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Background: The disruption of the balance between osteogenic and adipogenic differentiation of mesenchymal stem cells (MSCs) in bone marrow contributes to the adipocytes accumulation and bone loss, which leads to the development of osteoporosis (OP). The circular RNA (circRNA), circRBM23, was generated from the RNA binding motif protein 23 (RBM23) gene. It was reported that circRBM23 was down-regulated in OP patients, but it remains unknown whether its down-regulation is involved in the lineage switch of MSCs. Objective: We aimed to explore the role and mechanism of circRBM23 in regulating the switch between osteogenic and adipogenic differentiation of MSCs. Methods: The expression and function of circRBM23 in vitro were detected by qRT-PCR, alizarin red staining, and oil Red O staining. The interactions between circRBM23 and microRNA-338-3p (miR-338-3p) were analyzed by RNA pull-down assay, FISH, and dual-luciferase reporter assay. MSCs treated with lentivirus overexpression of circRBM23 was applied for both in vitro and in vivo experiments. Results: CircRBM23 was expressed at lower levels in OP patients. Besides, circRBM23 was up-regulated during osteogenesis and down-regulated during adipogenesis of MSCs. CircRBM23 could promote the osteogenic differentiation but inhibit the adipogenic differentiation of MSCs. Mechanistically, circRBM23 acted as a sponge for microRNA-338-3p (miR-338-3p) to enhance the expression of RUNX family transcription factor 2 (RUNX2). Conclusions: Our research indicates that circRBM23 could promote the switch from adipogenic to osteogenic differentiation of MSCs via sponging miR-338-3p. It might improve the understanding of the lineage switch of MSCs and provide a potential target for diagnosing and treating OP.

Activating primary afferent TRPV1-positive (TRPV1

This study investigated possible therapeutic effect mechanisms of exosomes from bone marrow-derived mesenchymal stem cells (BMSC) in neuronal and microglial cells and in a Parkinson disease (PD) model. Neuronal SH-SY5Y cells and microglial HMC3 cells were subjected to 1-methyl-4-phenylpyridinium (MPP+) or LPS, respectively. The mRNA and protein expression was assessed using qRT-PCR, Western blotting, and enzyme-linked immunosorbent assay. Cell viability and apoptosis of SH-SY5Y cells were examined using the MTT assay and flow cytometry. Chromatin immunoprecipitation assays were performed to assess the binding relationship between glioma-associated oncogene homolog 1 (Gli1) and the Sp1 transcription factor promoter. BMSC-derived exosomes promoted cell proliferation and inhibited apoptosis in MPP+-treated SH-SY5Y cells and suppressed inflammatory markers in LPS-treated HMC3 cells. Sp1 knockdown decreased SH-SY5Y cell damage and HMC3 immune activation. Gli1 carried by BMSC exosomes directly bound with Sp1 to inhibit Sp1-mediated LRRK2 activation whereas exosomes secreted by Gli1-knockdown in BMSC did not. In a PD mouse model induced with MPTP, BMSC exosomes decreased neuron loss injury and the inflammatory response by inhibiting Sp1 signaling. Thus, BMSC-derived exosomal Gli1 alleviates inflammatory damage and neuronal apoptosis by inhibiting Sp1 in vitro and in vivo. These findings provide the basis for the potential clinical use of BMSC-derived exosomes in PD.

Hog1 is the yeast homolog of p38 MAPK in mammals that is conserved across eukaryotes, and it plays crucial roles in stress tolerance, fungal pathogenesis, and disease treatments. Here, we provide evidence that modification of Set5 phosphorylation sites regulates the expression and phosphorylation of Hog1, which expands current knowledge on upstream regulation of the Hog1 stress signaling network.

Purpose To ascertain the risk factors and prevalence of non-infectious diarrhea among participants with multiple myeloma who treated with chimeric antigen receptor T-cell immunotherapy. Methods This study enrolled 88 patients with multiple myeloma who received chimeric antigen receptor T-cell immunotherapy at one tertiary general hospital in China. Participants were categorized into diarrhea subgroup and non-diarrhea subgroup according to the occurrence of diarrhea. Demographic data and self-reported measurements and planning were obtained from questionnaires and clinical data from hospital databases. Results In total, 50 patients suffered from non-infectious diarrhea, with the prevalence of 56.8%. Multiple logistic regression analysis showed that severe cytokine release syndrome (OR = 5.980), underlying diseases (OR = 4.184), previous treatment lines ≥ 6 (OR = 6.292) were prominent hazardous factors for non-infectious diarrhea (p

Superoxide dismutase 1 (SOD1) modulates intestinal barrier integrity and intestinal homeostasis as an antioxidant enzyme. Intestinal homeostasis is maintained by the intestinal stem cells (ISCs). However, whether and how SOD1 regulates ISCs is unknown. In this study, we established intestinal organoids from tamoxifen–inducible intestinal epithelial cell–specific Sod1 knockout (Sod1f/f; Vil-creERT2) mice. We found that loss of Sod1 in organoids suppressed the proliferation and survival of cells and Lgr5 gene expression. SOD1 is known for nearly half a century for its canonical role as an antioxidant enzyme. We identified its enzyme-independent function in ISC: inhibition of SOD1 enzymatic activity had no impact on organoid growth, and enzymatically inactive Sod1 mutants could completely rescue the growth defects of Sod1 deficient organoids, suggesting that SOD1-mediated ISC growth is independent of its enzymatic activity. Moreover, Sod1 deficiency did not affect the ROS levels of the organoid, but induced the elevated WNT signaling and excessive Paneth cell differentiation, which mediates the occurrence of growth defects in Sod1 deficient organoids. In vivo, epithelial Sod1 loss induced a higher incidence of apoptosis in the stem cell regions and increased Paneth cell numbers, accompanied by enhanced expression of EGFR ligand Epiregulin (EREG) in the stromal tissue, which may compensate for Sod1 loss and maintain intestinal structure in vivo. Totally, our results show a novel enzyme-independent function of SOD1 in ISC growth under homeostasis.

