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Background: Early screening is critical for the prevention of ischemic stroke. miR-574–5p was considered a promising biomarker for ischemic stroke but lacks direct confirmation. This study evaluated miR-574–5p in discriminating ischemic stroke and predicting the severity and prognosis of patients, aiming to provide novel insights into the clinical prevention of ischemic stroke. Methods: The clinical significance of miR-574–5p was evaluated in 103 ischemic stroke patients with 87 healthy individuals as control. The potential of serum miR-574–5p in the diagnosis and prognosis of ischemic stroke was assessed by ROC and logistic regression analyses. In vitro, oxygen-glucose deprivation (OGD)-induced microglia was established. The regulation of inflammation, oxidative stress, and proliferation of microglia by miR-574–5p were assessed by cell transfection. The downstream targets of miR-574–5p were predicted from public databases, and the targeting relationship was evaluated by luciferase reporter assay. Results: Reducing serum miR-574–5p was observed in ischemic stroke patients relative to healthy individuals, which discriminated ischemic stroke patients. Serum miR-574–5p was negatively correlated with the NIHSS score of ischemic stroke patients and was identified as a risk factor for patients’ adverse prognosis. In OGD-induced microglia, overexpressing miR-574–5p could alleviate OGD-induced inflammation and oxidative stress and promote cell growth. Among predicted targets, ATP2B2 was upregulated in ischemic stroke and showed a negative correlation with miR-574–5p. miR-574–5p negatively regulated ATP2B2 in OGD-induced microglia, and the overexpression of ATP2B2 reversed the protective effect of miR-574–5p. Conclusion: miR-574–5p acted as a biomarker for ischemic stroke and mediated neuroinflammation via targeting ATP2B2.

ObjectivePatients with hematological malignancies have an elevated risk of developing pneumonia after contracting COVID-19. Lymphoma is the most prevalent hematologic malignancy. It is critical to identify patients at high risk of contracting COVID-19-associated pneumonia.MethodsFrom January 11–31, 2023, we distributed questionnaires to patients diagnosed with lymphoma according to 2016 World Health Organization diagnostic and classification criteria. COVID-19 infection was confirmed based on symptoms and laboratory tests. Pneumonia was confirmed using computed tomography scans.ResultsIn total, 257 patients were included in this study; 221 patients (86.0%) had COVID-19 infection and 61 (27.6%) of these had pneumonia. Patients with B-cell non-Hodgkin lymphoma (B-NHL) had a significantly higher pneumonia incidence than patients with other lymphoma types (31.8% vs. 27.6%, P=0.005). Higher incidence of pneumonia was observed in patients receiving anti-CD20 therapy (30.0% vs. 16.3%, P=0.048) and Bruton’s tyrosine kinase (BTK) inhibitor therapy (51.3% vs. 22.5%, P=0.001). B-NHL (hazard ratio [HR]=3.7, 95% confidence interval [CI] 1.4–10.0, P=0.009), anti-CD20 therapy (HR=2.3, 95% CI 1.0–5.2, P=0.050), BTK inhibitor (HR=3.6, 95% CI 1.8–7.4, P

Abstract To investigate the response of post-installed rebar connectors in steel frame retrofitted concrete structures under combined shear and tension, seven shear-and-tensile tests were conducted. The bearing capacity, stiffness, and hysteresis behavior of the connectors were investigated during the tests. Both Monotonic and cyclic load regimes were applied in the loading process. The results show that with the increase of the loading angle, the deformation capacity, the yield force, ultimate tensile force, and tensile stiffness of the specimen decrease, while the maximum shear force and shear stiffness of the specimen increase. The bearing capacity, stiffness, and energy dissipation performance of the specimen under a monotonic load is greater than that under the coupled shear-and-pull load. The bearing capacity, stiffness, hysteresis curve, and failure status of the specimens are not affected by different loading regimes. At the end, the design formula of anchor bolt for this type of connectors from the design code of China, United States, and Japan were compared. Formulas to calculate the shear strength under combined shear and tension is developed.

ABSTRACT Introduction The efficacy and safety of Ivabradine for patients with acute heart failure (AHF) is controversial, and there are few clinical trials addressing this topic. Methods We performed this meta‐analysis to evaluate efficacy and safety of Ivabradine treatment for patients with acute heart failure. We obtained data for controlled trials using the PubMed, Cochrane Library, EMBASE, and Clinical Trials.gov databases. The efficacy endpoints included change in heart rate, brain natriuretic peptide (BNP) levels, N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) levels, ejection fraction (EF) values, and a 6‐min walk distance. The safety endpoints included mortality, cardiogenic mortality, incidents of hospital readmission, bradycardia, and atrial fibrillation. Ten randomized controlled trials (RCTs) met our criteria, and data from 656 patients were included for the study. Results Ivabradine treatment significantly decreased heart rate and BNP and NT‐proBNP levels compared with those seen in the control group. EF values were significantly increased upon ivabradine treatment. No significant differences were observed in the endpoints of the 6‐min walk distance, all‐cause mortality, cardiogenic mortality, incidents of hospital readmission, bradycardia, and atrial fibrillation data between ivabradine treated and control groups. Conclusions Ivabradine can reduce heart rate and BNP and NT‐pro BNP levels and elevate EF values and 6‐min walk distance data significantly in acute heart failure patients. It also exhibits a stable safety profile, with similar risks of all‐cause mortality, cardiogenic mortality, incidents of readmission, and major adverse cardiovascular effects compared with those of the control group.

Abstract Sequestering CO2 in depleted oil reservoirs provides one of the most appealing measures to reduce greenhouse gases (GHG) concentration in the atmosphere. The remaining liquids after enhanced oil recovery (EOR) processes, including residual oil and remaining water, lead to the main challenges to this approach. How to effectively evacuate a depleted oil reservoir by recovering not only residual oil but also remaining water is a critical consideration for this type of CO2 sequestration. This paper presents conceptual investigations concerning the methods which effectively evacuate depleted oil reservoirs from both the displacement efficiency and the sweep efficiency points of view. To improve the displacement efficiency, surfactant slug and solvent slug injection was examined using a core scale numerical model. Investigations regarding improving sweep efficiency, such as horizontal well pattern infilling and foam injection, were carried out based on a typical row well pattern. Simulation results showed that surfactant slug which modified the relative permeability and capillary pressure remarkably reduced both residual oil saturation and remaining water saturation. A CO2 slug injected before surfactant slug can help improve the oil recovery. Solvent enriched CO2 slug also remarkably reduced the residual oil saturation to as low as 2%. Horizontal well pattern infilling had great advantage for thick or inclined reservoirs, and foam slug injection greatly improved CO2 storage capacity in thin reservoirs by improving the sweep efficiency. Maximum mobility reduction (MRF) is the most important parameter to maximize the storage capacity and the benefit. The variation of CO2 storage capacity along with CO2 slug size. Larger foam slug size will play a better storage performance. The conceptual simulation investigations confirmed that depleted oil reservoirs can be effectively evacuated for CO2 storage. Depleted oil reservoirs with maximum evacuation are the best candidates for CO2 sequestrations.

