAE is an alternative approach to the management of B3 lesions, reducing open surgical procedures.• Upgrade to malignancy after a vacuum-assisted excision of a B3 breast lesion is uncommon with an 8.6% upgrade rate. • The risk of a malignant diagnosis after a vacuum-assisted excision was significantly higher for B3 lesions with atypia compared to those without (+15.5% difference, p = .004).

Resumo Fundamento O ácido úrico (AU), produto final do metabolismo dos nucleotídeos das purinas, participa dos processos de doenças metabólicas e cardiovasculares. Evidências experimentais sugerem que o ácido úrico é um mediador importante na resposta fisiológica ao aumento da pressão arterial. Objetivo Avaliar a associação entre os níveis séricos de AU e pré-hipertensão e hipertensão em uma população chinesa. Métodos Conduziu-se um estudo transversal entre março e setembro de 2017, e 1.138 participantes com idades entre 35 e 75 anos foram incluídos neste estudo, onde 223 normotensos, 316 pré-hipertensos e 599 hipertensos foram selecionados para avaliar a associação entre níveis séricos de AU e hipertensão. Considerou-se um valor de p

Objectives: The treatment of acute herpangina is inconsistent. We aim to evaluate the effectiveness and safety of interferon α-2b spray versus Ribavirin for this disease. Methods: A randomized, controlled trial was conducted in eight hospitals in China between 2016 and 2018. 668 patients (1–7 years old) were randomized into an experimental group (treated with Interferon α-2b spray) or control group (received Ribavirin Aerosol). Body temperature returning to normal within 72 h and remaining so for 24 h was the primary outcome; release of oral herpes and adverse events were the secondary outcomes. Results: (1) The average age of onset was 2.5 years old. (2) After 72 h treatment, body temperature of 98.5% patients in experimental group and 94.3% in control group returned to normal and remained so for 24 h (P = 0.004). The differences were greater at 48 h treatment (95.2% vs. 85.9%, P < 0.001) and at 24 h (77.5% vs. 66.5%, P = 0.001). (3) The rate of improved oral herpes in the experimental group was higher than that in control group (46.7% vs.37.1%, P = 0.011). No adverse reaction occurred. Conclusions: Local application of recombinant interferon α-2b spray showed better efficacy for acute herpangina in children. It was safe for use.

Background Oral squamous cell carcinoma (OSCC) is a capricious cancer with poor survival rates, even for early-stage patients. There is a pressing need to develop more precise risk assessment methods to appropriately tailor clinical treatment. Genome-wide association studies have not produced a viable biomarker. However, these studies are limited by using heterogeneous cohorts, not focusing on methylation although OSCC is a heavily epigenetically-regulated cancer, and not combining molecular data with clinicopathologic data for risk prediction. In this study we focused on early-stage (I/II) OSCC and created a risk score called the REASON score, which combines clinicopathologic characteristics with a 12-gene methylation signature, to predict the risk of 5-year mortality. Methods We combined data from an internal cohort (n = 515) and The Cancer Genome Atlas (TCGA) cohort (n = 58). We collected clinicopathologic data from both cohorts to derive the non-molecular portion of the REASON score. We then analyzed the TCGA cohort DNA methylation data to derive the molecular portion of the risk score. Results 5-year disease specific survival was 63% for the internal cohort and 86% for the TCGA cohort. The clinicopathologic features with the highest predictive ability among the two the cohorts were age, race, sex, tobacco use, alcohol use, histologic grade, stage, perineural invasion (PNI), lymphovascular invasion (LVI), and margin status. This panel of 10 non-molecular features predicted 5-year mortality risk with a concordance (c)-index = 0.67. Our molecular panel consisted of a 12-gene methylation signature (i.e., HORMAD2, MYLK, GPR133, SOX8, TRPA1, ABCA2, HGFAC, MCPH1, WDR86, CACNA1H, RNF216, CCNJL), which had the most significant differential methylation between patients who survived vs. died by 5 years. All 12 genes have already been linked to survival in other cancers. Of the genes, only SOX8 was previously associated with OSCC; our study was the first to link the remaining 11 genes to OSCC survival. The combined molecular and non-molecular panel formed the REASON score, which predicted risk of death with a c-index = 0.915. Conclusions The REASON score is a promising biomarker to predict risk of mortality in early-stage OSCC patients. Validation of the REASON score in a larger independent cohort is warranted.

Chronic obstructive pulmonary disease (COPD) is a respiratory disease with a high incidence, mortality, and disability rate. Because there are few symptoms in the early stages of COPD, diagnosis and treatment are seriously insufficient. It is necessary to find effective clues for early COPD diagnosis and provide appropriate interventions. Several studies suggest that small airway disease is the earliest stage of COPD because it is correlated with subsequent development of airflow obstruction. However, there are currently no globally accepted criteria for defining early COPD. This study mainly introduced risk factors, definition, diagnosis, and treatment of early COPD from a new perspective.