Potted Italian ryegrasses (Lolium multiflorum L.) were used to investigate the effect of ammonia-oxidizing bacterial (AOB) strain that coexisted in rhizosphere soil on Italian ryegrass regrowth. The results showed that the isolated and screened AOB strain (S2_8_1) had 100% similarity to Ensifer sesbaniae. The inoculation of S2_8_1 on day 44 before defoliation caused its copy number in rhizosphere soils to increase by 83–157% from day 34 before defoliation to day 14 after defoliation compared with that in Italian ryegrass without S2_8_1 inoculation, indicating that S2_8_1 coexisted permanently with Italian ryegrass. The coexistence promoted the delivery of root-derived cytokinin to leaves and to increase its cytokinin concentrations; thus, the Italian ryegrass regrowth accelerated. During the 14-day regrowth period, the S2_8_1 coexistence with Italian ryegrass caused its leaf and xylem sap cytokinin concentrations, rhizosphere soil nitrification rates, net photosynthetic rates, and total biomass to increase by 38%, 58%, 105%, 18%, and 39% on day 14 after defoliation, respectively. The inoculation of S2_8_1 on day 2 before defoliation also increased the regrowth of Italian ryegrass. Thus, the coexistence of AOB with Italian ryegrass increased its regrowth by regulating the delivery of cytokinins from roots to leaves.

A novel and efficient strategy for trifluoromethylthiolation and dearomatization of activated alkynes with stable and readily available AgSCF3 has been developed. Reported herein is the unprecedented electrochemical generation of the SCF3 radical in the absence of persulfate for the synthesis of SCF3-containing spiro[5,5]trienones in good yields via a 6-exo-trig radical cyclization.

To observe the clinical effect of penetrating moxibustion on migraine without aura (MO) patients.Totally 60 MO patients from the Acupuncture Clinic of the Third Affiliated Hospital of Henan University of Chinese Medicine were collected from November 2015 to February 2017. All patients were assigned to a treatment group and a control group using a random number table, 30 cases in each group. The treatment group was treated with penetrating moxibustion, and the control group was treated with mild moxibustion, thrice a week for 4 consecutive weeks. The total effective rate, Visual Analogue Scale (VAS) scores, headache intensity, and Migraine Specific Quality of Life Questionnaire (MSQ) scores of patients after treatment were compared between the two groups. The moxibustion sensation and reaction after moxibustion were observed, and the adverse reactions were evaluated. All patients were followed up at 4 and 16 weeks after treatment.The total effective rate of the treatment group was significantly higher than that of the control group (93.33% vs. 80.00%, P0.05). The improvement of VAS scores, headache intensity, and the role restrictive and role preventive scores in MSQ in the treatment group was better than those in the control group (P0.05). The person-time of moxibustion sensations of itching, numbness and cold as well as flushing and sweating after moxibustion in the treatment group was all significantly higher than that in the control group (P0.01). There was no significant difference in safety evaluation between the two groups (P0.05).Penetrating moxibustion can significantly relieve pain and improve quality of life of MO patients. After penetrating moxibustion, flushing and sweating of patients were obvious, and the curative effect was superior to the mild moxibustion.

The purpose of this prospective study was to investigate the 4-year outcome and prognostic factors of nonsurgical root canal retreatment determined by measuring the volumetric change of periapical radiolucencies on cone-beam computed tomographic (CBCT) scans.Ninety-seven endodontically treated teeth from 80 patients diagnosed as apical periodontitis and indicated for root canal retreatment were included. Retreatment was performed by 7 endodontic specialists using a standardized treatment protocol. The teeth were reexamined clinically and radiographically 48-67 months after retreatment. The volume of preoperative and postoperative periapical radiolucencies on CBCT images was independently measured by 2 examiners. Radiographic outcome is presented in 4 categories: absence, reduction, enlargement, or unchanged. Reduction or enlargement was determined when the volumetric change of radiolucency was 20% or more. Multivariate logistic regression was performed for predictor analysis.Sixty-two teeth (63.9%) from 50 patients returned for follow-up. Fifty-eight teeth were included in the prognostic analysis, all of which were symptom free. The 4 remaining teeth that had been extracted because of fracture were excluded. The total volume of periapical radiolucencies at 4 years postoperatively decreased by 94.6% compared with that preoperatively (P.001), with an average reduction of 83.4% (95% confidence interval, 69.2%-97.5%). The periapical radiolucencies were determined as absence in 44 teeth (75.9%), reduction in 10 teeth (17.2%), unchanged in 1 tooth (1.7%), and enlargement in 3 teeth (5.2%). Tooth type was identified as an outcome predictor (P.05).The 4-year outcome of endodontic retreatment is predictable, with a significant volumetric reduction in periapical radiolucencies.

A Lewis-acid-promoted cyclization reaction of benzoyl chlorides with 2-(4,5-dihydrooxazol-2-yl)anilines, which can offer a series of N3-chloroethyl quinazolinones, is disclosed. The reaction is compatible with the functional groups of the substrates; environment-friendly AlCl3 is probably the chloride source. Moreover, the addition of NH4SCN can also produce a range of N3-thiocyanatoethyl quinazolinones in moderate-to-good yields.

