Search

Purpose: To investigate the role of neferine in ovalbumin (OVA)-induced asthma, and to reveal the possible mechanism. Methods: In OVA-induced asthmatic mice, enzyme-linked-immunosorbent serologic assay was performed to evaluate the level of interleukin (IL)-4, IL-5, IL-13, immunoglobulin E (IgE) in serum and tumor necrosis factor-α (TNF-α), IL-6, IL-1β, and monocyte chemoattractant protein-1 (MCP-1) in bronchoalveolar lavage fluid (BALF). Eosinophil, neutrophil, and lymphocyte counts in BALF were calculated to assess inflammation. The pulmonary function was measured by airway resistance, peak expiratory flow (PEF) and forced expiratory volume/forced vital capacity (FEV0.4/FVC) ratio, and respiratory rate. Hematoxylin and eosin staining and Masson staining were used to evaluate lung injury. Further, Western blot analysis was conducted to detect phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 of mitogen-activated protein kinase (MAPK) signaling pathways. Results: Neferine, 20 mg/kg or 40 mg/kg, could significantly decrease the levels of IL-4, IL-5, IL-13, and IgE in OVA-induced serum, and that of TNF-α, IL-6, IL-1β, and MCP-1 in OVA-induced BALF. Moreover, neferine could significantly decline eosinophil, neutrophil, and lymphocyte counts in BALF. Neferine contributed to improve OVA-induced airway resistance, promoted the value of PEF and FEV0.4/FVC ratio, and recovered the respiratory rate. It also reduced mucus secretion, distribution of inflammatory and goblet cells around bronchi, and attenuated collagen deposition in lung tissues. Furthermore, neferine reduced the phosphorylation of p38, JNK, and ERK to inhibit MAPK signaling pathways. Conclusion: Neferine relieves asthma-induced inflammatory reaction, airway resistance, and lung injury by inhibiting MAPK signaling pathways. This could serve neferine as a novel therapeutic candidate for treating asthma.

BACKGROUND: Ginkgo Folium has a favorable effect on non-alcoholic fatty live disease (NAFLD), but its mechanism remains unclear. OBJECTIVE: The aim of this study is to reveal the underlying mechanism of Ginkgo Folium in the treatment of NAFLD. METHODS: Ingredients of Ginkgo Folium and ingredients-related genes were collected from TCMSP database and SwissTargetPrediction website, respectively. Genecards database was used to obtain NAFLD-related genes. Next, the protein-protein interaction network and key ingredients-genes network were constructed via Cytoscape3.7.0. Based on the Metascape website, gene ontology function analysis and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were carried out for key genes. Finally, molecular docking was performed to present the interaction between components and genes using AutoDock Vina 1.1.2. RESULTS: Eighteen active ingredients and 10 target genes were screened from Ginkgo Folium. AKT1, TNF, EGFR, PTGS2, MAPK8, PPAγ, APP, ESR1, HIFα and PPAα were considered as potential therapeutic targets. These target genes were mainly enriched in insulin resistance, HIF-1, adipocytokine and AMPK signaling pathways. Molecular docking results suggested that Ginkgo Folium active ingredients including luteolin-4′-glucoside, sesamin, luteolin, chryseriol, isorhamnetin and laricitrin showed strong binding capacities with AKT1. CONCLUSION: The study showed that multi-components in Ginkgo Folium interacted with AKT1 and regulated AKT-AMPK/HIF pathway to alleviate NAFLD. Our findings provided an essential role and basis for new anti-NAFLD drug discovery and further research on Ginkgo Folium.