The majority of patients with Crohn's disease and a proportion of patients with ulcerative colitis will ultimately require surgical treatment despite advances in diagnosis, therapy, and endoscopic interventions. The surgical procedures that are most commonly done include bowel resection with anastomosis, strictureplasty, faecal diversion, and ileal pouch. These surgical treatment modalities result in substantial alterations in bowel anatomy. In patients with inflammatory bowel disease, endoscopy plays a key role in the assessment of disease activity, disease recurrence, treatment response, dysplasia surveillance, and delivery of endoscopic therapy. Endoscopic evaluation and management of surgically altered bowel can be challenging. This consensus guideline delineates anatomical landmarks and endoscopic assessment of these landmarks in diseased and surgically altered bowel.

As a signaling molecule, hydrogen sulfide (H2S) plays an indispensable role in the modulation of ripening and senescence in fruits and vegetables. To explore the role of H2S in regulating metabolism of postharvest tomato, ripening-related physiological parameters, activities of antioxidant enzymes and gene expression were analyzed in H2S-fumigated tomato fruits. These results show that H2S significantly delayed the color transition and softening of tomato fruit, and maintained higher level of flavonoids and lower level of anthocyanin during storage. Besides, H2S could maintain higher level of nutritional-related metabolites, such as reducing sugar, ascorbic acid during postharvest storage. Moreover, H2S decreased the rate of O2− production, inhibited the production of H2O2 and malondialdehyde (MDA), enhanced the activities of antioxidant enzymes including ascorbate peroxidase (APX), superoxide dismutase (SOD), catalase (CAT) and guaiacol peroxidase (POD) in tomato fruits, while reduced the activities of phenylalanine ammonia lyase (PAL), polyphenol oxidase (PPO) and lipoxygenase (LOX). Besides, the expression of the antioxidant-encoding genes SlCAT2, SlPOD12 was generally upregulated with H2S fumigation. Principal component analysis (PCA) suggests that H2S induced significant discrepancy mainly to the differences in firmness, anthocyanin, flavonoid and the activity of guaiacol peroxidase (POD), and the correlation analysis further shows that H2S affected pigment metabolism and nutritional quality. In conclusion, H2S could maintain better appearance and nutritional quality, and prolong the storage period of postharvest tomato fruits through activating the antioxidative system.

Vascular calcification is one of the most common effects of macrovascular complications in patients in aging with chronic kidney disease and diabetes. Previous studies showed that HOTAIR attenuated vascular calcification via the Wnt/β-catenin-signaling pathway, yet the molecular mechanism has not been fully elucidated. This study aimed to identify the explicit molecular mechanism underlying HOTAIR regulated vascular calcification. In the phosphate (Pi)-induced calcification model of human aortic smooth muscle cells (HASMCs), we investigated whether HOTAIR was involved in the regulation of miR-126. The luciferase reporter was used to examine the effect of HOTAIR on miR-126 and miR-126 on Klotho 3'-UTR. Furthermore, we overexpressed Klotho to verify the regulation of Klotho on SIRT1, as well as their roles in mediating Pi-induced calcification in HASMCs via the Wnt/β-catenin signaling pathway. Finally, the results were verified in an in vivo mice calcification model. Overexpression of HOTAIR reduced the expression of miR-126 in Pi-induced HASMCs. Additionally, knockdown of miR-126 increased SIRT1 expression by regulating Klotho expression. An increased level of Klotho inhibited Wnt/β-catenin signaling pathway, which eventually attenuated Pi-induced HASMCs calcification. Luciferase reporter assay revealed that HOTAIR targeted miR-126 and miR-126 could directly target Klotho. Eventually, HOTAIR overexpression reversed Pi-induced calcium calcification in vivo mouse models. This study demonstrated that HOTAIR overexpression attenuated Pi-induced calcification by regulating the miR-126/Klotho/SIRT1 axis, thereby inhibiting the Wnt/β-catenin signaling pathway. It provides new potential target genes for the clinical treatment of vascular calcification.

International audience; Many insects metamorphose from antagonistic larvae into mutualistic adult pollinators, with reciprocal adaptation leading to specialized insect-plant associations. It remains unknown how such interactions are established at molecular level. Here we assemble high-quality genomes of a fig species, Ficus pumila var. pumila, and its specific pollinating wasp, Wiebesia pumilae. We combine multi-omics with validation experiments to reveal molecular mechanisms underlying this specialized interaction. In the plant, we identify the specific compound attracting pollinators and validate the function of several key genes regulating its biosynthesis. In the pollinator, we find a highly reduced number of odorant-binding protein genes and an odorant-binding protein mainly binding the attractant. During antagonistic interaction, we find similar chemical profiles and turnovers throughout the development of galled ovules and seeds, and a significant contraction of detoxification-related gene families in the pollinator. Our study identifies some key genes bridging coevolved mutualists, establishing expectations for more diffuse insect-pollinator systems.