Abstract Background Uniparental disomy is the inheritance of a homologous chromosome pair or part of homologous chromosomes from only one parent. However, the clinical significance of uniparental disomy and the difference among the prognosis of involvement of different chromosomes remain unclear. Objective To assess the associated prenatal ultrasound presentations and clinical outcomes of uniparental disomy on different chromosomes and to analyze the relationship between prenatal ultrasound markers and clinical outcomes. Study design We retrospectively analyzed data from fetuses with uniparental disomy diagnosed using chromosome microarray analysis with the Affymetrix CytoScan HD array at our institution between January 2013 and September 2022. The relationship between prenatal ultrasound findings, the involved chromosome(s), and clinical outcomes was evaluated. Results During the study period, 36 fetuses with uniparental disomy were diagnosed, and two cases were excluded for non-available postnatal data. Finally, 34 fetuses were included in our study, of which 30 (88.2%) had uniparental disomy occurring on a single chromosome, while four (11.8%) were identified with uniparental disomy on different chromosomes. The most frequently involved chromosomes were chromosomes 16, X and 2, which presented in 8 (23.5%), 5 (14.7%) and 4 (11.8%), respectively. Prenatal ultrasound abnormalities were detected in 21 fetuses, with the most common category being multiple abnormalities (12 (57.1%)). Fetal growth restriction was identified in 14 (41.2%) fetuses, all of which coexisted with other abnormal findings. The rate of adverse perinatal outcomes in patients with uniparental disomy and fetal abnormalities was significantly higher than those without abnormalities (76.2% versus 15.4%, P = 0.002). The incidence of fetal or neonatal death was significantly higher in fetuses with fetal growth restriction than those without (85.7% versus 30.0%, P = 0.004). Conclusions The prognosis of fetuses with uniparental disomy combined with fetal abnormalities, especially fetal growth restriction, was much poorer than those without.

Senescence is an intricate physiological progression that can be instigated by a multiplicity of factors. Aberrant cellular senescence is capable of precipitating a substantial array of diseases. During chemotherapy, drugs typically tend to gradually accumulate in the liver, thereby inducing liver senescence and leading to a successive deterioration in its physiological function. β-galactosidase (β-gal), serving as a significant index in the exploration of senescence, has attracted considerable attention. In this study, a fluorescence/photoacoustic (FL/PA) biomodal probe (Gal-QCS) was developed based on a hemicyanine fluorophore for the imaging of β-gal in the process of drug-induced liver senescence. Gal-QCS demonstrates rapid responsiveness, high sensitivity, and remarkable selectivity in detecting β-gal in aqueous solutions. After incubation with β-gal, the fluorescence signal at 810 nm significantly increases, and concurrently, the photoacoustic signal at 775 nm also exhibits a substantial increment. Upon the induction of cell senescence with camptothecin, Gal-QCS can expeditiously and selectively image senescent cells. Moreover, after administering this probe to mice with liver senescence, the FL/PA signals in the livers of senescent mice were enhanced by 10.53-fold and 1.43-fold, respectively. This work robustly substantiates the potential and application prospects of Gal-QCS in detecting drug-induced liver senescence, with β-gal serving as a biomarker.

Abstract Endometrial cancer (EC) stands as the most prevalent gynecological tumor in women worldwide. Notably, differentiation diagnosis of abnormity detected by ultrasound findings (e.g., thickened endometrium or mass in the uterine cavity) is essential and remains challenging in clinical practice. Herein, we identified a metabolic biomarker panel for differentiation diagnosis of EC using machine learning of high-performance serum metabolic fingerprints (SMFs) and validated the biological function. We first recorded the high-performance SMFs of 191 EC and 204 Non-EC subjects via particle-enhanced laser desorption/ionization mass spectrometry (PELDI-MS). Then, we achieved an area-under-the-curve (AUC) of 0.957–0.968 for EC diagnosis through machine learning of high-performance SMFs, outperforming the clinical biomarker of cancer antigen 125 (CA-125, AUC of 0.610–0.684, p

Objective To investigate the relationship between the thresholds of intraoperative facial nerve response and postoperative facial nerve function recovery in patients with Bell's palsy. Methods Clinical data from Bell's palsy patients who underwent facial nerve decompression surgery at Beijing Tiantan Hospital from October 2015 to October 2022 were collected. The patients selected for analysis had intraoperative facial nerve monitoring with accurate recording of the facial nerve direct stimulation threshold and at least 1 year of detailed follow-up. The patients with postoperative facial nerve function recovery to grade Ⅰ-Ⅱ (HB grading) were defined as having good recovery, while those recovering to grade Ⅲ or higher were defined as having poor recovery. The patients were divided into two groups (A and B) according to facial nerve reaction excitability, with group A having a direct stimulation threshold of ≤1.5 mA and group B having a direct stimulation threshold of > 1.5 mA or a stimulation volume up to 3 mA without being able to record neural response waveform. The relationship between postoperative facial nerve function recovery and facial nerve direct stimulation threshold was analyzed. Results A total of 36 Bell's palsy patients were included in this study, who underwent facial nerve decompression surgery through the transmastoid-epitympanum approach within 1-3 months after onset. Of the 36 patients, 24 (66.7%) had good recovery and 12 (33.3%) had poor recovery. Only 20 (55.6%, 20/36) patients had facial nerve direct stimulation threshold recorded during the operation, and all were ≤1.5 mA(0.1-1.5 mA). The reaction waveforms of 16 (44.4%, 16/36) patients could not be recorded even when facial nerve stimulation increased to 3 mA. There was no significant difference in age, gender, lateral discourse, timing of surgery, and preoperative electroneurography (ENoG) between the two groups(all P > 0.05), but the good recovery rate of the patients in group A was significantly higher than that in group B, and the difference was statistically significant (P=0.009). Conclusion For patients with Bell's palsy undergoing decompression surgery of the facial nerve, the intraoperative direct stimulation threshold of the facial nerve may have some predictive value for postoperative facial nerve function recovery.