BACKGROUND: In recent years, people have paid more and more attention to the health hazards caused by O3 exposure, which will become a major problem after fine particulate matter (PM). OBJECTIVE: To investigate the effects of ozone (O3) exposure on blood glucose levels in rats under different concentrations and times. METHODS: Eighty rats were divided into control group and three ozone concentration groups. Each group was continuously exposed for 1d, 3d and, 6d, and exposed for 6 hours daily. After exposure, GTT, FBG, and random blood glucose were measured. RESULTS: The FBG value increased significantly on the 6th day of 0.5 ppm and the 3rd and 6th days of 1.0 ppm exposure compared with the control group (P< 0.05). The random blood glucose value was significantly increased on the 3rd and 6th days of each exposure concentration (P< 0.05). When exposed to 1 ppm concentration, the 120 min GTT value of 1 d, 3 d and, 6 d was significantly higher than that of the control group (P< 0.05). CONCLUSION: After acute O3 exposure, the blood glucose level of rats was affected by the exposure concentration and time. The concentration of 0.1 ppm had no significant impact on FBG and random blood glucose, and O3 with a concentration of 0.1 ppm and 0.5 ppm had no significant impact on values of GTT at 90 min, and 120 min.

The aims of this study were to evaluate and compare the pharmacokinetic profiles and bioequivalence of two tablet formulations of methylprednisolone (test formulation: Zhejiang Xianju Pharmaceutical Co., Ltd., China; reference formulation: Medrol, Pfizer Italia SRL) in healthy Chinese subjects under fasting and fed conditions.Subjects were randomly allocated to either the fasting group or the fed group and also to one of two sequences (test-reference or reference-test), according to which they received a single 16-mg dose of the test or reference methylprednisolone tablet in the study periods. Blood samples were collected pre dose and at intervals up to 16 hours after administration. Plasma methylprednisolone concentrations were determined using a validated liquid chromatography tandem mass spectrometry method. The safety of the medications was monitored throughout the study. The primary pharmacokinetic parameters measured were CA total of 56 subjects were enrolled, and all completed the study. The 90% confidence intervals for CThe test methylprednisolone 16 mg tablet produced in China is bioequivalent to the reference formulation (Medrol) in healthy Chinese subjects measured under both fasting and fed conditions. Both formulations were well tolerated by all study participants.

Transcutaneous electrical cranial-auricular acupoint stimulation (TECAS) is a novel non-invasive therapy that stimulates acupoints innervated by the trigeminal and auricular vagus nerves. An assessor-blinded, randomized, non-inferiority trial was designed to compare the efficacy of TECAS and escitalopram in mild-to-moderate major depressive disorder.468 participants received 2 TECAS sessions per day at home (n = 233) or approximately 10-13 mg/day escitalopram (n = 235) for 8 weeks plus 4-week follow-up. The primary outcome was clinical response, defined as a baseline-to-endpoint ≥50% reduction in Montgomery-Åsberg Depression Rating Scale (MADRS) score. Secondary outcomes included remission rate, changes in the severity of depression, anxiety, sleep and life quality.The response rate was 66.4% on TECAS and 63.2% on escitalopram with a 3.2% difference (95% confidence interval [CI], -5.9% to 12.9%) in intention-to-treat analysis, and 68.5% versus 66.2% with a 2.3% difference (95% CI, -6.9% to 11.4%) in per-protocol analysis. The lower limit of 95% CI of the differences fell within the prespecified non-inferiority margin of -10% (P ≤ 0.004 for non-inferiority). Most secondary outcomes did not differ between the two groups. TECAS-treated participants who experienced psychological trauma displayed a markedly greater response than those without traumatic experience (81.3% versus 62.1%, P = 0.013). TECAS caused much fewer adverse events than escitalopram.TECAS was comparable to escitalopram in improving depression and related symptoms, with high acceptability, better safety profile, and particular efficacy in reducing trauma-associated depression. It could serve an effective portable therapy for mild-to-moderate depression. This article is protected by copyright. All rights reserved.