Fish as an important food source, with the increase of consumption rate, the resulting allergic phenomenon increased year by year. Food allergen in aquatic products was an important allergy-inducing factor, which had a great impact on the body’s tissue, inflammatory factors, immunoglobulin and intestinal flora. The research objective of this study was to evaluate the allergenic risk of turbot parvalbumin (PV) and provided effective biological reference markers for the safety assessment of aquatic products. Results showed PV has high purity, high binding capacity with IgE and IgG, influenced release of inflammatory factors in DCs (IL-6/10/12p70), induced allergic response in mice. PV increased the levels of PV-specific IgE, total IgE, IgG1, monocyte chemotactic protein 1(MCP-1), histamine, tryptase significantly. PV obviously mutagenic effect on spleen, intestinal tissue. Sequencing of microbial diversity showed that microorganism Ruminiclostridium and Alistipes in PV group changed significantly, which proved that the structure of intestinal microorganism has changed. In summary, Turbot parvalbumin triggered fish allergic responses by induced imbalance of inflammatory factors and microbial composition of IL-6/10/12p70, IgE/IgG and Ruminiclostridium, Alistipes. These results indicated that PV had high-risk allergy inducing ability, and the changes of the above indicators provided biological reference markers for risk assessment of the safety of aquatic products intake.

Objective The aim of the present study was to investigate the feasibility and efficacy of one‐stage surgical resection of thoracic dumbbell tumors using a paravertebral approach and a micro‐tubular technique. Methods Clinical data of thoracic dumbbell tumors resected using a paravertebral approach and a micro‐tubular technique (14 mm, non‐expandable type) in the Department of Neurosurgery at our hospital from July 2014 to July 2019 were retrospectively analyzed. Tumors were found between T1 and T12 vertebrae. Operation time, blood loss, hospitalization, recovery of neurological function, complications, the Japanese Orthopaedic Association (JOA) score, and the visual analogue scale (VAS) score were used to evaluate clinical efficacy. Results In all 31 cases, tumors were completely resected in one operation, with a mean blood loss of 53.23 ± 33.08 mL (20–150 mL) and a mean operation time of 95.16 ± 20.31 min (60–180 min). According to the Eden classification, there were four type II cases, 16 type III cases, and 11 type IV cases. The incidence of tumors in the lower thoracic segment (T8–T12) was 51.6% (16/31 cases), while the incidences in the upper thoracic segment (T1–T4) and middle segment (T5–T8) were 25.8% (8/31 cases) and 22.6% (7/31 cases), respectively. Pathological diagnoses were schwannoma (n = 22), gangliocytoma (n = 4), metastatic tumor (n = 2), neurofibroma (n = 1), granuloma (n = 1), and lipoma (n = 1). After surgery, symptoms were relieved in all patients. VAS and JOA scores significantly improved (P, Preoperative T2‐weighted MRI on axial (A) and coronal (B) planes, revealing a dumbbell tumor in the left T8–9 foramen (arrows). Rebuilding the relationship between the vertebrae (yellow) and the dumbbell tumor (purple) and designing the operational approach with micro‐tubule (number 1, brown and number 2, green) using 3D software. Location of the tumor after partial resection of vertebrae(G).

Background To determine treatment effects on the incidence of post-stroke epilepsy (PSE) using different doses of statin, a prospective hospital-based cohort study was designed to explore whether a double-dose statin treatment can better prevent the occurrence of PSE. Methods A total of 1152 patients with newly diagnosed ischemic stroke admitted to our hospital from March to August 2017 were selected, 1033 of whom were followed-up. Patients were divided into two treatment groups:(1) standard-dose (20 mg atorvastatin or 10 mg rosuvastatin,daily oral; 788 patients); and (2) double-dose (40 mg atorvastatin or 20 mg rosuvastatin, daily oral; 245 patients).At 18 months follow-up was conducted to compare the incidence of PSE between groups. Results In general, in the standard-dose group we observed two cases of early seizure (ES) (0.25%), 22 cases oflate seizure (LS) (2.79%) and 20 cases of PSE (2.54%). In the double-dose group, onepatient had ES (0.41%), two patients had LS (0.82%), and onepatient had PSE (0.41%). The incidence of PSE was significantly lower in the double-dose group as compared to the standard-dose group. There was a higher proportion of PSE in patients younger than 65 years and in males. Three patients had ES; one presented with focal aware seizure (FAS), and two had focal to bilateral tonic-clonic seizure (FBTCS). Among the 21 patients with PSE, there were two cases of FAS, five cases of focal impaired awareness seizure (FIAS), five cases of FBTCS, and nine cases of GTCS, suggesting that partial seizure is the most common type of PSE. Cerebral cortex was involved in 85.75% of cases with PSE, and multiple lobes were involved in 61.9% of cases with PSE. Conclusion Increasing the dose of statin treatment during the acute phase of ischemic stroke reduces the incidence of PSE. Further research is needed to understand the mechanisms underlying the potential preventative effects of statins against PSE.