IntroductionThis study investigates the intricate relationship between parents’ education anxiety and children’s learning anxiety, examining the mediating role of parenting style and the moderating effect of extracurricular tutoring.MethodsUtilizing data from the “Survey of Parents and Students in Primary and Secondary Schools,” the study employs stratified sampling (n = 3,298) and various psychological scales to measure education anxiety, parenting styles, and extracurricular tutoring.ResultsThis study reveals that parents’ education anxiety significantly influences children’s learning anxiety, with a notable positive correlation (r = 0.301**). Parenting styles particularly rejection and overprotection style increase this anxiety, while emotional warmth style decreases it. Academic tutoring serves as a moderator, reducing the impact of parental anxiety on children’s learning anxiety (β = −0.033, p

Summary: Bronchoscopic-assisted discrimination of lung tumors presents challenges, especially in cases with contraindications or inaccessible lesions. Through meta-analysis and validation using the HumanMethylation450 database, this study identified methylation markers for molecular discrimination in lung tumors and designed a sequencing panel. DNA samples from 118 bronchial washing fluid (BWF) specimens underwent enrichment via multiplex PCR before targeted methylation sequencing. The Recursive Feature Elimination Cross-Validation and deep neural network algorithm established the CanDo classification model, which incorporated 11 methylation features (including 8 specific to the TBR1 gene), demonstrating a sensitivity of 98.6% and specificity of 97.8%. In contrast, bronchoscopic rapid on-site evaluation (bronchoscopic-ROSE) had lower sensitivity (87.7%) and specificity (80%). Further validation in 33 individuals confirmed CanDo’s discriminatory potential, particularly in challenging cases for bronchoscopic-ROSE due to pathological complexity. CanDo serves as a valuable complement to bronchoscopy for the discriminatory diagnosis and stratified management of lung tumors utilizing BWF specimens.

Abstract Background and Aim To evaluate the efficacy and safety of minocycline, vonoprazan, amoxicillin, and bismuth quadruple therapy for Helicobacter pylori (H. pylori) treatment. Methods From August 2022 to May 2023, clinical data were collected from patients who received H. pylori eradication treatment at West China Fourth Hospital, Sichuan University. One group received the MVAB regimen (amoxicillin, minocycline, vonoprazan, and colloidal bismuth pectin), while another group received the FOAB regimen (amoxicillin, furazolidone, omeprazole, and colloidal bismuth pectin), both administered for 14 days. Follow‐up assessments of safety and compliance were conducted within 1 week after treatment completion. One and a half months after treatment, the success of eradication was evaluated using the urea breath test. Results For the MVAB regimen as a first‐line treatment, the eradication rate was 90.1% (127/141, 95% CI: 85.1–95.1%) in the ITT analysis and 93.4% (127/136, 95% CI: 89.2–97.6%) in the PP analysis as a first‐line treatment. As a second‐line treatment, the eradication rate was 91.3% (21/23, 95% CI: 78.8–103.8%) in both analyses. For the FOAB regimen as a first‐line treatment, the eradication rate was 98.0% (50/51, 95% CI: 94.1–101.2%) in the ITT analysis and 100% (50/50, 95% CI: 100%) in the PP analysis. As a second‐line treatment, the eradication rate was 100% (6/6, 95% CI: 100%) in both analyses. Moreover, there was no significant difference in the incidence of adverse events between the two groups (MVAB regimen: 5.5% and FOAB regimen: 8.8%; P > 0.05). Conclusions The MVAB regimen could indeed be a viable alternative treatment option to conventional therapies.

Following the recent report by Dasenbrock-Gammon et al. [Nature 615, 244–250 (2023)] of near-ambient superconductivity in nitrogen-doped lutetium trihydride (LuH3−δNε), significant debate has emerged surrounding the composition and interpretation of the observed sharp resistance drop. Here, we meticulously revisit these claims through comprehensive characterization and investigations. We definitively identify the reported material as lutetium dihydride (LuH2), resolving the ambiguity surrounding its composition. Under similar conditions (270–295 K and 1–2 GPa), we replicate the reported sharp decrease in electrical resistance with a 30% success rate, aligning with the observations by Dasenbrock-Gammon et al. However, our extensive investigations reveal this phenomenon to be a novel pressure-induced metal-to-metal transition intrinsic to LuH2, distinct from superconductivity. Intriguingly, nitrogen doping exerts minimal impact on this transition. Our work not only elucidates the fundamental properties of LuH2 and LuH3, but also critically challenges the notion of superconductivity in these lutetium hydride systems. These findings pave the way for future research on lutetium hydride systems, while emphasizing the crucial importance of rigorous verification in claims of ambient-temperature superconductivity.

Abstract Purpose Ovarian clear cell carcinoma (OCCC) is a distinct and highly malignant subtype of ovarian cancer with high individual heterogeneity in survival that requires specific prognostic predictive tools. Thus, this study aimed to construct and validate nomograms for predicting individual survival in OCCC patients. Methods In total, 91 patients with OCCC who were diagnosed and treated at Renji Hospital between 2010 and 2020 were extracted as the training cohort, then 86 patients from the First Affiliated Hospital of USTC were used as the external validation cohort. Prognostic factors that affect survival were identified using least absolute shrinkage and selection operator regression. Nomograms of progression‐free survival (PFS) and overall survival (OS) were then established with the Cox regression model and the performance was subsequently evaluated using the concordance index (C‐index), calibration plots, decision curve analysis (DCA), and risk subgroup classification. Results Advanced tumor, ascites of >400 mL, lymph node‐positive, CA199 of >142.3 IU/mL, and fibrinogen of >5.36 g/L were identified as risk factors for OS while advanced tumor, ascites of >400 mL, lymph node‐positive, and fibrinogen of >5.36 g/L were risk factors for PFS. The C‐indexes for the OS and PFS nomograms were 0.899 and 0.731 in the training cohort and 0.804 and 0.787 in the validation cohort, respectively. The calibration plots showed that nomograms could provide better consistency in predicting patient survival than the FIGO staging system. DCA also demonstrated that nomograms were more clinically beneficial than the FIGO staging system. Additionally, patients could be classified into two risk groups based on scores using nomograms, with significant survival differences. Conclusions We developed nomograms that could more objectively and reliably predict the individual survival of patients with OCCC compared with the FIGO staging system. These tools might assist in clinical decision‐making and management of patients with OCCC to improve their survival outcomes.

Seismic deconvolution is a useful tool in seismic data processing. Classical non-machine learning deconvolution methods usually apply quite a few constraints to both wavelet inversion and reflectivity inversion. Supervised machine learning deconvolution methods often require appropriate training labels. The existing self-supervised machine learning deconvolution methods need a given wavelet, which is a non-blind process. To overcome these issues, we propose a blind deconvolution method based on self-supervised machine learning. This method first estimates an initial zero-phase wavelet by smoothing the amplitude spectrum of averaged seismic data. Then, the loss function of self-supervised machine learning is taken as the error between the observed seismic data and the reconstructed seismic data that come from the convolution of phase-rotated wavelet and reflectivity generated by the network. We utilize a residual neural network with long skip connections as the reflectivity inversion network and a fully connected convolutional neural network as the wavelet phase inversion network. Numerical experiments on synthetic data and field data show that the proposed method can obtain reflectivity inversion results with higher resolution than the existing self-supervised machine learning method without given wavelet.