We found that in regenerative erythropoiesis, the erythroid progenitor landscape is reshaped, and a previously undescribed progenitor population with colony-forming unit-erythroid (CFU-E) activity (stress CFU-E [sCFU-E]) is expanded markedly to restore the erythron. sCFU-E cells are targets of erythropoietin (Epo), and sCFU-E expansion requires signaling from the Epo receptor (EpoR) cytoplasmic tyrosines. Molecularly, Epo promotes sCFU-E expansion via JAK2- and STAT5-dependent expression of IRS2, thus engaging the progrowth signaling from the IGF1 receptor (IGF1R). Inhibition of IGF1R and IRS2 signaling impairs sCFU-E cell growth, whereas exogenous IRS2 expression rescues cell growth in sCFU-E expressing truncated EpoR-lacking cytoplasmic tyrosines. This sCFU-E pathway is the major pathway involved in erythrocytosis driven by the oncogenic JAK2 mutant JAK2(V617F) in myeloproliferative neoplasm. Inability to expand sCFU-E cells by truncated EpoR protects against JAK2(V617F)-driven erythrocytosis. In samples from patients with myeloproliferative neoplasm, the number of sCFU-E-like cells increases, and inhibition of IGR1R and IRS2 signaling blocks Epo-hypersensitive erythroid cell colony formation. In summary, we identified a new stress-specific erythroid progenitor cell population that links regenerative erythropoiesis to pathogenic erythrocytosis.

To apply shear wave elastography (SWE) combined with transperineal ultrasonography (TPUS) to study the association between urethral funneling in stress urinary incontinence (SUI) and the biological properties of the urethral rhabdosphincter muscle in women.This single-center retrospective study included 166 women with SUI (SUI group) and 185 women who underwent a routine physical examination (control group). The control group and SUI group were divided into nonfunneling and funneling groups according to the presence or absence of urethral funneling, respectively, and their ultrasound findings were compared to analyze the association between funneling and ultrasound measurements.The SUI group had a lower mean E than the control group (15.54 vs. 20.82 kPa, p 0.001). The SUI-funneling group had a lower mean E than the SUI-nonfunneling group (15.50 vs. 17.21 kPa, p 0.001). The area under the (AUC) receiver operating characteristic (ROC) curve of the mean E for predicting SUI was 0.864, with a cutoff value of 19.19 kPa. The AUC of the mean E for predicting urethral funneling was 0.832, with a cutoff value of 17.15 kPa. The stiffness of the urethral rhabdosphincter was an independent factor related to SUI and urethral funneling in SUI.SWE can be used to assess the biological properties of the urethral rhabdosphincter, and reduced stiffness of the rhabdosphincter was significantly correlated with SUI and funneling in SUI. Thus, women with urethral funneling in SUI may have a weak urethral rhabdosphincter.

Genome-wide association studies (GWAS) are commonly employed to study the genetic basis of complex traits and diseases, and a key question is how much heritability could be explained by all variants in GWAS. One widely used approach that relies on summary statistics only is LD score regression (LDSC), however the approach requires certain assumptions on the SNP effects (all SNPs contribute to heritability and each SNP contributes equal variance). More flexible modeling methods may be useful. We previously developed an approach recovering the true z-statistics from a set of observed z-statistics with an empirical Bayes approach, using only summary statistics. However, methods for standard error (SE) estimation are not available yet, limiting the interpretation of results and applicability of the approach. In this study we developed several resampling-based approaches to estimate the SE of SNP-based heritability, including two jackknife and three parametric bootstrap methods. Simulations showed that delete-d-jackknife and parametric bootstrap approaches provide good estimates of the SE. Particularly, the parametric bootstrap approaches yield the lowest root-mean-squared-error (RMSE) of the true SE. In addition, we applied our method to estimate SNP-based heritability of 12 immune-related traits (levels of cytokines and growth factors) to shed light on their genetic architecture. We also implemented the methods to compute the sum of heritability explained and the corresponding SE in an R package SumVg, available at https://github.com/lab-hcso/Estimating-SE-of-total-heritability/ . In conclusion, SumVg may provide a useful alternative tool for SNP heritability and SE estimates, which does not rely on distributional assumptions of SNP effects.

The usefulness of live attenuated virus vaccines has been limited by suboptimal immunogenicity, safety concerns or cumbersome manufacturing processes and techniques. Here we describe the generation of a live attenuated influenza A virus vaccine using proteolysis-targeting chimeric (PROTAC) technology to degrade viral proteins via the endogenous ubiquitin-proteasome system of host cells. We engineered the genome of influenza A viruses in stable cell lines engineered for virus production to introduce a conditionally removable proteasome-targeting domain, generating fully infective PROTAC viruses that were live attenuated by the host protein degradation machinery upon infection. In mouse and ferret models, PROTAC viruses were highly attenuated and able to elicit robust and broad humoral, mucosal and cellular immunity against homologous and heterologous virus challenges. PROTAC-mediated attenuation of viruses may be broadly applicable for generating live attenuated vaccines.