Background As newly emerging evidence was given, we conducted a meta-analysis of randomized controlled trials (RCTs) with the following objectives: (I) to evaluate the effect of long-term noninvasive ventilation (NIV) on posthospital chronic obstructive pulmonary disease (COPD) patients with respiratory failure in mortality, blood gas, exacerbation frequency; (II) to distinguish different follow-up length of longterm NIV and its effect on these outcomes. Methods We tried to conduct and report this meta-analysis in accordance with the Cochrane Handbook (version 5.1.0) by searching the PubMed, Embase, Cochrane Library, and Chinese Biomedical Literature for RCTs in humans through April 2020. Studies comparing treatment effects of domiciliary NIV with control therapy in posthospital COPD patients were conducted, and at least one of the following parameters were reviewed: mortality, gas exchange, and exacerbation frequency. Results Five studies with 419 subjects were identified. The exacerbation frequency significantly decreased in patients who received domiciliary NIV [weighted mean difference (WMD) -1.74, 95% CI: -2.90 to -0.57, P=0.004]. No significant difference was found in mortality, partial pressure of arterial oxygen (PaO2), PaCO2, and pH. Subgroup analysis of PaCO2 showed that domiciliary NIV of 3 months was most likely to decrease PaCO2, but not significant (WMD -2.95, 95% CI: -6.11 to 0.21, P=0.07). Conclusions The results indicate that domiciliary NIV decreases the exacerbation frequency of posthospital COPD patients, but may not improve mortality or gas exchange. Further studies are needed to evaluate the benefit of domiciliary NIV on COPD patients.

Purpose PR loss in ER+/HER2- breast cancer indicates worse prognosis and insensitivity to anti-estrogen therapy, while the mechanisms of PR loss in ER+/HER2- breast cancer remain unrevealed. Methods In this study, ER+/PR+/HER2- and ER+/PR-/HER2- breast cancer cases from TCGA were used. 1387 pathways were analyzed and used as variables for classifying the two groups with LASSO regression. Results ER+/PR+/HER2- and ER+/PR-/HER2- breast cancer groups can be classified by a combination of 13 pathways using their activity score. Among the 13 pathways, those involving growth factors and ion-channel transporters were most significant in the distinction, followed by pathways involving immune modulation and cell metabolism. Two growth factor pathways, EGF and IGF-1, were deferentially regulated in ER+/PR+/HER2- and ER+/PR-/HER2- groups. Conclusions In conclusion, this study indicated in ER+/HER2- breast cancers the various status of PR expression can be an indication of molecular variation, particularly for the growth factor pathway activation.

Qing Song,1– 3 Yi-Yang Zhao,1– 3 Yu-Qin Zeng,1– 3 Cong Liu,1– 3 Wei Cheng,1– 3 Min-Hua Deng,4 Xin Li,5 Li-Bing Ma,6 Yan Chen,1– 3 Shan Cai,1– 3 Ping Chen1– 3 1Department of Respiratory and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, People’s Republic of China; 2Research Unit of Respiratory Disease, Central South University, Changsha, Hunan, 410011, People’s Republic of China; 3Diagnosis and Treatment Center of Respiratory Disease, Central South University, Changsha, Hunan, 410011, People’s Republic of China; 4Department of Respiratory, PLA Rocket Force Characteristic Medical Center, Beijing, 100088, People’s Republic of China; 5Division 4 of Occupational Disease, Hunan Occupational Disease Prevention and Treatment Hospital, Changsha, Hunan, 410000, People’s Republic of China; 6Department of Respiratory and Critical Care Medicine, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, 541000, People’s Republic of ChinaCorrespondence: Ping ChenDepartment of Respiratory and Critical Care Medicine, The Second Xiangya Hospital, Central South University, 139 Renmin Middle Road, Changsha, Hunan, 410011, People’s Republic of ChinaTel +86 731 8529 5248Fax +86 731 8529 5848Email pingchen0731@csu.edu.cnBackground: The Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017 separated pulmonary function from combined assessment. We aimed to analyze the characteristics of airflow limitation and future exacerbations in different GOLD groups of chronic obstructive pulmonary disease (COPD) patients.Methods: For this prospective observational study, stable COPD outpatients were enrolled and divided into Groups A, B, C and D based on GOLD 2017, and followed-up for 18 months. Data on demographics, pulmonary function, COPD assessment test (CAT), Clinical COPD Questionnaire (CCQ), modified Medical Research Council (mMRC), exacerbations, mortality and treatments were collected. A post-bronchodilator ratio of forced expiratory volume in one second to forced vital capacity < 0.70 confirms the presence of airflow limitation.Results: A total of 993 subjects were classified into Groups A (n = 170, 17.1%), B (n = 360, 36.3%), C (n = 122, 12.3%), and D (n = 341, 34.3%). There were significant differences in mMRC, CAT, CCQ, exacerbations and hospitalizations rates among the different groups (P < 0.001). Groups B and D had more severe airflow limitation than Groups A and C (P < 0.05). In the same groups with different severity of airflow limitation, the differences were mainly observed in body mass index, CAT, CCQ and treatment with long-acting muscarinic antagonist (LAMA) and LAMA + long-acting β 2-agonist + inhaled corticosteroid (P < 0.05). After 18 months of follow-up, the exacerbations and hospitalizations rates were significantly different among different groups (P < 0.05). However, in the same groups with different airflow limitation severity, the mortality rates and number of exacerbations, hospitalizations and frequent exacerbators showed no differences.Conclusion: In the GOLD groups, different severity of airflow limitation had no impact on future exacerbations and mortality rate. It implies that pulmonary function is not a good indicator for predicting exacerbation.Keywords: chronic obstructive pulmonary disease, Global Initiative for Chronic Obstructive Lung Disease, pulmonary function, exacerbation