Background and aims Add-on devices have been widely used in clinical practice. The aim of this meta-analysis was to compare the adenoma detection rate between Endocuff-assisted colonoscopy (EAC) and cap-assisted colonoscopy (CAC). Methods PubMed, EMBASE, SCOPUS, and Cochrane databases were searched. Outcomes included adenoma detection rate, cecal intubation rate, cecal intubation time, and withdrawal time. Dichotomous data were pooled to obtain the odds ratio or risk ratio. Continuous data were pooled using the mean difference. Results Of the 240 articles reviewed, six randomized controlled trials were included, with a total of 1994 patients. In the meta-analysis, no statistical difference in adenoma detection rate was detected between EAC and CAC (47.0% vs 45.1%; P = 0.33). EAC significantly improved detection rate of diminutive adenomas/polyps compared with CAC (P = 0.01). Cecal intubation was achieved in 96.5% in EAC group and 97.9% in CAC group (P = 0.04). Besides, no statistical difference was found in cecal intubation time (P = 0.86), withdrawal time (P = 0.88), small adenomas/polyps (P = 0.60), or large adenomas/polyps (P = 0.95). Conclusion EAC and CAC have their respective merits. EAC significantly improve the detection of diminutive adenomas/polyps. CAC was better in cecal intubation rate.

Objective To explore the influence of scarring moxibustion on the changes of serum melatonin (MT) and neuropeptide Y (NPY) expressions in the insomnia model rats. Methods A total of 40 SD rats were randomly divided into a blank group, a model group, a scarring moxibustion group, an embedding needling group and a mild moxibustion group, 8 rats in each group. The intraperitoneal injection of p-chlorophenylalanine (PCPA) was adopted to establish the insomnia model rats and the corresponding interventions were given, consecutively for 6 days. Separately, before modeling and the first intervention as well as before sample collection, the body weight was measured and the serum was collected in the insomnia model rats. The enzyme linked immunosorbent assay (ELISA) was used to detect the levels of serum MT and NPY. Results Compared with the blank group, the body weight of rat in the model group was lower (P 0.05). Conclusion The regulation mechanism of sleep-wake circadian rhythm may be related to the levels of serum MT and NPY in the insomnia model rats. Scarring moxibustion increases the levels of MT and NPY more effectively and displays the effect in the intervention as compared with embedding needling and mild moxibustion in the insomnia model rats.

Cancer stem cells (CSCs) are reported to play essential roles in chemoresistance and metastasis. Pathways regulating CSC self-renewal and proliferation, such as Hedgehog, Notch, Wnt/β-catenin, TGF-β, and Myc, may be potential therapeutic targets. Here, a functional screening from the focused library with 365 compounds is performed by a step-by-step strategy. Among these candidate molecules, phenyl-2-pyrimidinyl ketone 4-allyl-3-amino selenourea (CU27) is chosen for further identification because it proves to be the most effective compound over others on CSC inhibition. Through ingenuity pathway analysis, it is shown CU27 may inhibit CSC through a well-known stemness-related transcription factor c-Myc. Gene set enrichment analysis, dual-luciferase reporter assays, expression levels of typical c-Myc targets, molecular docking, surface plasmon resonance, immunoprecipitation, and chromatin immunoprecipitation are conducted. These results together suggest CU27 binds c-Myc bHLH/LZ domains, inhibits c-Myc-Max complex formation, and prevents its occupancy on target gene promoters. In mouse models, CU27 significantly sensitizes sorafenib-resistant tumor to sorafenib, reduces the primary tumor size, and inhibits CSC generation, showing a dramatic anti-metastasis potential. Taken together, CU27 exerts inhibitory effects on CSC and CSC-associated traits in hepatocellular carcinoma (HCC) via c-Myc transcription activity inhibition. CU27 may be a promising therapeutic to treat sorafenib-resistant HCC.

IntroductionChimeric antigen receptor (CAR) T-cell (CAR-T) therapy followed by haploidentical hematopoietic stem cell transplantation (haplo-HSCT) markedly improves the long-term survival of patients with refractory/relapsed (R/R) B-cell acute lymphoblastic leukemia (B-ALL).MethodsWe performed a parallel comparison of transplant outcomes in 168 B-ALL patients undergoing haplo-HSCT after achieving minimal residual disease (MRD)-negative complete remission (CR) from CAR-T therapy (n = 28) or chemotherapy (n = 140) between January 2016 and August 2021. We further divided the chemotherapy group into the first CR group (chemo+CR1, n = 118) and a second or more CR group (chemo+≥CR2, n = 22).ResultsWith a median follow-up period of 31.0 months, the 2-year overall survival (OS), leukemia-free survival (LFS), non-relapse mortality (NRM), and relapse rates in the CAR-T and chemotherapy groups did not differ significantly (OS, 87.9% vs. 71.5 %; LFS, 72.0% vs. 66.8%; NRM, 3.9% vs. 13.7%; relapse, 24.1% vs. 19.4%). Multivariate analysis confirmed that ≥CR2 at transplantation following chemotherapy was an independent risk factor associated with poor OS (hazard ratio (HR) 4.22 [95% CI, 1.34–13.293], p = 0.014) and LFS (HR 2.57 [95% CI, 1.041–6.343], p = 0.041). The probabilities of OS and LFS at 2 years in the CAR-T group were comparable to those in the chemo+CR1 group but significantly higher than those in the chemo+≥CR2 group (OS, 87.9% vs. 37.8%, p = 0.007; LFS, 72.0% vs. 41.7%, p = 0.043). No significant differences in the incidences of NRM were noted among the three groups.ConclusionsOur results demonstrated that patients with R/R B-ALL receiving haplo-HSCT after CAR-T therapy achieved comparable outcomes to patients transplanted post-chemotherapy-based MRD-negative CR1, without increased risk of transplant-related mortality and toxicity.