Albumin is successfully applied as a nanocarrier in the clinical nanomedicine and the abnormal miR-503 expression is related to the development of myocardial infarction (MI). This study aimed to explore the efficacy of albumin nanoparticles (NPs)-based delivery of miR-503 antagonist for MI therapy. After establishment of an animal model of MI, mice were administered albumin NPs loaded with miR-503 agonist or antagonist, normal saline (model group), CCNE1 agonist, or CCNE1 inhibitor (n = 10) with 10 mice sham-operated. Murine peripheral blood was collected to measure endothelial progenitor cells (EPCs) in peripheral blood along with analysis of miR-503, CCNE1 and SDF-1α expression by RT-qPCR, formation of new blood vessels and EPCs viability. Albumin NPs loaded with miR-503 antagonist increased EPCs number and new blood vessels formation, accompanied with down-regulation of miR-503 and up-regulation of SDF-1α and CCNE1. The NPs carrying miR-503 agonist exerted an opposite activity with less EPCs and new blood vessels than sham-operated group without significant difference between agonist group and model group. Besides, miR-503 antagonist promoted EPCs viability. Furthermore, inhibition of CCNE1 suppressed blood vessel formation and miR-503 targeted CCNE1. In conclusion, albumin-based NPs loaded with miR-503 antagonist decrease miR-503 expression and increase CCNE1 and SDF-1α expression to promotes EPCs viability and enhance the formation of new blood vessels, thereby improving MI.

Background Decreased bioavailability of nitric oxide (NO) under hypoxic conditions can lead to endothelial dysfunction. NO supplementation may protect endothelial function in ischemia-reperfusion (IR) injury. Therefore, a meta-analysis of randomized controlled trials (RCTs) was performed to verify the protective effect of NO donors on endothelium in IR injury. Methods Medline, Embase, Cochrane Library, and Web of Science databases were searched from inception to April 1, 2023. The specific inclusion criteria were as follows: (1) RCTs; (2) trials comparing NO donors with placebo control groups; and (3) trials reporting the effects of these interventions on vascular endothelial functional outcomes in IR injury. Random-effects models were used to assess pooled effect sizes, which were expressed as standardized mean differences (SMD). Results Seven studies satisfied the inclusion criteria and consisted of a total of 149 participants. NO donors were protective of endothelial function in IR injury (SMD: − 1.60; 95% confidence interval [CI]: − 2.33, − 0.88, P 2 = 66%, P = 0.001]). Results of the subgroup analysis showed the following: absence of protective effect of NO donor use following ischemia on endothelial function in IR injury − 1.78 (95% CI: − 2.50, − 1.07) and loss of protective effect on endothelial function after prolonged NO donor use − 0.89 (95% CI: − 2.06, 0.28). Conclusion The short-period use of NO donors before the onset of ischemia can protect endothelial function in IR injury.

Severe COVID-19 is characterized by an increase in the number and changes in the function of innate immune cells including neutrophils. However, it is not known how the metabolome of immune cells changes in patients with COVID-19. To address these questions, we analyzed the metabolome of neutrophils from patients with severe or mild COVID-19 and healthy controls. We identified widespread dysregulation of neutrophil metabolism with disease progression including in amino acid, redox, and central carbon metabolism. Metabolic changes in neutrophils from patients with severe COVID-19 were consistent with reduced activity of the glycolytic enzyme GAPDH. Inhibition of GAPDH blocked glycolysis and promoted pentose phosphate pathway activity but blunted the neutrophil respiratory burst. Inhibition of GAPDH was sufficient to cause neutrophil extracellular trap (NET) formation which required neutrophil elastase activity. GAPDH inhibition increased neutrophil pH, and blocking this increase prevented cell death and NET formation. These findings indicate that neutrophils in severe COVID-19 have an aberrant metabolism which can contribute to their dysfunction. Our work also shows that NET formation, a pathogenic feature of many inflammatory diseases, is actively suppressed in neutrophils by a cell-intrinsic mechanism controlled by GAPDH.