Ubiquitin-specific peptidase 18 (USP18) plays an important role in the development of CD11b + dendritic cells (DCs) and Th17 cells, however, its role in the differentiation of other T cell subsets, especially in regulatory T (Treg) cells, is unknown. In our study, we used Usp18 KO mice to study the loss of USP18 on the impact of Treg cell differentiation and function. We found that USP18 deficiency upregulates the differentiation of Treg cells, which may lead to disrupted homeostasis of peripheral T cells, and downregulates INF-γ, IL-2, IL-17A producing CD4 + T cells and INF-γ producing CD8 + T cells. Mechanistically, we also found that the upregulation of Tregs is due to elevated expression of CD25 in Usp18 KO mice. Finally, we found that the suppressive function of Usp18 KO Tregs is downregulated. Altogether, our study was the first to identify the role of USP18 in Tregs differentiation and its suppressive function, which may provide a new reference for the treatment of Treg function in many autoimmune diseases, and USP18 can be used as a new therapeutic target for precise medical treatment.

AIMS This study aims to evaluate the effects of dexmedetomidine on organ function, inflammation response, and oxidative stress in elderly patients following iatrogenic lower limb ischaemia-reperfusion (IR) during unilateral total knee arthroplasty. METHODS Following unilateral total knee arthroplasty, 54 elderly patients were randomized to receive either intraoperative intravenous injection of dexmedetomidine (n = 27) or equivalent volume of 0.9% saline (n = 27). Blood samples were harvested at 5 minutes before lower limb tourniquet release (baseline); and 1, 6 and 24 hours after tourniquet release. Surrogate markers of cardiac, pulmonary, hepatic and renal function, oxidative stress, inflammatory response, along with parasympathetic and sympathetic activity were recorded and analysed. RESULTS The levels of blood xanthine oxidase, creatine kinase, lactic acid and respiratory index increased in patients following tourniquet-induced lower limb IR injury. Dexmedetomidine administration decreased the respiratory index (P = .014, P = .01, and P = .043) and the norepinephrine level (P

BACKGROUND Gastric carcinoma (GC) is a digestive system disease with high morbidity and mortality. However, early clinical detection is difficult, and the therapeutic effect for advanced disease is not satisfactory. Thus, finding new tumor markers and therapeutic targets conducive to the treatment of GC is imperative. MRPL35 is a member of the large subunit family of mitochondrial ribosomal protein. MRPL35 shows the characteristic of oncogene in colorectal cancer and esophageal cancer, which promotes the exploration of the correlation between MRPL35 and GC. We proposed that the expression of MRPL35 might be critical in GC. AIM To study the effect of MRPL35 knockdown on GC cell proliferation. METHODS The expression of MRPL35 in GC was evaluated based on data from the public tumor database UALCAN (www.ualcan.path.uab.edu). The effect of the expression of MRPL35 on the prognosis was evaluated with KMplot (www.kmplot.com). The expression of MRPL35 was assessed on the tissue microarray by immunohistochemistry and the level of MRPL35 mRNA in 25 pairs of clinical GC tissues and matched adjacent tissues was detected by quantitative reverse transcription-polymerase chain reaction. Celigo cell count assay, colony formation assay, and flow cytometry were used to assess the role of MRPL35 in GC cell proliferation and apoptosis in vitro. Additionally, tumor formation experiment in BALB/c nude mice was utilized to determine the effect of MRPL35 on GC cell proliferation. After knockdown of MRPL35, related proteins were identified by isobaric tags for relative and absolute quantification analysis, and the expression of related proteins was detected by Western blot. RESULTS The expression of MRPL35 was up-regulated in GC (P = 1.77 × 10-4). The Kaplan-Meier plots of the overall survival indicated that high expression of MRPL35 was associated with a poor survival in GC. Compared with adjacent tissues, the expression of MRPL35 in GC tissues was increased, which was related to age (P = 0.03), lymph node metastasis (P = 0.007), and pathological tumor-node-metastasis stage (P = 0.024). Knockdown of MRPL35 inhibited GC cell proliferation and colony formation and induced apoptosis. Animal experiment results showed that knockdown of MRPL35 inhibited tumor formation in BALB/c nude mice. Western blotting analysis showed that after knockdown of MRPL35, the expression of PICK1 and BCL-XL proteins decreased, and that of AGR2 protein increased. CONCLUSION Collectively, our findings demonstrate that knockdown of MRPL35 inhibits GC cell proliferation through related proteins including PICK1, BCL-XL, and AGR2.