Aim: The effects of tirofiban combined with nicorandil on effective reperfusion, and the levels of interleukin-4 (IL-4) and soluble intercellular adhesion molecule-1 (sICAM-1) after percutaneous coronary intervention (PCI) for chronic coronary total occlusion (CTO) were investigated. Method: From January 1, 2017, to June 31, 2019, a total of 40 patients with CTO receiving PCI in Shandong Qianfoshan Hospital were randomly divided into a control group (treated with single tirofiban) and a cocktail group (treated with nicorandil combined with tirofiban). Effective reperfusion was compared between groups. In addition, differences in coronary serum IL-4 and sICAM-1 levels before and 10 min after the operation were compared between groups, and the incidence rates of adverse reactions were observed. Finally, patient follow-up occurred at 1 month and 6 months, and the total incidence rates of adverse cardiac events in both groups were assessed. Results: The levels of IL-4 and sICAM-1 in the cocktail group significantly decreased after the operation (P0.05). Conclusion: The treatment of patients with CTO undergoing PCI with nicorandil and tirofiban alleviated the inflammatory response, improved the SAQ scores, and decreased the occurrence of angina pectoris in patients. Moreover, this treatment is safe and reliable, and has important clinical significance.

Neurotensin (NT) is an endogenous tridecapeptide in the central nervous system. NT-containing neurons and NT receptors are widely distributed in the spinal dorsal horn (SDH), indicating their possible modulatory roles in nociception processing. However, the exact distribution and function of NT, as well as NT receptors (NTRs) expression in the SDH, have not been well documented. Among the four NTR subtypes, NTR2 is predominantly involved in central analgesia according to previous reports. However, the expression and function of NTR2 in the SDH has not yet been directly elucidated. Specifically, it remains unclear how NT-NTR2 interactions contribute to NT-mediated analgesia. In the present study, by using immunofluorescent histochemical staining and immunohistochemical staining with in situ hybridization histochemical staining, we found that dense NT- immunoreactivity (NT-ir) and moderate NTR2-ir neuronal cell bodies and fibers were localized throughout the superficial laminae (laminae I-II) of the SDH at the light microscopic level. In addition, γ-aminobutyric acid (GABA) and NTR2 mRNA were colocalized in some neuronal cell bodies, predominantly in lamina II. Using confocal and electron microscopy, we also observed that NT-ir terminals made both close contacts and asymmetrical synapses with the local GABA-ir neurons. Second, electrophysiological recordings showed that NT facilitated inhibitory synaptic transmission but not glutamatergic excitatory synaptic transmission. Inactivation of NTR2 abolished the NT actions on both GABAergic and glycinergic synaptic release. Moreover, a behavioral study revealed that intrathecal injection of NT attenuated thermal pain, mechanical pain, and formalin induced acute inflammatory pain primarily by activating NTR2. Taken together, the present results provide direct evidence that NT-containing terminals and fibers, as well as NTR2-expressing neurons are widely distributed in the spinal dorsal horn, GABA-containing neurons express NTR2 mainly in lamina II, GABA coexists with NTR2 mainly in lamina II, and NT may directly increase the activity of local inhibitory neurons through NTR2 and induce analgesic effects.

Robust yeast strains that are tolerant to multiple stress environments are desired for an efficient biorefinery. Our previous studies revealed that zinc sulfate serves as an important nutrient for stress tolerance of budding yeast Saccharomyces cerevisiae. Acetic acid is a common inhibitor in cellulosic hydrolysate, and the development of acetic acid-tolerant strains is beneficial for lignocellulosic biorefineries. In this study, comparative proteomic studies were performed using S. cerevisiae cultured under acetic acid stress with or without zinc sulfate addition, and novel zinc-responsive proteins were identified. Among the differentially expressed proteins, the protein kinase Kic1p and the small rho-like GTPase Cdc42p, which is required for cell integrity and regulation of cell polarity, respectively, were selected for further studies. Overexpression of KIC1 and CDC42 endowed S. cerevisiae with faster growth and ethanol fermentation under the stresses of acetic acid and mixed inhibitors, as well as in corncob hydrolysate. Notably, the engineered yeast strains showed a 12 h shorter lag phase under the three tested conditions, leading to up to 52.99% higher ethanol productivity than that of the control strain. Further studies showed that the transcription of genes related to stress response was significantly upregulated in the engineered strains under the stress condition. Our results in this study provide novel insights in exploring zinc-responsive proteins for applications of synthetic biology in developing a robust industrial yeast.

Integrins are transmembrane receptor heterodimers composed of α and β subunits. They are known to mediate extracellular signals to promote cell adhesion and spreading, and are therefore essential for cellular immunity. However, proteins that bind to integrin cytoplasmic domains and mediate intracellular signaling to promote cell adhesion require identification. Calcium and integrin-binding protein 1 (CIB1) that binds to the integrin α-cytoplasmic domain has rarely been examined in insects. In this study, we found that 20-hydroxyecdysone promoted cell phagocytosis and spreading in Helicoverpa armigera. Transcriptomic analyses of hemocytes identified an integrin α gene (HaINTα-PS1) whose expression could be induced by either 20-hydroxyecdysone injection or bead challenge. Isothermal titration calorimetry assays showed that H. armigera CIB1-like (HaCIB1-like) weakly bound to the cytoplasmic domain of HaINTα-PS1 in the presence of calcium. HaINTα-PS1 or HaCIB1-like knockdown inhibited hemocytic encapsulation and phagocytosis, and plasmatocyte spreading. Moreover, HaCIB1-like overexpression in a H. armigera epidermal cell line overexpanded cells and impaired cell phagocytosis. Thus, insect CIB1-like potentially interacted with integrin α-cytoplasmic domain and facilitated cell adhesion. This study enriches our understanding of the molecular mechanism underlying integrin-mediated cellular immunity in insects.