Abstract Background Fetal growth restriction (FGR) occurs in up to 10% of pregnancies and is a leading cause of perinatal mortality and neonatal morbidity. Three-dimensional ultrasonography of intracranial structure volume revealed significant differences between fetuses with FGR and appropriate for gestational age (AGA) fetuses. We aimed to compare the frontal lobe development between fetuses with FGR and appropriately grown fetuses and evaluate the impact of fetal circulatory redistribution (FCR) on frontal lobe development in fetuses with FGR. Methods We performed a case–control study at our institution from August 2020 to April 2021. The frontal antero-posterior diameter (FAPD) and occipito-frontal diameter (OFD) were measured on the trans-ventricle view and we calculated the Z-scores for FAPD and OFD standardized for gestational age (GA) and transverse cerebellar diameter (TCD) by performing a standard regression analysis followed by weighted regression of absolute residual values in appropriately grown fetuses. We calculated the FAPD/OFD ratio as 100 × FAPD/OFD and FAPD/HC (head circumference) as 100 × FAPD/HC. To compare intracranial parameters, we randomly selected a control group of appropriately grown fetuses matched with the FGR group at the time of ultrasonography. We performed between-group comparisons of the FAPD Z-score, OFD Z-score, FAPD/OFD ratio and FAPD/HC. Similarly, we compared intracranial parameters between fetuses with FGR with and without FCR. Results FAPD/OFD ratio was curvilinear related to all the independent variables (GA, BPD, FL, and TCD). Compared with appropriately grown fetuses, fetuses with FGR showed a significantly lower FAPD/OFD ratio, FAPD Z-score, and FAPD/HC. There was no significant difference in the FAPD Z-score, FAPD/OFD ratio, and FAPD/HC between FGR fetuses with and without FCR. Conclusions The FAPD/OFD ratio varied during pregnancy, with a mild reduction before and a mild increase after about 33 gestational weeks. Fetuses with FGR showed reduced frontal lobe growth; moreover, fetal frontal lobe development disorders were not significantly different in fetuses with FCR. Trial registration Date: 09–27-2017; Number: [2017]239.

Summary: The tumor heterogeneity, which leads to individual variations in tumor microenvironments, causes poor prognoses and limits therapeutic response. Emerging technology such as companion diagnostics (CDx) detects biomarkers and monitors therapeutic responses, allowing identification of patients who would benefit most from treatment. However, currently, most US Food and Drug Administration-approved CDx tests are designed to detect biomarkers in vitro and ex vivo, making it difficult to dynamically report variations of targets in vivo. Various medical imaging techniques offer dynamic measurement of tumor heterogeneity and treatment response, complementing CDx tests. Imaging-based companion diagnostics allow for patient stratification for targeted medicines and identification of patient populations benefiting from alternative therapeutic methods. This review summarizes recent developments in molecular imaging for predicting and assessing responses to cancer therapies, as well as the various biomarkers used in imaging-based CDx tests. We hope this review provides informative insights into imaging-based companion diagnostics and advances precision medicine.

ABSTRACT The prevalence of superbugs, represented by methicillin-resistant Staphylococcus aureus (MRSA), has become a serious clinical and public safety concern with rising incidence in hospitals. Polyketides with diverse chemical structures harbor many antimicrobial activities, including those of rifampin and rapamycin against MRSA. Streptomyces sp. QHH-9511 was isolated from a niche habitat in the Qinghai-Tibet Plateau and used to produce antibacterial metabolites. Herein, an integrated approach combining genome mining and metabolic analysis were employed to decipher the chemical origin of the antibacterial components with pigmented properties in strain QHH-9511, a novel Streptomyces species from a lichen symbiont on the Qinghai-Tibet Plateau. Genomic phylogeny assembled at the chromosome level revealed its unique evolutionary state. Further genome mining uncovered 36 candidate gene clusters, most of which were uncharacterized. Meanwhile, based on liquid chromatography coupled to diode array detection mass spectrometry, a series of granaticins, BSMs, chromones, phaeochromycins, and related molecules were discovered by using the Global Natural Product Social molecular networking platform. Subsequently, several pigment compounds were isolated and identified by high-resolution mass spectrometry and/or nuclear magnetic resonance, among which the structure-activity relationships of seven aromatic polyketides showed that the fused lactone ring of the C-2 carboxyl group could increase antibacterial activity. Genetic experiments indicated that all seven aromatic polyketides are a series of metabolic shunts produced by a single type II polyketide synthase (PKS) cluster. Comparative genomic analysis of granaticin producers showed that the granaticin gene cluster is widely distributed. This study provides an efficient method to combine genome mining and metabolic profiling techniques to uncover bioactive metabolites derived from specific habitats, while deepening our understanding of aromatic polyketide biosynthesis. IMPORTANCE Undescribed microorganisms from special habitats are being screened for anti-superbug drug molecules. In a project to screen actinomycetes for anti-MRSA activity, we isolated a Streptomyces strain from Qinghai Lake lichens. The phylogeny based on the genome assembled at the chromosome level revealed this strain's unique evolutionary state. The chemical origins of the antibacterial components with pigment properties in strain QHH-9511 were determined using an integrated approach combining genome mining and metabolic analysis. Further genome mining uncovered 36 secondary metabolite gene clusters, the majority of which were previously unknown. A series of aromatic compounds were discovered using molecular network analysis, separation, and extraction. Genetic experiments revealed that all seven aromatic polyketides are a series of metabolic shunts produced by a single cluster of type II PKSs. This study describes a method for identifying novel Streptomyces from specific habitats by combining genome mining with metabolic profiling techniques.

Background. Thoracoscopic lung cancer surgery is accompanied by severe pain. Both continuous paravertebral block (CPVB) and continuous wound infiltration (CWI) are widely used for perioperative analgesia in thoracoscopic surgery. However, the effects of these different methods on chronic postsurgical pain (CPSP) are still unknown. Patients and Methods. This prospective randomized controlled trial assessed the eligibility of 113 patients. Ninety-seven patients who met the inclusion criteria were randomly divided into a CPVB group and a CWI group, and 80 patients were analyzed in the final study. The primary outcome measures were the incidence and intensity of chronic postsurgical pain (CPSP) at 3, 6, and 9 months after surgery. The secondary outcome measures were the numerical rating scale (NRS) score of rest and activity at 12, 18, and 24 hours and on the 2nd, 3rd, and 7th days postoperatively; the Barthel Activities of Daily Living (ADL) score of activity levels on the 1st, 2nd, 3rd, and 7th days postoperatively; and the long-term quality of the life score at 3, 6, and 9 months postoperatively. Results. The incidence of chronic postsurgical pain in the CWI group was significantly higher than that in the CPVB group at 3, 6, and 9 months after surgery (all P

Shaken Hunan black tea is an innovative Hunan black tea processed by adding shaking to the traditional Hunan black tea. The quality of shaken black tea is influenced by leaf grades of different maturity. In this study, the taste and aroma quality of shaken Hunan black tea processed with different grades were analyzed by sensory evaluation (SP, HPLC, and HS-SPME/GC-MS). The results showed that shaken Hunan black tea processed with one bud and two leaves has the best quality, which has a sweet, mellow, and slightly floral taste, as well as a floral, honey, and sweet aroma. Moreover, caffeine and EGCG were identified as the most important bitter and astringent substances in shaken Hunan black. Combined with the analysis of GC-MS and OAV analysis, geraniol, jasmone, β-myrcene, citral, and trans-β-ocimene might be the most important components that affect the sweet aroma, while methyl jasmonate, indole, and nerolidol were the key components that affect the floral aroma of shaken Hunan black tea. This study lays a foundation for this study of the taste and aroma characteristics of shaken Hunan black tea and guides enterprises to improve shaken black tea processing technology.