Chemokines are important regulators of the immune system, inducing specific cellular responses by binding to receptors on immune cells. In SLE patients, decreased expression of CCL2 on mesenchymal stem cells (MSC) prevents inhibition of B-cell proliferation, causing the characteristic autoimmune phenotype. Nevertheless, the intrinsic role of CCL2 on B-cell autoimmunity is unknown. In this study using Ccl2 KO mice, we found that CCL2 deficiency enhanced BCR signaling by upregulating the phosphorylation of the MST1-mTORC1-STAT1 axis, which led to reduced marginal zone (MZ) B cells and increased germinal center (GC) B cells. The abnormal differentiation of MZ and GC B cells were rescued by in vivo inhibition of mTORC1. Additionally, the inhibition of MST1-mTORC1-STAT1 with specific inhibitors in vitro also rescued the BCR signaling upon antigenic stimulation. The deficiency of CCL2 also enhanced the early activation of B cells including B-cell spreading, clustering and signalosome recruitment by upregulating the DOCK8-WASP-actin axis. Our study has revealed the intrinsic role and underlying molecular mechanism of CCL2 in BCR signaling, B-cell differentiation, and humoral response.

Poorly differentiated colorectal cancer (CRC) is characterized by aggressive invasion and stromal fibroblast activation, which results in rapid progression and poor therapeutic consequences. However, the regulatory mechanism involved remains unclear. Here, we showed that ZNF37A, a member of KRAB-ZFP family, was upregulated in poorly differentiated CRCs and associated with tumor metastasis. ZNF37A enhanced the metastatic potential of multiple CRC cell lines and promoted distant metastasis in an orthotopic CRC model. Further investigation attributed the ZNF37A-exacerbated metastasis to increased extracellular TGF-β and the consequent activation of cancer-associated fibroblasts (CAFs) in tumor microenvironment (TME). Mechanistically, ZNF37A formed a complex with KAP1 and bound to the promoter of THSD4, a TME modulator, to suppress its transcription, which is required for ZNF37A-mediated TGF-β activation and CRC metastasis. Collectively, our study indicates that ZNF37A promotes TGF-β signaling in CRC cells and activates CAFs by transcriptionally repressing THSD4 to drive CRC metastasis, implicating ZNF37A as a potential biomarker for CRC differentiation and progression.

Objective To derive and validate a predictive algorithm integrating clinical and laboratory parameters to stratify a full‐term neonate's risk level of having bacterial meningitis (BM). Methods A multicentered dataset was categorized into derivation (689 full‐term neonates aged ≤28 days with a lumbar puncture [LP]) and external validation (383 neonates) datasets. A sequential algorithm with risk stratification for neonatal BM was constructed. Results In the derivation dataset, 102 neonates had BM (14.8%). Using stepwise regression analysis, fever, infection source absence, neurological manifestation, C‐reactive protein (CRP), and procalcitonin were selected as optimal predictive sets for neonatal BM and introduced to a sequential algorithm. Based on the algorithm, 96.1% of BM cases (98 of 102) were identified, and 50.7% of the neonates (349 of 689) were classified as low risk. The algorithm’s sensitivity and negative predictive value (NPV) in identifying neonates at low risk of BM were 96.2% (95% CI 91.7%–98.9%) and 98.9% (95% CI 97.6%–99.6%), respectively. In the validation dataset, sensitivity and NPV were 95.9% (95% CI 91.0%–100%) and 98.8% (95% CI 97.7%–100%). Interpretation The sequential algorithm can risk stratify neonates for BM with excellent predictive performance and prove helpful to clinicians in LP‐related decision‐making.