Soluble Klotho (sKL) is closely related to insulin resistance, which is a major factor in the progression of diabetic cardiomyopathy (DCM). The purpose of this study was to investigate the role of sKL in the regulation of DCM and the mechanism involved. A mouse model of type 2 diabetes was induced by high-fat diet and streptozotocin injection. An insulin-resistant cardiac fibroblast model was established by high glucose and high insulin. KL gene overexpression was achieved in vivo and vitro through transfection with an adenovirus-harboring KL-cDNA. Gene overexpression was used to evaluate the role of sKL in the pathophysiologic characteristics of DCM. Insulin-resistant cardiac fibroblasts reduced sKL expression and collagen deposition. Diabetic mice constructed by streptozotocin exhibited severe insulin resistance, inflammation, fibrosis, left ventricular dysfunction, and sKL downregulation. The overexpression of sKL mitigated insulin resistance and metabolic disturbance; inflammation, fibrosis, and upregulated collagen I/III content ratio in diabetic state were significantly reduced. Our findings were accompanied by notable moderation of cardiac function. Further, blunted phosphorylation of Akt was restored with sKL gene overexpression, and activated phosphorylation of extracellular signal-regulated kinase 1/2 in DCM was reduced. Our results suggest that sKL protein overexpression exerts a defensive measure by ameliorating selective insulin resistance in mouse DCM, thus revealing its underlying mechanism for potential human DCM treatment.

A novel and efficient strategy for trifluoromethylthiolation and dearomatization of activated alkynes with stable and readily available AgSCF

One case of seborrheic dermatitis, male patient, aged 73 years is reported. After treated with acupuncture, penetrating moxibustion and bloodletting therapies, skin lesions on the neck and shoulder regions disappeared, the epidermis returned to normal and itching disappeared. There was no recurrence in the follow-up visit 3 months later. Hence, acupuncture, combined with penetrating moxibustion and bloodletting has a definite effect on this case in the patient and it is worthy of promotion and application in clinical practice.

Objective To compare the performances, tolerability and acceptability of mannitol and polyethylene glycol (PEG) as oral contrast agents in patients undergoing computed tomography enterography (CTE). Methods Patients aged 18‐75 years indicated for CTE were randomized to receive either mannitol or PEG as contrast agents. The coronal reconstructed images of each abdominal quadrant were assessed for maximum distention, proportion of distended bowel loops, presence of inhomogeneous contents and visibility of the small bowel wall. Overall subjective imaging quality assessment and patients’ tolerability and acceptability were recorded. Results Seventy patients were enrolled and randomized into two groups. In the per‐protocol analysis, no significant differences in imaging quality was found in bowel distention maximum diameter, wall visibility and intestinal homogeneity (all P > 0.05). The mean nausea score was lower in the mannitol group (0 [0‐0] vs 1.0 [0‐3.0], P

We have developed a copper-mediated one-pot synthesis of 2,3,5-trisubstituted pyrroles from 1,3-dicarbonyl compounds and acrylates using ammonium acetate as a nitrogen source. The reaction achieves C–C and C–N bond formation and provides an efficient approach to access highly functionalized pyrroles without further raw material preparation. This method is operationally simple, compatible with a wide range of functional groups, and provides the target products in moderate to good yields.

Riblet is one of the most promising passive drag reduction techniques in turbulent flows. In this paper, hot-wire measurements on a turbulent boundary layer perturbed by a drag-reducing riblet surface are carried out to further understand the riblet effects on the turbulent flows and the drag reduction mechanism. Compared with the smooth case, different energy variations in the near-wall region and the logarithmic region are observed over riblets. Then, by using a spectral filter of a given wavelength, the time series of the hot-wire data are decomposed into large- and small-scale components. It is indicated that large-scale structures in the logarithmic region impose a footprint (amplitude modulating effect) on the near-wall small-scale structures. By quantifying this footprint, it is found that the interactions between large- and small-scale structures over riblets are weakened in the near-wall region. Furthermore, the bursting process of large and small scales is studied. For both large- and small-scale structures, a shorter bursting duration and a higher bursting frequency are observed over the riblet surface, which indicates that riblets impede the formation of large- and small-scale bursting events. The flow physics behind these phenomena are also discussed in detail.

Background and aim The effect of real-time analysis of needle-based confocal laser endomicroscopy (nCLE) for gastric subepithelial lesions (SELs) on the diagnostic value is unclear. The study aimed to investigate the diagnostic efficacy of real-time nCLE for gastric SELs and to assess the technical aspects and safety of real-time nCLE. Methods Consecutive patients with gastric SELs ≥ 1 cm were prospectively investigated by endoscopic ultrasound (EUS), followed by nCLE. During EUS-nCLE, real-time nCLE diagnosis was made by an expert endoscopist. The procedure-relative adverse events were assessed and recorded. One-month washout period later, nCLE videos were reviewed off-line by the same endoscopist. The nCLE diagnoses were compared with corresponding pathological results. Additionally, image quality and interobserver agreements for the criteria were evaluated by three experienced endomicroscopists. Results Except for one failing to be punctured, 60 patients completed EUS-nCLE procedures successfully. Real-time nCLE had high diagnostic accuracies of ≥ 88.3% for gastric SELs. There were no significant differences between real-time and off-line nCLE diagnoses for gastric SELs (P > 0.05). The overall accuracy of real-time nCLE for diagnosis of gastric SELs was 86.7%. There were no procedure-relative adverse events occurred. In addition, the mean image quality score was 3.6 (1 = poor and 5 = excellent). The interobserver agreement was "almost perfect" for ectopic pancreas and "substantial" for gastrointestinal stromal tumor, leiomyoma, and carcinoma. Conclusions Endoscopic ultrasound-nCLE could provide in vivo real-time diagnostic imaging with a high diagnostic accuracy. Meanwhile, real-time nCLE was feasible and had a satisfactory safety profile.