Noise pollution has been a burden to the global economy, environment, and human health. Here the authors demonstrate a facile route to produce flexible ceramic nanofibrous sponges with hierarchically entangled graphene networks and its excellent noise absorption properties at elevated temperatures.

Objective To analyze the clinical effects of modified infratemporal fossa type A approach for glomus jugulare tumors. Methods The clinical data of patients with glomus jugulare tumors who received modified infratemporal fossa approach type A from May 2014 to December 2019 were retrospectively collected in the Beijing Tiantan Hospital, Capital Medical University. Modified infratemporal fossa approach type A was performed and improved on two aspects: anterior transfer of facial nerve and management of sigmoid sinus. CT was performed 6 hours after surgery to exclude intracranial hemorrhage. MRI was reviewed 2 weeks after surgery to define residual tumor, and every year to determine recurrence. Follow-up was conducted to assess the facial nerve function. Results A total of 39 patients were included in this study. Patients' grades of preoperative facial nerve function according to House-Brackmann (HB) were as following: grade Ⅰ in 12 patients, grade Ⅱ in 6 cases, grade Ⅲ in 8 cases, grade Ⅳ in 9 cases, grade Ⅴ in 3 cases, and grade Ⅵ in 1 case. All 39 patients successfully completed surgery, and there were no deaths and no severe complications such as hemiplegia, or intracranial infections. Cerebrospinal fluid leakage occurred in 1 case and drainage was performed. There was no intracranial hemorrhage in the CT exam 6 hours after surgery. Total resection was performed in 37 cases (94.9%) and nearly total resection in 2 cases (5.1%). The postoperative facial function after 1 year was HB grade Ⅰ in 8 patients, grade Ⅱ in 16 cases, grade Ⅲ in 9 cases, grade Ⅳ in 4 cases, grade Ⅴ in 2 cases. The facial function was improved after the surgery(P < 0.05). One year after surgery, tumor recurrence occurred in 1 patient and radiotherapy was performed. There was no significant tumor enlargement during follow-up. Conclusions The modified infratemporal fossa approach type A keeps the advantage of classical approach. By adjusting the anterior transfer of the facial nerve, the preservation of facial nerve function was improved. By compressing the sigmoid sinus instead of ligation, the occurrence of brain injury and cerebrospinal fluid leakage were reduced.

Acoustic neuroma is the most common benign tumor in the internal auditory canal and cerebellopontine region.Its common clinical symptoms include unilateral sensorineural hearing loss, tinnitus and so on.Surgical resection is the predominant treatment of acoustic neuroma. The common approaches dominated by otologists include translabyrinthine approach, enlarged translabyrinthine approach, transotic approach, modified transotic approach, and middle cranial fossa approach; the approach dominated by neurosurgeons is retrosigmoid (suboccipital) approach. For small tumors with intact hearing, it is recommended to choose the middle cranial fossa approach. Those with large tumors who wish to preserve their hearing can adopt the suboccipital retrosigmoid approach; those who do not consider retaining hearing and have medium or small acoustic neuromas can adopt the translabyrinthe approach or through the transotic approach. With the development of microsurgical technology and the wide application of intraoperative nerve monitoring equipment, the retention rate of facial/cochlear nerve function for surgery of small and medium-sized acoustic neuroma has been significantly improved. In the future, more patients with acoustic neuroma are expected to be completely cured on the basis of preserving facial/cochlear nerve function.

Head and neck paragangliomas(HNPGL) are rare neurogenic tumors, in which genetic factors play a certain role. So far, 10 genes related to HNPGL(SDHA, SDHB, SDHC, SDHD, SDHAF2, VHL, HIF2A, RET, NF1 and TMEM127) have been found. The clinical phenotypes of different gene mutations are different. SDHD, SDHC and SDHAF2 gene mutations are almost 100% related to HNPGL. SDHD and SDHAF2 gene mutations tend to form multiple paragangliomas, and its genetic pattern has obviously maternal imprinting. SDHB mutations have sympathetic paraganglioma and malignant tendency. Understanding the molecular mechanism and genotype-phenotypic relationship of paraganglioma can provide significant help for genetic counseling, diagnosis and treatment, and development of follow-up strategies in patients with HNPGL.

Objective:To observe the effects of exercise preconditioning on cardiac function, myocardial infarct area, cardiomyocyte ultrastructure and antioxidant capacity of aged rats after isolated myocardial ischemia-reperfusion injury.Methods:A total of 60 SPF male SD aged rats were randomly divided into the control group (Con group), the ischemia-reperfusion model group (IR group), the exercise preconditioning+ischemia-reperfusion group (EP+IR group), the ischemic preconditioning group (IPC group) and the exercise preconditioning+ischemic preconditioning group (EP+IPC group), with 12 rats in each group. The Con group, IR group and IPC group received no special exercise intervention, while the EP+IR group and the EP+IPC group received exercise preconditioning intervention (using electric animal experimental treadmill for gradient exercise training, once a day, five days a week, continuous training for six weeks). The isolated myocardial ischemia-reperfusion model of aged rats was made by using Langendorff device. The details were as follows: the Con group only received isolated myocardial perfusion, continuous balance perfusion for 180 minutes without ischemia operation; the IR group balanced preperfusion for 20 minutes, and then kept the heart temperature constant at 37℃, the whole heart was subjected for 40 minutes by controlling the three-way valve of the perfusion equipment, and then reperfusion for 120 minutes; After rats'heart were separated, the model preparation method of the EP+IR group was the same as the IR group; After balance perfusion for 20 minutes in vitro, the hearts of rats in the IPC group received ischemia preconditioning for three times (transient ischemia for 5 minutes, followed by reperfusion for 10 minutes), followed by ischemia for 40 minutes, and then was reperfused for 120 minutes; the model preparation method of the EP+IPC group was the same as the IPC group. The changes of cardiac function were recorded by multi-channel physiological recorder before reperfusion and after reperfusion for 30, 60 and 120 minutes; the TTC staining was used to determine infarct area, the colorimetry was used to determine the activity of LDH in coronary effluent, MDA content and SOD activity in myocardial tissue.Results:①Indexes of cardiac function: compared with the Con group at the same time, the indexes of cardiac function[heart rate (HR), left ventricular developed pressure (LVDP), ±dp/dtmax, coronary flow (CF) ]decreased significantly in the IR group before reperfusion and after reperfusion for 30, 60 and 120 min. Compared with the IR group at the same time, the indexes of cardiac function in the EP+IR, IPC and EP+IPC group increased significantly after reperfusion for 30, 60 and 120 min (P< 0.05). Compared with the IPC group at the same time, the indexes of cardiac function (such as HR, LVDP, ±dp/dtmax, CF) after reperfusion for 30, 60 and 120 min in the EP+IPC group were significantly higher (P< 0.05). ②Myocardial infarct area: compared with the Con group, the myocardial infarct area in the IR group increased significantly (P< 0.05); compared with the IR group, the myocardial infarct area in the EP+IR, IPC and EP+IPC group decreased significantly (P< 0.05). ③LDH activity, MDA content and SOD activity: compared with the Con group, LDH activity in the IR group was significantly higher (P< 0.05); compared with the IR group, LDH activity in EP+IR, IPC and EP+IPC group was lower (P< 0.05); compared with the EP+IR, IPC group, the LDH activity in the EP+IPC group was significantly lower (P< 0.05). Compared with the Con group, MDA content of the IR group increased significantly and SOD activity of the IR group decreased significantly (P< 0.05); compared with the EP+IR, IPC group, MDA content of the EP+IPC group was significantly lower and SOD activity of the EP+IPC group was significantly higher (P< 0.05).Conclusion:Exercise preconditioning can induce the protective effect of IPC in aged myocardium, improve effectively the cardiac function of aged rats with myocardial ischemia-reperfusion injury, reduce the area of myocardial infarction and alleviate cardiomyocyte injury, which may be related to the decrease of myocardial LDH activity and MDA content, the increase of SOD activity and the enhancement of myocardial antioxidant capacity during myocardial ischemia-reperfusion.