Summary Safflower (Carthamus tinctorius L.), a member of the Asteraceae, is a popular crop due to its high linoleic acid (LA) and flavonoid (such as hydroxysafflor yellow A) contents. Here, we report the first high‐quality genome assembly (contig N50 of 21.23 Mb) for the 12 pseudochromosomes of safflower using single‐molecule real‐time sequencing, Hi‐C mapping technologies and a genetic linkage map. Phyloge nomic analysis showed that safflower diverged from artichoke (Cynara cardunculus) and sunflower (Helianthus annuus) approximately 30.7 and 60.5 million years ago, respectively. Comparative genomic analyses revealed that uniquely expanded gene families in safflower were enriched for those predicted to be involved in lipid metabolism and transport and abscisic acid signalling. Notably, the fatty acid desaturase 2 (FAD2) and chalcone synthase (CHS) families, which function in the LA and flavonoid biosynthesis pathways, respectively, were expanded via tandem duplications in safflower. CarFAD2‐12 was specifically expressed in seeds and was vital for high‐LA content in seeds, while tandemly duplicated CarFAD2 genes were up‐regulated in ovaries compared to CarFAD2‐12, which indicates regulatory divergence of FAD2 in seeds and ovaries. CarCHS1, CarCHS4 and tandem‐duplicated CarCHS5˜CarCHS6, which were up‐regulated compared to other CarCHS members at early stages, contribute to the accumulation of major flavonoids in flowers. In addition, our data reveal multiple alternative splicing events in gene families related to fatty acid and flavonoid biosynthesis. Together, these results provide a high‐quality reference genome and evolutionary insights into the molecular basis of fatty acid and flavonoid biosynthesis in safflower.

This study was to investigate the effects of oxidative stress in cigarette smoke (CS)-induced cell apoptosis in mice with emphysema. Thirty-two mice were divided into four groups: the control group, the CS group, the CS + Pifithrin-α group, and the CS + NAC group. Pathological changes and apoptosis in lung tissue of mice were detected. The activity of malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), and total antioxidant capacity (T-AOC) were measured using spectrophotometer. The proteins expression of p53, Bcl-2, Bax, and caspase-3 were determined by western blot. The results showed that cell apoptosis, lung structural damage, and the activity of MDA, as well as the expression of apoptosis-related proteins Bax, total caspase-3, and cleaved caspase-3 were increased in CS-treated mice. The activity of SOD, CAT, and T-AOC, as well as the expression of anti-apoptosis protein Bcl-2 were decreased in CS-treated mice when compared with the control group. However, Pifithrin-α (p53 inhibitor) and N-Acetylcysteine (NAC) could reduce cell apoptosis, lung structural damage and oxidative stress, accelerate the expression of Bcl-2, while suppressing the expression of Bax, total caspase-3 and cleaved caspase-3. More importantly, the treatment with NAC even inhibited the expression of p53. In conclusions, oxidative stress linking the p53 is involved in cell apoptosis in CS-treated emphysema mice.

Zinc (Zn) is found in many neuronal pathways in the brain and has implications for neuromodulation and cerebrovascular disease. However, the association between Zn levels and stroke risk remains controversial. Therefore, we conducted a meta-analysis to explore these relationships. A systematic literature search using PubMed, EMBASE database, and Google Scholar was performed for relevant articles from inception to August 2020. Standardized mean differences (SMDs) and 95% confidence intervals (CIs) were considered the effect sizes and statistical analyses were performed using Stata 12.0. A total of 12 studies involving 1878 cases of stroke and 1754 controls were enrolled. Overall, the meta-analysis demonstrated no significant difference in Zn levels between the stroke group and control group (SMD =-0.18, 95% CI =-0.69 to 0.32, P = 0.480). Subgroup analysis showed that type of stroke had an influence on the Zn levels. A meta-analysis of nine ischemic stroke (IS) studies, which included 1645 cases and 1585 controls, revealed that the Zn levels were significantly higher in IS patients than in controls (SMD (95% CI): 0.61(0.04, 1.19), P = 0.036), but no significant association was found between Zn levels and risk of hemorrhagic stroke (P = 0.113). Egger's test indicated no significant publication bias. This meta-analysis indicates that higher Zn levels may be associated with increased risk of IS; however, these findings should be further confirmed.

Background Although several measures have been taken to control hand foot and mouth disease (HFMD) and herpangina (HA), these two diseases have been prevalent in China for 10 years with high incidence. We suspected that adults’ inapparent infection might be the cause of the continued prevalence of HFMD/HA infection in mainland China. Methods To explore the role of adults (especially caregivers) in the transmission process of HFMD/HA among children, 330 HFMD/HA cases and 330 healthy children (controls) were selected for a case–control study. Then, data were analyzed by logistic regression. Results Single-variable analyses revealed that caregivers who tested positive for enterovirus was a significant risk factor of HFMD/HA transmission to children (adjusted odds ratio (OR) = 9.22; 95% CI, 1.16 to 73.23). In the final multivariable model, caregiver behavior, such as cooling children’s food with mouth (OR = 1.85; 95% CI, 1.11 to 3.08) and feeding children with their own tableware (OR = 2.19; 95% CI, 1.07 to 4.45), significantly increased the risk of transmitting HFMD/HA to children. On the contrary, washing hands before feeding children reduced such risk. Conclusions These results implied that the caregivers might be the infectious source or carriers of enterovirus. Therefore, preventing or treating the caregivers’ enterovirus infection and improving their hygiene habits, especially when they are in contact with children, could provide a breakthrough for the effective control of HFMD/HA.