Background Research has shown that reprogramming of fatty acid metabolism (FAM) is involved in tumorigenicity and cancer progression, as well as the impact of tumor immune microenvironments (TME) on tumorigenesis, metastasis, and the prognosis of head and neck squamous cell carcinoma (HNSCC). However, no reliable molecular markers based on fatty acid metabolism have been identified to predict prognosis, immune infiltration, and treatment in HNSCC.Methods In the HNSCC samples of TCGA, we performed a consensus clustering algorithm to separate molecular subtypes. And then we established a risk model for prognosis with Cox regression and the least absolute shrinkage and selection operator (LASSO) regression. The predictive efficacy of risk model was also verified by another HNSCC cohort from GEO.We also evaluated the risk score association with the clinicopathological features and explored differences of immune cell infiltration, immune status and chemotherapeutic drugs IC 50 value concentration between high and low risk subgroup.Results Three distinct fatty acid metabolism subtypes were identified among 494 HNSCC samples, which were also associated with different clinical outcomes, TME characteristics and clinical features. 9 prognosisrelated genes which were different expressed among three subgroups were screened out for prognostic signature. According to the risk score caculated by the signature genes, patients in TCGA cohort can be divided into high and low risk score subgroups. The low risk score subgroup patients displayed a better prognosis. Further analysis indicated that low risk score correlated with higher immune cells infiltration. In addition, patients with higher risk scores showed a better chemotherapy sensetivity of cisplatin and docetaxel.Conclusions We developed a signature capable of predicting prognosis, representing the TME, enhancing individualized therapy, and providing a novel immunotherapeutic marker in HNSCC.

Background: Elevated levels of d-dimer during pregnancy are thought to be associated with adverse outcomes of pregnancy. Some obstetrician suspect maternal hypercoagulability may lead placenta or umbilical vascular thrombosis, which could cause fetal death in third trimester. However those hypothesis is lack of evidence of evidence-based medicine.Our case is unique because we regular screening level of d-dimer since first trimester. And we had ran scrutinize detailed inspection in other possible causes of umbilical artery thrombosis, including fetal chromosome abnormalities, umbilical cord abnormalities, immunological abnormalities, which all show negative results. This leads us to the conclusion that maternal hypercoagulability can directly lead to the formation of umbilical artery thrombosis. Case presentation: A 29-year-old patient, a primigravida, was revealed the elevating d-dimer levels of 0.51mg/L in early pregnancy(normal level Conclusions: Maternal hypercoagulable state could cause umbilical vascular thrombosis.As a reliable indicator of coagulation function, it’s maybe necessary for regular screening the level of d-dimer for pregnant women in different trimester.The cut off values of d-dimer in different gestational weeks should be determined according to different race and inspection methods. Low molecular weight heparin maybe effective treatment for pregnant women with abnormal elevation of d-dimer.

Supplementary Fig. S2 from The antitumoral effect of Paris Saponin I associated with the induction of apoptosis through the mitochondrial pathway

Rhizoma Paridis, a traditional Chinese medicine, has shown promise in cancer prevention and therapy. In the present study, we isolated Paris Saponin I (PSI), an active component of Rhizoma paridis, and evaluated its effects on a panel of human cell lines and in a mouse model of human ovarian cancer to explore the mechanisms of its activity. PSI had more potent and selective cytotoxic effects on tumor cell lines than etoposide had, promoting dramatic G2-M phase arrest and apoptosis in SKOV3 cells in a time- and dose-dependent manner. Furthermore, PSI treatment increased levels of Bax, cytochrome c, activated caspase-3, active caspase-9, and cleaved poly(ADP-ribose) polymerase and decreased both Bcl-2 expression levels and extracellular signal–regulated kinase-1/2 activity. We also assessed the antitumor efficacy of i.p. and p.o. PSI administration in mice bearing SKOV3 tumors; both significantly inhibited the growth of SKOV3 cells in a subcutaneous xenograft mouse model (by 66% and 52%, respectively). These results indicate that PSI mediates its effects via mitochondrial apoptosis, mitogen-activated protein kinase pathways, and G2-M cell cycle arrest. Most important, the efficacy of PSI in xenografts when administered p.o. or i.p. suggests its clinical potential. Thus, PSI is a potent antitumor compound and should be developed as a natural agent for cancer therapy.[Mol Cancer Ther 2009;8(5):1179–88]

Supplementary Figures S1-S2; Supplementary Tables S1-S2.