Objective. Cardiopulmonary exercise testing (CPET) has been used to explore the blood pressure response and potential cardiovascular system structure and dysfunction in male patients with essential hypertension during exercise, to provide a scientific basis for safe and effective exercise rehabilitation and improvement of prognosis. Methods. A total of 100 male patients with essential hypertension (aged 18–60) who were admitted to the outpatient department of the Center for Diagnosis and Treatment of Cardiovascular Diseases of Jilin University from September 2018 to January 2021 were enrolled in this study. The patients had normal cardiac structure in resting state without clinical manifestations of heart failure or systematic regularization of treatment at the time of admission. Symptom-restricted CPET was performed and blood pressure was measured during and after exercise. According to Framingham criteria, male systolic blood pressure (SBP) ≥210 mmHg during exercise was defined as exercise hypertension (EH), and the subjects were divided into EH group (n = 47) and non-EH group (n = 53). Based on whether the oxygen pulse (VO2/HR) plateau appeared immediately after anaerobic threshold (AT), the EH group was further divided into the VO2/HR plateau immediately after AT (EH-ATP) group (n = 19) and EH-non-ATP group (n = 28). The basic clinical data and related parameters, key CPET indicators, were compared between groups. Result. Body mass index (BMI) visceral fat, resting SBP, and SBP variability in EH group were significantly higher than those in non-EH group. Moreover, VO2/HR at AT and the ratio of VO2/HR plateau appearing immediately after AT in EH group were significantly higher than those in the non-EH group. The resting SBP, 15-minute SBP variability, and the presence of VO2/HR plateau were independent risk factors for EH. In addition, work rate (WR) at AT but also WR, oxygen consumption per minute (VO2), VO2/kg, and VO2/HR at peak were significantly lower in the EH-ATP group compared to the EH-non-ATP group. Peak diastolic blood pressure (DBP) increment and decreased △VO2/△WR for AT to peak were independent risk factors for VO2/HR plateau appearing immediately after AT in EH patients. Conclusion. EH patients have impaired autonomic nervous function and are prone to exercise-induced cardiac dysfunction. EH patients with exercise-induced cardiac dysfunction have reduced peak cardiac output and exercise tolerance and impaired vascular diastolic function. CPET examination should be performed on EH patients and EH patients with exercise-induced cardiac dysfunction to develop precise drug therapy and effective individual exercise prescription, to avoid arteriosclerosis and exercise-induced cardiac damage. The retrospective study protocol was approved by medical ethics committee of the First Hospital of Jilin University (AF-IRB-032-06 No. 2021-015). The study was registered with the Chinese Clinical Trials Register, registration number: ChiCTR2100053140.

Polyvinyl alcohol (PVA) is a commonly used emulsifier for the preparation of DL-lactide-co-glycolide (PLGA) and polylactic acid (PLA) microspheres with sustained-release profile. Although water-soluble PVA is normally considered to have low toxicity, monitoring residual level of PVAs is still necessary, especially for the chronic disease treatment medications containing PVA. In this study, a robust and validated method was developed for the determination of PVA using high-performance liquid chromatography (HPLC) and refractive index detector (RID). PVA in sustained-release microspheres containing PLGA, aripiprazole, mannitol, and PVA as active substances was analyzed by size exclusion chromatography (SEC) using acetonitrile/water/trifluoroacetic acid (TFA) (300 : 700 : 1; v/v/v) as mobile phase at a flow rate of 0.5 mL/min. The retention time was 11.2 min and PVA was well separated with other components with good linearity (r2 = 0.9997) in the range of 2.5∼75 μg/mL. The limit of detection (LOD) was 0.51 μg/mL and the limit of quantification (LOQ) was 2.53 μg/mL. The relative standard deviations of intra- and interday precision under different concentrations were not more than 2.1%, and the recoveries were all in the ranges of 95∼105%. The established method has been demonstrated to be accurate, precise, repeatable, specific, and robust and, therefore, suitable for routine analysis of PVA in not only pharmaceutical field but also food and textile industries.

The physical-informed neural network (PINN) model can greatly improve the ability to fit nonlinear data with the incorporation of prior knowledge, which endows traditional neural networks with interpretability. Considering the seepage law in the tight reservoir after hydraulic fracturing, a model based on PINN and two-dimensional seepage physical equations was proposed, which can effectively predict the flow field distribution of the tight reservoir after fracturing. Firstly, the dataset was obtained based on physical and numerical models of the tight reservoirs developed by volume fracturing. Furthermore, coupling the neural networks and the two-dimensional unsteady seepage equation, a PINN model was developed to predict the flow field distribution of the tight reservoir. Finally, a systematic study was performed concerning the noise corruption levels, training iterations, and training sample size that affect the prediction results of PINN models. Besides, a comparison between PINN and traditional deep neural networks (DNN) was presented. The results show that the DNN model was not only sensitive to noisy data but also more vulnerable to overfitting as the training iterations increase. In addition, the prediction accuracy cannot be guaranteed when the samples are inadequate (

With the rapid development of China's social economy and the rise of agricultural industrialization, the problem of agricultural non-point source pollution is becoming increasingly prominent. Reducing nitrogen and phosphorus nutrients in agricultural runoff is the key to control agricultural non-point source pollution, and it is also a hot research topic at home and abroad. The traditional methods to remove nitrogen and phosphorus nutrients in agricultural runoff mainly include ecological ditch, ecological buffer zone, and constructed wetland, etc. At present, ecological ditch, ecological buffer zone and constructed wetland are widely used in the treatment of agricultural runoff, while Microbial Fuel Cell (MFC) technology and biofilm-electrode reactor (BER) have gained wide attention in recent years, it is the key technology of agricultural runoff treatment and has been widely recognized in the world. The purpose of this text is to explore the mechanism and technology of nutrient removal from farmland wastewater by in-situ biological treatment.