BACKGROUND Spontaneous renal rupture is a rare disease in the clinic. The causes of spontaneous renal rupture include extrarenal factors, intrarenal factors, and idiopathic factors. Reports on infection secondary to spontaneous renal rupture and the complications of spontaneous renal rupture are scarce. Furthermore, there are few patients with spontaneous renal rupture who present only with fever. CASE SUMMARY We present the case of a 52-year-old female patient who was admitted to our hospital. She presented only with fever, and the cause of the disease was unclear. She underwent a contrast-enhanced computed tomography (CT) scan, which showed that the left renal capsule had a crescent-shaped, low-density shadow; the perirenal fat was blurred, and exudation was visible with no sign of calculi, malignancies, instrumentation, or trauma. Under ultrasound guidance, a pigtail catheter was inserted into the hematoma, and fluid was drained and used for the bacterial test, which proved the presence of Klebsiella pneumoniae. Two months later, abdominal CT showed that the hematoma was absorbed, so the drainage tube was removed. The abdominal CT was normal after 4 mo. CONCLUSION Spontaneous renal rupture due to intrarenal factors causes a higher proportion of shock and is more likely to cause anemia.

Biliary atresia (BA) is an immune-related disorder and signal transducer and activator of transcription 3 (STAT3) is a key signalling molecule in inflammation. The present study was designed to clarify the function of STAT3 in BA. STAT3 expression was examined in patients and a mouse BA model in which STAT3 levels were further altered with a specific inhibitor or activator. Neutrophil accumulation and the levels of the neutrophil chemoattractants (C–X–C motif) ligand 1 (CXCL1) and IL-8 were determined. The effects of STAT3 inhibition on IL-8 expression were examined in human biliary epithelial cell (BEC) cultures. Functional changes in liver STAT3+ neutrophils in the mouse model were analysed with 10× single cell RNA-seq methods. Results showed STAT3 and p-STAT3 expression was reduced in BA liver tissue compared with control samples. Administration of a STAT3 inhibitor increased jaundice and mortality and reduced body weight in BA mice. In contrast, the STAT3 activator ameliorated BA symptoms. Extensive neutrophil accumulation together with CXCL1 up-regulation, both of which were suppressed by an anti-CXCL1 antibody, were observed in the STAT3 inhibitor-treated group. Recombinant IL-8 administration increased disease severity in BA mice, and the STAT3 activator had the reverse effect. Inhibiting STAT3 increased apoptosis of human BECs together with up-regulated IL-8 expression. RNA-seq analysis revealed reduced the numbers of STAT3 expressing neutrophil in BA which was accompanied by marked enhanced interferon-related antiviral activities. In conclusion, STAT3 reduction, enhanced IL-8 and CXCL1 expression and promoted the accumulation of interferon-responsive neutrophils resulting in BEC damage in BA.

Purpose Ixazomib is a selective, effective, and reversible inhibitor of 20S proteasome and is approved for the treatment of multiple myeloma. Ubiquitin-conjugating enzyme E2 (UBE2K) is involved in the synthesis of K48-linked ubiquitin chains and is the target of certain drugs used for the treatment of tumors. The purpose of this study was to investigate the relationship between ixazomib and UBE2K in myeloma cells. Methods We used CCK-8 and Annexin V-FITC/propidium iodide kit to detect the effects of ixazomib on survival and apoptosis of RPMI-8226 and U-266 myeloma cell lines. Quantitative polymerase chain reaction and western blot were used to detect the change in gene and protein expression levels of myeloma cells treated with ixazomib. Furthermore, the regulatory effects of ixazomib on UBE2K and its downstream targets were investigated following the overexpression of UBE2K. Results In myeloma cells, ixazomib decreased cell survival and increased apoptosis in a dose-dependent manner. Ixazomib significantly increased the expression of HIST1H2BD, MNAT1, NEK3, and TARS2, while decreasing the expression of HSPA1B and UBE2K. In addition, ixazomib inhibited the proliferation of myeloma cells, blocked cell cycle, induced cell apoptosis, and increased the production of reactive oxygen species by inhibiting UBE2K expression. Lastly, ixazomib regulates mitosis- and apoptosis-related genes by lowering UBE2K expression. Conclusion In summary, ixazomib leads to impaired proliferation of myeloma cells by targeting UBE2K.