Supplementary Data from CXCR2 Promotes Ovarian Cancer Growth through Dysregulated Cell Cycle, Diminished Apoptosis, and Enhanced Angiogenesis

Purpose: Chemokine receptor CXCR2 is associated with malignancy in several cancer models; however, the mechanisms involved in CXCR2-mediated tumor growth remain elusive. Here, we investigated the role of CXCR2 in human ovarian cancer.Experimental Design: CXCR2 expression was silenced by stable small hairpin RNA in ovarian cancer cell lines T29Gro-1, T29H, and SKOV3. Western blotting, immunofluorescence, enzyme-linked immunosorbent assay, flow cytometry, electrophoretic mobility shift assay, and mouse assay were used to detect CXCR2, interleukin-8, Gro-1, cell cycle, apoptosis, DNA binding of NF-κB, and tumor growth. Immunohistochemical staining of CXCR2 was done in 240 high-grade serous ovarian carcinoma samples.Results: Knockdown of CXCR2 expression by small hairpin RNA reduced tumorigenesis of ovarian cancer cells in nude mice. CXCR2 promoted cell cycle progression by modulating cell cycle regulatory proteins, including p21 (waf1/cip1), cyclin D1, CDK6, CDK4, cyclin A, and cyclin B1. CXCR2 inhibited cellular apoptosis by suppressing phosphorylated p53, Puma, and Bcl-xS; suppressing poly(ADP-ribose) polymerase cleavage; and activating Bcl-xL and Bcl-2. CXCR2 stimulated angiogenesis by increasing levels of vascular endothelial growth factor and decreasing levels of thrombospondin-1, a process likely involving mitogen-activated protein kinase, and NF-κB. Overexpression of CXCR2 in high-grade serous ovarian carcinomas was an independent prognostic factor of poor overall survival (P < 0.001) and of early relapse (P = 0.003) in the univariate analysis.Conclusions: Our data provide strong evidence that CXCR2 regulates the cell cycle, apoptosis, and angiogenesis through multiple signaling pathways, including mitogen-activated protein kinase and NF-κB, in ovarian cancer. CXCR2 thus has potential as a therapeutic target and for use in ovarian cancer diagnosis and prognosis. Clin Cancer Res; 16(15); 3875–86. ©2010 AACR.

Supplementary Fig. S1 from The antitumoral effect of Paris Saponin I associated with the induction of apoptosis through the mitochondrial pathway

Epigraphene, which is graphene that is epitaxially grown on a single crystal silicon carbide (SiC) substrate, was proposed as a path to extend Moore’s roadmap beyond silicon at the beginning of the millennium. Despite considerable progress, the lack of a bandgap in graphene and steps on the substrate continued to be roadblocks. Here we show a new method to produce millimeter scale step-free terraces covered with a graphene-like interface that is bonded to the SiC surface. This so-called buffer layer is found to be two-dimensional semiconducting epigraphene (SEG) with a 0.6 eV bandgap and a room temperature mobility exceeding 4000 cm2V-1s-1, which surpasses all current 2D single layer semiconductors by a factor of 10. A top-gated SEG field-effect transistor demonstrates an on-to-off ratio of 104 which is suitable for digital electronics. In addition, we also find that hydrogen intercalation converts SEG into a high-mobility semi-metallic epigraphene monolayer that can be seamlessly integrated with SEG. Centimeter scale mean free paths are observed in the epigraphene edge state of this quasi-freestanding monolayer, which is by a factor of 1000, the largest room temperature electronic mean free path observed in any material.

