Visible light driven photoredox/nickel-catalyzed stereoselective synthesis of Z- or E-vinyl thioethers from thiosilane and terminal alkynes.

A new method for the synthesis of anti-Markovnikov Z- or E-vinyl thioethers from thiosilane and terminal alkynes under visible-light-induced photoredox/nickel dual catalysis conditions is described. With a judicious choice of a simple nickel catalyst and a ligand, this strategy enables efficient and divergent access to both Z- or E-vinyl thioethers from the same set of simple starting materials. Notably, the approach is free of odorous thiol and has excellent compatibility with functional groups and substrate scope.

TACC3 is an independent prognostic marker, and knockdown of TACC3 enhances the efficacy of CDK1 inhibitor RO3306 in liver cancer cells.

The drug resistance of single-target therapy has gradually become an intractable clinical problem. Combination therapy may be an effective treatment to overcome or postpone drug resistance in cancer. Herein, we discussed the synergistic effect of transforming acidic coiled-coil containing protein 3 (TACC3) suppression and cyclin-dependent kinase 1 (CDK1) in hepatocellular carcinoma (HCC). The Cancer Genome Atlas database and bioinformatics methods were implemented to analyze the expression of CDK1 and TACC3, and predict the biological function of TACC3-related genes in HCC. In addition, in vitro experiments, including cell counting kit 8, transwell and flow cytometry were utilized to evaluate cell proliferation, migration, invasion, cell cycle arrest and apoptosis of HCC cells. Our results demonstrated that TACC3 is an unfavorable and independent prognostic factor to predict poor overall survival (OS) in HCC patients. Genetic inhibition of TACC3 exhibited a remarkable antineoplastic activity of HCC cell lines. Bioinformatic prediction proposed that CDK1 may be the main regulator of TACC3-related genes in HCC. In vitro experimental measurements suggested that a combination of si-TACC3 and CDK1 inhibitor synergistically inhibited cell proliferation and migration, and induced G2 cell cycle arrest and apoptosis of HepG2 or MHCC97H cells. In conclusion, our results revealed a prospective dual-target, TACC3 and CDK1, therapeutic strategy to improve the treatment of HCC.

Electrochemical Regioselective Cross-Dehydrogenative Coupling of Indoles with Xanthenes.

An electrochemical cross-dehydrogenative coupling of indoles with xanthenes has been established at room temperature. This coupling reaction could proceed in the absence of any catalyst or external oxidant, and generate the indole derivatives in moderate yields. Mechanistic experiments support that a radical pathway maybe involved in this reaction system.

Therapeutic Efficacy of a Staged Hybrid Technique vs. Coronary Artery Bypass Surgery Grafting in The Treatment of Multi-Vessel Coronary Artery Disease.

OBJECTIVE: Hybrid coronary revascularization (HCR) integrates the advantages of coronary artery bypass surgery grafting (CABG) and percutaneous coronary intervention (PCI) and provides another effective treatment for multi-vessel coronary artery disease (CAD). This study aimed to investigate the short- and intermediate-term efficacies of a staged hybrid technique vs. CABG in treating older patients with multi-vessel CAD. METHODS: Patients, who received elective revascularization for multi-vessel CAD between May 2016 and May 2018, were recruited. They were divided into the CABG group (N = 38) and HCR group (N = 38). The major adverse cardiovascular and cerebrovascular events (MACCE), including myocardial infarction and stroke, were recorded. The results of death and second revascularization also were recorded. RESULTS: In this study, 90.1% of patients received follow up for a median time of 24 months. At 60 days after surgery, the cumulative mortality in the CABG group was significantly higher than in the HCR group, but the incidence of second revascularization in the CABG group was markedly lower than in the HCR group. The incidence of MACCE was comparable between the two groups. CONCLUSION: In older patients with multi-vessel CAD, the mortality after CABG is higher than after HCR, but the incidence of second revascularization after CABG is lower than after HCR.

Exploring the impact of under-reported cases on the COVID-19 spatiotemporal distributions using healthcare workers infection data.

A timely understanding of the spatiotemporal pattern and development trend of COVID-19 is critical for timely prevention and control. However, the under-reporting of casesis widespread in fields associated with public health. It is also possible to draw biased inferences and formulate inappropriate prevention and control policies if the phenomenon of under-reporting is not taken into account. Therefore, in this paper, a novel framework was proposed to explore the impact of under-reporting on COVID-19 spatiotemporal distributions, and empirical analysis was carried out using infection data of healthcare workers in Wuhan and Hubei (excluding Wuhan). The results show that (1) the lognormal distribution was the most suitable to describe the evolution of epidemic with time; (2) the estimated peak infection time of the reported cases lagged the peak infection time of the healthcare worker cases, and the estimated infection time interval of the reported cases was smaller than that of the healthcare worker cases. (3) The impact of under-reporting cases on the early stages of the pandemic was greater than that on its later stages, and the impact on the early onset area was greater than that on the late onset area. (4) Although the number of reported cases was lower than the actual number of cases, a high spatial correlation existed between the cumulatively reported cases and healthcare worker cases. The proposed framework of this study is highly extensible, and relevant researchers can use data sources from other counties to carry out similar research.