Objective Qishen Yiqi Drop Pill (QSYQ) has been recognized as a potential protective agent for various cardiovascular diseases. However, the effect of QSYQ in cardiac complications associated with diabetes is not clear currently. In this study, we investigate whether QSYQ could exert cardiac protective effects against high glucose‐induced injuries in cardiac H9c2 cells. Methods H9c2 cells were exposed to 24 hours of high glucose in presence or absence of QSYQ and LY294002. Cell cytotoxicity, apoptosis, reactive oxygen species (ROS) generation, mitochondrial membrane potential and mitochondrial permeability transition pore (mPTP) opening were determined. Levels of bax, bcl‐2, p53, cleaved caspase‐3, PI3K and Akt were evaluated by Western blot. Results Our data indicated that QSYQ significantly increased the cell viability and decreased cytotoxicity. By analysing the apoptotic rate as well as the expression levels of cytoapoptosis‐related factors including cleaved caspase‐3, bax, bcl‐2, and p53, we found that QSYQ could remarkably suppress apoptosis of cardiomyoblasts caused by high glucose. In addition, it also showed that QSYQ reduced the generation of ROS. We further found that QSYQ treatment could inhibit the loss of mitochondrial membrane potential and mPTP opening. Moreover, Western blot analysis showed enhanced phosphorylation of PI3K/Akt. The specific inhibitor of PI3K, LY294002 not only inhibited QSYQ induced PI3K/Akt signalling pathway activation, but alleviated its protective effects. Conclusions In summary, these findings demonstrated that QSYQ effectively protected H9c2 cells against the series injuries due to high glucose at least partially by activating the PI3K/Akt signalling pathway.

Ficus carica is an Asian species of flowering plant belonging to the genus Ficus of the family Moraceae, native to Western Asia and the Middle East. Its fruits, usually known as common fig or fig, have been consumed as a very popular health-promoting fruit worldwide since ancient times. To investigate the potential health-promoting chemical constituents of the fruits of F. carica, a systematic phytochemical study on its fruits was therefore carried out. In our study, four new structurally diverse prenylated isoflavone derivatives, ficucaricones A-D (1-4), along with 12 known analogues (5-16) were separated from the fruits of F. carica. Their chemical structures were ambiguously elucidated based on extensive spectroscopic methods. The anti-inflammatory effects and antiproliferative activities of these isolated prenylated isoflavone derivatives were tested. Prenylated isoflavone derivatives (1-16) displayed remarkable inhibitory effects against nitric oxide (NO) production with the IC50 values ranging from 0.89 ± 0.05 to 8.49 ± 0.18 μM, comparable to that of the positive control (hydrocortisone). Furthermore, compounds 1-16 also exhibited pronounced antiproliferative activities against diverse human cancer cell lines in vitro, holding the IC50 values ranging from 0.18 ± 0.03 to 18.76 ± 0.09 μM. These findings indicate that regular consumption of the fruits of F. carica may help to prevent the occurrence of inflammatory diseases and tumors. Moreover, the isolation and characterization of these prenylated isoflavone derivatives possessing remarkable anti-inflammatory effects and antiproliferative activities could be meaningful to the discovery of new anti-inflammatory and antitumor agents.

Electrochemical sulfonylation/cyclization of 2-alkynylthioanisoles with sodium sulfinates was developed under catalyst-, external oxidant- and metal-free conditions. The electrosynthesis provides sustainable and efficient access to 3-sulfonated benzothiophenes with good substrate scope and functional group tolerance. This cascade radical process has been triggered through a sulfonyl radical addition to alkynes using sodium sulfinates under electrochemical conditions.

The establishment of protected areas is the bottom line of ecological security for promoting the construction of ecological civilization and supporting economic and social development, which is an important strategy to realize sustainable development and maintain ecological security. In order to reveal the large spatial process of protected areas and its influencing factors, we used the methods of nearest neighbor index, kernel density, and standard deviational ellipse to analyze the temporal-spatial variation characteristics of the protected areas in Guizhou Province from 2002 to 2017, as well as the influencing factors combined with geo-detectors. The results showed that, during the study period, the number, area, and types of protected areas in Guizhou Province showed a diversified and rapid development, forming a protected area system with nature reserves, forest parks and scenic spots as the main body and wetland parks, geoparks and natural heritage sites as the supplement. The spatial cohesion of protected areas was strengthened, the scope of spatial distribution was expanding, and the speed of spatial movement was declining, forming a spatial pattern dominated by the northeast-southwest direction and gradually stable. The coalescence process in protected areas was strongly influenced by topography and vegetation distribution. The protected areas tended to cluster in gentle terrain around rivers and mountains and in areas of concentrated vegetation. The spatial differentiation of protected areas was jointly affected by multiple factors at different levels. The explanatory power of different factors to the spatial differentiation of protected areas was different. Among them, the normalized difference vegetation index, areas of forest and highway mileage were the common main factors affecting the spatial differentiation of the number and area of protected areas, and the explanatory power of different factors was significantly consolidated after interaction, characterized as nonlinear or bi-factor enhancement.建立自然保护地是推进生态文明建设和支撑经济社会发展的生态安全底线,是实现可持续发展和维护国土生态安全的重要举措。为了揭示自然保护地的宏观空间过程及其影响因素,本研究以贵州省为例,采用最邻近点指数、核密度分析、标准差椭圆等方法,对2002—2017年全省自然保护地的时空分布特征进行分析,并结合地理探测器分析其影响因素。结果表明: 研究期间,贵州省自然保护地的数量、面积、类别呈现出多元化的快速发展状态,形成了以自然保护区、森林公园、风景名胜区为主体,以湿地公园、地质公园、自然遗产地为补充的自然保护地体系。自然保护地空间凝聚的态势不断加强,空间分布的范围不断扩大,空间移动的速度不断下降,形成了以东北-西南方向为主导且逐渐稳定的空间格局。自然保护地凝聚过程受地形和植被分布的影响较大;自然保护地趋向于在河流、山脉周围的地势平缓处和植被集中连片处聚集。自然保护地空间分异受多种影响因素的共同作用,不同影响因素对自然保护地空间分异的解释力存在一定的差异。其中,归一化植被指数、森林面积和公路里程是影响自然保护地数量、面积空间分异的共同主要因素;不同影响因素交互后的解释力明显加强,表现为非线性增强或双因子增强。.