Growth hormone secretagogue receptor 1a (GHS-R1a) is an important G protein-coupled receptor (GPCR) that regulates a variety of functions by binding to ghrelin. It has been shown that the dimerization of GHS-R1a with other receptors also affects ingestion, energy metabolism, learning and memory. Dopamine type 2 receptor (D2R) is a GPCR mainly distributed in the ventral tegmental area (VTA), substantia nigra (SN), striatum and other brain regions. In this study we investigated the existence and function of GHS-R1a/D2R heterodimers in nigral dopaminergic neurons in Parkinson’s disease (PD) models in vitro and in vivo. By conducting immunofluorescence staining, FRET and BRET analyses, we confirmed that GHS-R1a and D2R could form heterodimers in PC-12 cells and in the nigral dopaminergic neurons of wild-type mice. This process was inhibited by MPP+ or MPTP treatment. Application of QNP (10 μM) alone significantly increased the viability of MPP+-treated PC-12 cells, and administration of quinpirole (QNP, 1 mg/kg, i.p. once before and twice after MPTP injection) significantly alleviated motor deficits in MPTP-induced PD mice model; the beneficial effects of QNP were abolished by GHS-R1a knockdown. We revealed that the GHS-R1a/D2R heterodimers could increase the protein levels of tyrosine hydroxylase in the SN of MPTP-induced PD mice model through the cAMP response element binding protein (CREB) signaling pathway, ultimately promoting dopamine synthesis and release. These results demonstrate a protective role for GHS-R1a/D2R heterodimers in dopaminergic neurons, providing evidence for the involvement of GHS-R1a in PD pathogenesis independent of ghrelin.

Inhibition of host DNA damage response (DDR) is a common mechanism used by viruses to manipulate host cellular machinery and orchestrate viral life cycles. Epstein-Barr virus tegument protein BKRF4 associates with cellular chromatin to suppress host DDR signaling, but the underlying mechanism remains elusive. Here, we identify a BKRF4 histone binding domain (residues 15–102, termed BKRF4-HBD) that can accumulate at the DNA damage sites to disrupt 53BP1 foci formation. The high-resolution structure of the BKRF4-HBD in complex with a human H2A–H2B dimer shows that BKRF4-HBD interacts with the H2A–H2B dimer via the N-terminal region (NTR), the DWP motif (residues 80–86 containing D81, W84, P86), and the C-terminal region (CTR). The “triple-anchor” binding mode confers BKRF4-HBD the ability to associate with the partially unfolded nucleosomes, promoting the nucleosome disassembly. Importantly, disrupting the BKRF4–H2A–H2B interaction impairs the binding between BKRF4-HBD and nucleosome in vitro and inhibits the recruitment of BKRF4-HBD to DNA breaks in vivo. Together, our study reveals the structural basis of BKRF4 bindings to the partially unfolded nucleosome and elucidates an unconventional mechanism of host DDR signal attenuation.

Frequent relapse and chemoresistance cause poor outcome in ovarian cancer (OC) and cancer stem cells (CSCs) are important contributors. While most studies focus exclusively on CSCs, the role of the microenvironment in providing optimal conditions to maintain their tumor-initiating potential remains poorly understood. Cancer associated fibroblasts (CAFs) are a major constituent of the OC tumor microenvironment and we show that CAFs and CSCs are enriched following chemotherapy in patient tumors. CAFs significantly increased OC cell resistance to carboplatin. Using heterotypic CAF-OC cocultures andin vivolimiting dilution assay, we confirmed that the CAFs act by enriching the CSC population. CAFs were found to increase the symmetric division of CSCs as well as the dedifferentiation of bulk OC cells into CSCs. The effect of CAFs was limited to OC cells in their immediate neighborhood, which could be prevented by inhibiting Wnt. Analysis of single cell RNA-seq data from OC patients revealed that Wnt5a as the highest expressed Wnt in CAFs and that certain subpopulations of CAFs express higher levels of Wnt5a. We found that Wnt5a from CAFs activated a noncanonical Wnt signaling pathway involving the ROR2/PKC/CERB1 axis in the neighboring CSCs. While canonical Wnt signaling was predominant in interactions between cancer cells in patients, non-canonical Wnt pathway was activated by CAF-OC crosstalk. Treatment with a Wnt5a inhibitor sensitized tumors to carboplatinin vivo. Together, our findings demonstrate a novel mechanism of CSC maintenance by signals from the microenvironmental CAFs, which can be targeted to treat OC chemoresistance and relapse.Statement of significanceCAFs serve as CSC niche through a Wnt5a mediated noncanonical Wnt signaling. Disease relapse and development of chemoresistance is a major problem in OC, which can be potentially addressed by targeting Wnt5a.