With the development of aging society, the number of stroke patients in China has been rising steadily, and ischemic stroke accounts for a large proportion. At present, the problem of ischemic stroke has aroused wide public concern. China is facing an increasingly severe situation of prevention and treatment, and the disease has brought a heavy burden to patients, families and even the whole society, which has become one of the focuses and difficulties of modern medical research. Many studies have shown that inflammatory response plays an important role in the occurrence and development of ischemic stroke and participates in the process of pathological injury. At the same time, inflammatory response in the late stage to participate in the recovery of the disease, to protect and repair the nerve, play a dual role. Inflammatory response may be one of the targets in the treatment of ischemic stroke and has a significant research value. Inflammatory response is an important part of physiological and pathological changes of ischemic stroke, which determines the transformation and prognosis of stroke. Immunotherapy for inflammatory response is one of the hot spots at present, with a broad prospect. FasL, microglia and T lymphocytes are involved in the process of ischemic stroke and are closely related to inflammatory response. FasL can induce cell apoptosis and immune inflammatory response, and microglia and T lymphocytes all play protective or damaging roles to varying degrees, which can greatly broaden the treatment thinking and plan of ischemic stroke and meet the diversified challenges in the treatment of stroke. Therefore, FasL, microglia and T lymphocytes can be used to further explore the relationship between inflammatory response and ischemic stroke, providing a solid theoretical basis for clinical promotion and application. This article reviews the research progress of immune inflammatory response stage in ischemic stroke and its relationship with FasL, microglia and T lymphocytes.

Objective:To explore the protective effect of exercise preconditioning on myocardial ischemia-reperfusion injury (MIRI) in rats and its mechanism based on autophagy.Methods:A total of 45 adult male Sprague-Dawley (SD) rats were randomly divided into model group (MIRI group), sham group (Sham group) and model+exercise preconditioning group (EP group), with 15 rats in each group. No myocardial ischemia-reperfusion were done in the Sham group. Left anterior descending coronary artery (LAD) was ligated in the MIRI group and EP group. Before modeling the Sham group and MIRI group didn't receive intervention, and the EP group was given electric treadmill training for four weeks. The ultrastructure and autophagic bodies of rat cardiac myocytes were observed by transmission electron microscopy, the infarct size was measured by Evans blue-TTC double staining, and the expression ofPI3K-Akt-mTOR signal pathway related proteins was detected by Western blot.Results:In the Sham group, the nuclear membrane was intact and continuous, the myofibrillar bundles arranged orderly, the structure of mitochondria was intact and no edema, the morphology of myocardial cells was normal, and no autophagic bodies were found; in the MIRI group, the myofibrillar bundles were loose and disordered with interstitial edema, mitochondria and myocardial cells were damaged seriously, the structure of cells was disordered, and autophagy was observed in the field of vision; in the EP group, some of sarcoplasmic reticulum was edema and expanding, mitochondrial structure was more complete with slight edema, myocardial cell was less damaged, and autophagy was less. The Sham group had no myocardial ischemia and infarction; compared with the MIRI group, the area of myocardial infarction in the EP group was significantly reduced, the difference was statistically significant (P< 0.05). Compared with the MIRI group, p-PI3K/PI3K and p-mTOR/mTOR in the EP group increased (P< 0.05).Conclusion:Exercise preconditioning has a significant protective effect on myocardial ischemia-reperfusion injury in rats. Its mechanism may be related to the activation of PI3K-Akt-mTOR signaling pathway to inhibit excessive autophagy.

Abstract Background Epithelial ovarian cancer (EOC) is the malignant tumor of the female reproductive system with the highest fatality rate. Tolerance of chemotherapeutic drugs like cisplatin (DDP) occurring in very early stage is one of the important factors of the poor prognosis of epithelial ovarian cancer. Here we aim to study the dysregulation of a particular long noncoding RNA, lncRNA GAS5, and its role in EOC progression. Methods The low expression of lncRNA GAS5 in EOC tissues and OC cell lines was determined by microarray analyses and Real-Time qPCR. Flow cytometer assays were used to detect cell cycle and apoptosis of OC cells. CCK8 assay were performed to investigate the DDP sensitivity of OC cells. Western blot was carried out to detect cell growth markers, apoptotic markers, PARP1, E2F4, MAPK pathway protein expression and other protein expression in OC cell lines. The binding of GAS5 and E2F4 were proved by RNA pull-down and RIP assay. The effect of E2F4 on PARP1 were determined by CHIP-qPCR assay and luciferase reporter assay. The effect of lncRNA GAS5 on OC cells was assessed in vitro and in vivo. Results By microarray (3 EOC tissues νs. 3 normal ovary tissues) and RT- qPCR (53 EOC tissues νs. 10 normal ovary tissues) we identified lncRNA GAS5 to be dramatically low expressed in EOC samples and correlated with prognosis. Compared with sensitive cell lines, GAS5 was also low expressed in DDP resistant OC cell lines, and over-expression of GAS5 significantly enhanced the sensitivity of OC cells to DDP in vivo and in vitro. Meanwhile the over-expression of GAS5 also caused OC cells G0/G1 arrest and apoptosis increase. Mechanistically, GAS5 might regulate PARP1 expression by recruiting the transcription factor E2F4 to its promoter, and then affect the MAPK pathway activity. Due to the 5’TOP structure, GAS5 could be regulated by transcription inhibitor rapamycin in OC cells. Conclusion Here we explored the specific mechanisms of EOC cisplatin resistance and tumor progress due to lncRNA-GAS5, presented the GAS5-E2F4-PARP1-MAPK axis and its role in OC drug-sensitivity and progression for the first time, and the results may provide experimental basis for clinical application.

Pipe jackets are widely used in engineering as a component for heating or cooling reactors or other equipment. In this paper, fluid flow and heat transfer performances in straight or helical pipes having bow cross-sections with the central angle α in the range of 90–180° were numerically simulated using water as the medium under turbulent flow conditions. The results show that, under the same volume flow rate, the bow cross-sectional pipe with α less than 180° can enhance heat transfer and shows better comprehensive heat transfer performance compared with the half-pipe with α being 180°. As a result, less heat exchange surface (or the weight) of the bow cross-sectional pipe is needed for transferring the same amount of heat. Specifically, for the helical pipe having the bow cross-section with α being 90°, the weight of the pipe can be reduced by about 80%. In order to facilitate the engineering design of bow cross-sectional pipe jackets, correlation formulas for Nu and f of the whole straight pipe and the helical pipe were modified to include the influence of the central angle α of the bow cross-sections.