Central sensitization is essential in maintaining chronic pain induced by chronic pancreatitis (CP), but cortical modulation of painful CP remains elusive. Here, we examined the role of the anterior cingulate cortex (ACC) in the pathogenesis of abdominal hyperalgesia in a rat model of CP induced by intraductal administration of trinitrobenzene sulfonic acid (TNBS). TNBS treatment resulted in long-term abdominal hyperalgesia and anxiety in rats. Morphological data indicated that painful CP induced a significant increase in FOS-expressing neurons in the nucleus tractus solitarii (NTS) and ACC, and some FOS-expressing neurons in the NTS projected to the ACC. In addition, a larger portion of ascending fibers from the NTS innervated pyramidal neurons, the neural subpopulation primarily expressing FOS under the condition of painful CP, rather than GABAergic neurons within the ACC. CP rats showed increased expression of vesicular glutamate transporter 1, and increased membrane trafficking and phosphorylation of the N-methyl-D-aspartate receptor (NMDAR) subunit NR2B and the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) subunit GluR1 within the ACC. Microinjection of NMDAR and AMPAR antagonists into the ACC to block excitatory synaptic transmission significantly attenuated abdominal hyperalgesia in CP rats, which was similar to the analgesic effect of endomorphins injected into the ACC. Specifically inhibiting the excitability of ACC pyramidal cells via chemogenetics reduced both hyperalgesia and comorbid anxiety, whereas activating these neurons via optogenetics failed to aggravate hyperalgesia and anxiety in CP rats. Taken together, these findings provide neurocircuit, biochemical, and behavioral evidence for involvement of the ACC in hyperalgesia and anxiety in CP rats, as well as novel insights into the cortical modulation of painful CP, and highlights the ACC as a potential target for neuromodulatory interventions in the treatment of painful CP.

Empathic pain has attracted the interest of a substantial number of researchers studying the social transfer of pain in the sociological, psychological, and neuroscience fields. However, the neural mechanism of empathic pain remains elusive. Here, we establish a long-term observational pain model in mice and find that glutamatergic projection from the insular cortex (IC) to the basolateral amygdala (BLA) is critical for the formation of observational pain. The selective activation or inhibition of the IC-BLA projection pathway strengthens or weakens the intensity of observational pain, respectively. The synaptic molecules are screened, and the upregulated synaptotagmin-2 and RIM3 are identified as key signals in controlling the increased synaptic glutamate transmission from the IC to the BLA. Together, these results reveal the molecular and synaptic mechanisms of a previously unidentified neural pathway that regulates observational pain in mice.

Context: Self-expandable metal stents (SEMSs) are commonly used in the treatment of malignant biliary obstruction. We performed a meta-analysis to compare the efficacy of covered self-expandable metallic stents (CSEMSs) and uncovered self-expandable metallic stents (UCSEMSs) for patients with malignant distal biliary obstruction. Methods: A comprehensive search was conducted using PubMed, Embase, Cochrane, and CNKI databases from 2010 to 2019. All randomized controlled trials, which compared the use of the CSEMSs and UCSEMSs for the treatment of malignant distal biliary obstruction were included in this study. Results: This meta-analysis included 1,539 patients enrolled in 13 trials. There was no difference between the two groups in terms of patients’ survival (hazard ratio (HR) 0.96, 95% confidence interval (CI): 0.87 - 1.07; I2 = 32.6%), stent patency (HR 0.92, 95% CI: 0.69 - 1.22; I2 = 56.3%), and the overall complication rate (relative risks (RR) 1.35, 95% CI: 0.82 - 2.23; I2 = 0%). In particular, the CSEMSs group presented a lower rate of tumor ingrowth (RR 0.30, 95% CI: 0.15 - 0.57; I2 = 58.5%) than the UCSEMSs group. However, the CSEMSs group exhibited a higher rate of tumor overgrowth (RR 1.63, 95% CI: 1.00 - 2.66; I2 = 0%), sludge formation (RR 2.28, 95% CI: 1.36 - 3.82; I2 = 0%), and migration (RR 5.14, 95% CI: 1.90 - 13.88; I2 = 0%). Conclusions: Our meta-analysis indicated that there was no significant difference between the two stents, and each one had its advantages and disadvantages.

Macrophage foam cell formation and inflammation are a pathological hallmark of atherosclerosis. ClC-2 has been implicated in various pathological processes, including inflammation and lipid metabolic disorder. However, the functional role of ClC-2 in macrophage foam cell formation and inflammation is unclear. Here, we found that ClC-2 was dominantly expressed in macrophages of atherosclerotic plaque and increased in atherogenesis. Knockdown of ClC-2 inhibited ox-LDL -induced lipid uptake and deposition in macrophages. The increase in CD36 expression and the decrease in ABCA1 expression induced by ox-LDL were alleviated by ClC-2 downregulation. Further, ClC-2 lacking limited the ox-LDL-induced secretion of inflammatory cytokines and chemokine, and suppressed Nlrp3 inflammasome activation. Restoration of Nlrp3 expression reversed the effect of ClC-2 downregulation on macrophage lipid accumulation and inflammation. Collectively, our study demonstrates that ClC-2 knockdown ameliorates ox-LDL-induced macrophage foam cell formation and inflammation by inhibiting Nlrp3 inflammasome activation. Macrophage ClC-2 lacking limits inflammation and foam cell formation, suggesting that ClC-2 may be a therapeutic target for atherosclerosis treatment.