Natural ventilation is an important form of sustainable building technique that can be used to adjust the indoor environment to ensure indoor thermal comfort and maintain acceptable indoor air quality. Correct estimation of the ventilation rate is a necessary step in natural ventilation design. Natural wind fluctuation and interaction between the wind and buildings determine models of mean flow rate inaccuracy in predicting actual ventilation. In this paper, a summary of calculation models for unsteady natural ventilation is given. Unsteady natural ventilation mechanisms are classified into continuous airflow, pulsating flow, eddy penetration and diffusion phenomena. The theories of different ventilation mechanisms and the differences between various research reports are expounded and discussed. Additionally, an in-situ measurement of the eddy penetration caused by wind turbulence at the opening was conducted to verify the proposed model. The actual application condition of different eddy penetration models is proposed via the comparison between previous models. With respect to the ‘pumping’ mechanism, this is regarded as a special type of eddy penetration for the first time. Research on ‘pumping’ airflow has just started, the mechanism and influencing factors of which will need to be further explored.

The COVID-19 pandemic has had a great impact on the mental health of the medical staff in China, especially those on the first-line (frontline) of the pandemic. But the profile of the mental problem of nationwide Chinese medical staff is still unclear, especially about the sleep problems.There are five databases (PubMed, Embase, CNKI, Wanfang Database and Web of Science) searched to identify the published studies on the mental health of the medical staff in China during the COVID-19 outbreak. The pooled prevalence of mental problems of Chinese medical staff during the pandemic were calculated, especially for the first-line medical staff. Subgroup analysis and meta-regression analysis were performed to identify the potential impact factors.A total of 71 articles including 98,533 participants are included in this meta-analysis. The results showed that the pooled prevalence of the mental problems was as follows: anxiety problem 27%, depression problem 29%, sleep problem 40%. Subgroup analysis showed that there were significant differences in the prevalence of anxiety and depression problems between first-line and non-first-line medical staff (p0.01). Sex had a significant impact on the sleep of first-line medical staff (p0.01).There may be heterogeneity among the included studies. The analysis of potential influencing factors remains limited.The prevalence of adverse mental problems among medical staff is high during the COVID-19 outbreak. We need to pay special attention to the mental health of first-line medical staff, especially the sleep problems of female first-line workers.

Kernel size, one of the traits that determine wheat yield, is controlled by multiple quantitative trait loci. Polish wheat (Triticum polonicum) has elongated and plump kernel and is a valuable material for breeding high-yielding wheat cultivars. However, genes or loci determining kernel length (KL) in Polish wheat are unknown. We identified and validated a major KL gene, KL-PW, at the P1 locus in Polish wheat. KL-PW is VRT-A2, which encodes a MIKC-type MADS-box protein (MADS55). An insertion/deletion mutation in intron 1 of VRT-A2PW led to an alternatively spliced transcript, VRT-A2PW2. Quantitative PCR analysis showed that VRT-A2PW was more highly expressed in developing seeds than was VRT-A2Ailanmai. Brassinosteroid (BR) sensitivity experiment and the expression of BR-related genes indicated that VRT-A2PW functions as a positive regulator of BR responses. VRT-A2PW significantly increased KL of wheat. These findings not only reveal the molecular basis of KL-PW in controlling KL, but also provide a valuable genetic resource for increasing kernel size in wheat.

In this study, we establish some new Hermite-Hadamard type inequalities for s-convex functions in the second sense using the post-quantum calculus. Moreover, we prove a new ( p , q ) \left(p,q) -integral identity to prove some new Ostrowski type inequalities for ( p , q ) \left(p,q) -differentiable functions. We also show that the newly discovered results are generalizations of comparable results in the literature. Finally, we give application to special means of real numbers using the newly proved inequalities.