Aortopulmonary window is a rare congenital heart disease that can increase pulmonary vascular resistance, exacerbate left-to-right shunt and lead to heart failure and respiratory tract infections. Most patients die during childhood. We report a 53-year-old male patient with a large aortopulmonary window combined with anomalous origin of the right pulmonary artery from the aorta, with Eisenmenger syndrome and without surgery.

Thermally activated delayed fluorescent (TADF) materials, as the third generation of organic electroluminescent materials, have many advantages over other organic light-emitting diodes (OLEDs) materials, such as 100% internal quantum efficiency, no doping of heavy metals, and avoiding the shortages of ordinary fluorescent materials and phosphorescent materials. So it is considered to be the most competitive organic light-emitting materials, and has great application prospects in the field of OLEDs. So far, small-molecule TADF materials have achieved high quantum yield and full-color range of red, green, and blue. However, TADF polymers suitable for low-cost and easily scalable solution processing are less developed, which are confined by the preparation methods and polymers designing, and there are still challenges of increasing quantum efficiency and strengthening device performance. This review mainly summarizes different synthesis strategies of TADF polymers and the latest development in the field. Special attention is focused on illustrating the designing and structure-property relationship of TADF polymers, and finally, an outlook is given for the design and application prospect of TADF polymers in the future.

SDN architecture could bring excellent flexibility and manageability to the network.In order to provide a large-scale verification testbed and a pilot deployment environment for SDN-based new technologies and applications,a hierarchical and cross-regional SDN verification and demonstration system over CERNET was proposed,and a SDN verification and demonstration core network consisted of nine cities and thirteen nodes and an access network containing three data centers was built.Based on this system,several SDN-based technologies and applications such as CPE virtualization line service,IPv4/IPv6 transition technology,traffic monitoring and scheduling application and data center applications were deployed,verified and demonstrated.

Chronic heart failure (CHF) is one of the end forms of heart disease. Because of long duration and the upgoing recurrence rate, the rates of hospitalization, mortality and morbidity are high in recent years. At present, the treatment of CHF mainly focuses on drug treatment, but long-term drug treatment has liver and kidney toxicity. Compared with drug treatment, exercise rehabilitation training has many advantages, such as high safety, low cost, high compliance with patients, and saving social resources. In this paper, assessments and precautions before exercise rehabilitation, development and implementation of exercise rehabilitation program and the nursing after exercise rehabilitation are summarized and concluded, in order to develop the clinical treatment of CHF.

We reported previously that nuclear factor erythroid 2-related factor 2 (Nrf2) and metallothionein (MT) play critical roles in preventing intermittent hypoxia (IH)-induced cardiomyopathy. In addition, positive feedback regulation between Nrf2 and MT is required for the efficient compensative responses of the heart to IH. As an activator of Nrf2, sulforaphane (SFN) has attracted attention as a potential protective agent against cardiovascular disease. Here, we investigated whether SFN can up-regulate cardiac Nrf2 expression and function, as well as MT expression, to prevent IH-induced cardiomyopathy, and if so, whether Nrf2 and MT are indispensable for this preventive effect. Nrf2-knock-out (Nrf2-KO) or MT-KO mice and their wild-type (WT) equivalents were exposed to IH for 4 weeks with or without SFN treatment. SFN almost completely prevented IH-induced cardiomyopathy in WT mice, and this preventive effect was abolished in Nrf2-KO mice but retained in MT-KO mice. In IH-exposed WT mice, SFN induced significant increases in the expression levels of Nrf2 and its downstream antioxidant target genes, as well as those of MT, but these effects were not seen in IH-exposed Nrf2-KO mice. By contrast, KO of MT did not affect the ability of SFN to up-regulate the expression of Nrf2 and its downstream antioxidant targets. These results suggest that SFN-induced MT expression is Nrf2-dependent, and SFN prevents IH-induced cardiomyopathy in a Nrf2-dependent manner, for which MT is dispensable. This study provides important information that is relevant to the potential use of SFN to prevent IH-induced cardiomyopathy. Keywords: Intermittent hypoxia, Cardiomyopathy, Nuclear factor erythroid 2-related factor 2, Metallothionein, Sulforaphane

MCL1, a pro-survival BCL-2 related protein with rapid turnover rate, is often dysregulated in cancers. Here, the authors show that MCL1’s stability is regulated by deubiquitinase USP13, and its inhibition sensitises tumor cells to BH3 mimetic inhibitors.

PAX8 is a prototype lineage-survival oncogene in epithelial ovarian cancer. However, neither its underlying pro-tumorigenic mechanisms nor potential therapeutic implications have been adequately elucidated. Here, we identified an ovarian lineage-specific PAX8 regulon using modified cancer outlier profile analysis, in which PAX8-FGF18 axis was responsible for promoting cell migration in an autocrine fashion. An image-based drug screen pinpointed that PAX8 expression was potently inhibited by small-molecules against histone deacetylases (HDACs). Mechanistically, HDAC blockade altered histone H3K27 acetylation occupancies and perturbed the super-enhancer topology associated with PAX8 gene locus, resulting in epigenetic downregulation of PAX8 transcripts and related targets. HDAC antagonists efficaciously suppressed ovarian tumor growth and spreading as single agents, and exerted synergistic effects in combination with standard chemotherapy. These findings provide mechanistic and therapeutic insights for PAX8-addicted ovarian cancer. More generally, our analytic and experimental approach represents an expandible paradigm for identifying and targeting lineage-survival oncogenes in diverse human malignancies.

The Phenome-Wide Association Study (PheWAS) is increasingly used to broadly screen for potential treatment effects, e.g., IL6R variant as a proxy for IL6R antagonists. This approach offers an opportunity to address the limited power in clinical trials to study differential treatment effects across patient subgroups. However, limited methods exist to efficiently test for differences across subgroups in the thousands of multiple comparisons generated as part of a PheWAS. In this study, we developed an approach that maximizes the power to test for heterogeneous genotype-phenotype associations and applied this approach to an IL6R PheWAS among individuals of African (AFR) and European (EUR) ancestries. We identified 29 traits with differences in IL6R variant-phenotype associations, including a lower risk of type 2 diabetes in AFR (OR 0.96) vs EUR (OR 1.0, p-value for heterogeneity = 8.5 × 10-3), and higher white blood cell count (p-value for heterogeneity = 8.5 × 10-131). These data suggest a more salutary effect of IL6R blockade for T2D among individuals of AFR vs EUR ancestry and provide data to inform ongoing clinical trials targeting IL6 for an expanding number of conditions. Moreover, the method to test for heterogeneity of associations can be applied broadly to other large-scale genotype-phenotype screens in diverse populations.