Background The diagnostic yield of current techniques for gastric subepithelial tumors (SETs) is suboptimal. This prospective study aimed to develop diagnostic criteria for needle-based confocal laser endomicroscopy (nCLE) of gastric SETs, and to evaluate the diagnostic efficacy, feasibility, and safety of endoscopic ultrasound-guided nCLE (EUS-nCLE). Methods Eligible patients were prospectively recruited to undergo EUS-nCLE. Four unblinded investigators evaluated nCLE videos and corresponding histopathology to develop the nCLE criteria. The recorded nCLE videos were reviewed off-line by one endoscopist 3 months later. Image quality (five-point scale, 1 = poor and 5 = very good) and the interobserver agreements were assessed. Results All 33 patients underwent successful EUS-nCLE procedures. The nCLE criteria for gastric SETs were established. Overall accuracy of off-line nCLE was significantly higher than that of EUS alone (87.9 % vs. 63.6 %; P = 0.02). The mean image quality score was 3.9. The kappa values of the interobserver agreements were 0.66 for gastrointestinal stromal tumor, 0.89 for ectopic pancreas, 0.58 for leiomyoma, and 0.72 for carcinoma. Conclusions EUS-nCLE was feasible and safe to accurately diagnose gastric SETs.

As HER2 is frequently overexpressed in various malignancies, targeting HER2 is considered an efficient, highly selective antitumor therapy. HER2-targeted immunoconjugates are being developed and result in persistent remission of HER2-overexpressing tumors. However, many of the antibodies used as the targeting moiety are of murine origin and exhibit risk of inducing immunogenicity, limiting their antitumor therapeutic efficacy. Here, we humanized e23sFv, an HER2-targeting murine scFv with excellent affinity and specificity, using a human antibody consensus sequence engraftment strategy. The affinity of the initially humanized e23sFv was then rescued and improved by selective mutagenesis followed by phage-display-based affinity panning of the mutant pool. The resulting humanized e23sFv candidates (husFvs) exhibited up-to-94-fold increased affinity to recombinant HER2. The immunogenicity of e23sFv was dramatically alleviated after humanization, as indicated by the impaired production of cytokines by husFv-stimulated human PBMCs. Two internalizable husFvs with optimal affinity were applied to generate humanized immunoapoptotins by infusion with the translocation domain Fdt and the proapoptotic domain truncated Bid. The husFv-immunoapoptotins demonstrated improved HER2-targeting and tumor-killing capacities in vitro and in vivo compared with the e23sFv-immunoapoptotins and would enable the administration of multiple treatment cycles to patients, resulting in improved antitumor efficacy. Furthermore, the husFvs recognized distinct HER2 epitopes and could thus be used in combination with trastuzumab or pertuzumab to achieve robust synergistic antitumor effects in HER2-positive malignancies.

OBJECTIVE We aimed to investigate the efficacy of a split-dose 4-L polyethylene glycol (PEG) regimen for the quality of bowel preparation in Asian patients with previous colorectal surgery for colorectal cancer (CRC). METHODS This was a prospective, single-center, randomized controlled, endoscopist-blinded study. Patients with previous colorectal surgery for CRC were randomly allocated to a routine, morning-only 2-L PEG (2-MO) group or a split-dose 4-L PEG (4-SD) group. The primary outcome was a successful bowel preparation rate. Secondary outcomes were polyp detection rate (PDR), adenoma detection rate (ADR), patient compliance, satisfaction, tolerance, willingness to repeat the preparation and difficulty of the bowel preparation process. RESULTS In total, 187 patients were included (93 in the 2-MO group, 94 in the 4-SD group) in this study. The rate of successful bowel preparation in the 4-SD group was higher than in the 2-MO group (89.4% vs 66.7%, P

Emerging evidence has identified that long non-coding RNAs (lncRNAs) may play an important role in the pathogenesis of many cancer types, including colorectal cancer (CRC). However, the role of PlncRNA-1 in CRC remains unclear. The aim of our present study was to investigate the potential functions of PlncRNA-1 in CRC and to identify the underlying mechanisms of action. We demonstrated that up-regulated PlncRNA-1 in CRC tissues and cells promoted cell proliferation by accelerating cell cycle process and inhibiting cell apoptosis in vitro, enhanced tumor growth and matastasis in vivo and was associated with cell migration and invasion, EMT process of CRC cells. In addition, PlncRNA-1 was a target of miR-204 and enhanced the expression of an endogenous miR-204 target, MMP9 in CRC cells. Furthermore, we found that PlncRNA-1 activates Wnt/β-catenin pathway through the miR-204 in CRC cells. These results suggest that the PlncRNA-1/miR-204/ Wnt/β-catenin regulatory network may shed light on tumorigenesis in CRC.

The combined value of RDW and GRACE risk score for cardiovascular prognosis in ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI) has not been fully investigated. This study was designed to explore the combined value of RDW and GRACE risk score on predicting long-term major adverse cardiac event (Mace) in STEMI patients undergoing primary PCI. This study included 390 STEMI patients. The primary endpoint at the (33.5 ± 7.1) months follow-up was composed of cardiac death and nonfatal myocardial infarction. The relationship between clinical parameters and clinical outcomes was evaluated using Cox regression model and receiver operating characteristic (ROC) analysis. Mace occurred in 126 (32.3%) patients including 54 (13.8%) cardiac deaths and 72 (18.5%) nonfatal myocardial infarctions. Patients in Mace group had significantly higher RDW and GRACE score than the patients in non-Mace group. According to the Cox model, RDW and GRACE score were the most important independent predictors of Mace and cardiac death. The best cut-off value for RDW to predict the occurrence of primary events was 13.25% (AUC = 0.694, 95% CI:0.639–0.750, P < 0.001) and that for GRACE score was 119.5 (AUC = 0.721, 95% CI:0.666–0.777, P < 0.001). The combination of RDW and GRACE score were more valuable (AUC = 0.775, 95% CI: 0.727–0.824, P < 0.001). Kaplan–Meier analysis provided significant prognostic information with the highest risk for cardiac death (Log-Rank χ2 = 24.684, P < 0.001) in group with both high RDW (> 13.25%) and high GRACE score (> 119.5). The combination of RDW level and GRACE score may be valuable and simple independent predictors of Mace and cardiac death in STEMI patients undergoing primary PCI. They may be useful tools for risk stratification and may indicate long-term clinical outcomes.