Bacillus aquiflavi sp. nov., isolated from yellow water of strongly flavored Chinese baijiu.

A Gram-stain-positive, strictly aerobic and rod-shaped bacterium, designated as 3 H-10T, was isolated from a yellow water sample collected from the manufacturing process of strong flavor Chinese baijiu in Yibin region of Sichuan province (PR China). Oval endospores were formed at the subtermini of cells with swollen sporangia. The isolate was able to grow at temperatures of 20-45 °C (optimum growth at 37 °C), at pH 6.0-10.0 (optimum growth at pH 8.0) and in the presence of 0-2 % (w/v) NaCl (optimum growth with 0 % NaCl). Ribose was the major cell-wall sugar, and meso-diaminopimelic acid (meso-DAP) was the diagnostic amino acid. The main polar lipids of 3 H-10T included diphosphatidylglycerol (DPG), phosphatidylglycerol (PG) and phosphatidylethanolamine (PE). MK-7 was predominant menaquinone and iso-C15 : 0 (60.7 %) was the major fatty acid. Comparisons of 16S rRNA gene sequence indicated that 3 H-10T was most closely related to Bacillus mesophilus SA4T (96.30 %), Bacillus ginsengihumi Gsoil 114T (96.27 %) and Bacillus shackletonii LMG 18435T (96.27 %). The average nucleotide identity (ANI) values between strain 3 H-10T and the three type strains mentioned above were 69.56, 70.19 and 70.67 %, respectively. The genomic DNA G+C content was 35.4 mol%. On the basis of its phenotypic, chemotaxonomic and phylogenetic properties, strain 3 H-10T represents a novel species of the genus Bacillus, for which the name Bacillus aquiflavi sp. nov. is proposed. The type strain is Bacillus aquiflavi 3 H-10T (=CICC 24755T=JCM 33703T).

Identification of the metabolites of erianin in rat and human by liquid chromatography/electrospray ionization tandem mass spectrometry.

RATIONALE: Erianin, a bioactive component isolated from Dctidrobium chrysotoxum Lindl, was demonstrated to have many biological properties relevant to cancer prevention and therapy. However, the metabolic profiles of erianin remain unknown. This study was carried out to investigate the metabolic profiles of erianin in rats and humans. METHODS: Erianin was orally administered to rats at a single dose of 50 mg/kg. Urine and bile samples were collected. For in vitro metabolism, erianin was co-incubated with rat or human hepatocytes at 37°C for 2 h. The samples from incubations and rat were analyzed by liquid chromatography combined with electrospray ionization high-resolution mass spectrometry. The data were processed by MetWorks software. The structures of the metabolites were proposed by comparing the mass spectra with that of the parent compound. RESULTS: A total of twenty-four metabolites were detected in vitro and in vivo, including seven phase I and eighteen phase II metabolites. The phase I metabolic pathways of erianin were hydroxylation, demethylation and dehydrogenation. Erianin undergoes metabolic activation to form reactive metabolites quinoid intermediates, which were further trapped by glutathione (GSH) or N-acetylcysteine. The phase II metabolic pathways were glucuronidation, glutathione and N-acetylcysteine conjugation. CONCLUSIONS: The present study provides an overview pertaining to the in vitro and in vivo metabolic profiles of erianin, which is indispensable for us to understand the efficacy and safety of erianin, as well as the herbal medicine D. chrysotoxum.

Metabolic profiles of ribociclib in rat and human liver microsomes using liquid chromatography combined with electrospray ionization high-resolution mass spectrometry.

Ribociclib is a highly specific CDK4/6 inhibitor. Determination of the metabolism of ribociclib is required during the drug development stage. In this study, metabolic profiles of ribociclib were investigated using rat and human liver microsomes. Metabolites were structurally identified by liquid chromatography electrospray ionization high-resolution mass spectrometry operated in positive-ion mode. The metabolites were characterized by accurate masses, MS2 spectra and retention times. With rat and human liver microsomes, a total of 10 metabolites were detected and further identified. No human-specific metabolites were detected. The metabolic pathways of ribociclib were oxygenation, demethylation and dealkylation. Most importantly, two glutathione (GSH) adducts were identified in human liver microsomes fortified with GSH. The formation of the GSH adducts was hypothesized to be through the oxidation of electron-rich 1,4-benzenediamine to a 1,4-diiminoquinone intermediate, which is highly reactive and can be trapped by GSH to form stable metabolites. The current study provides an overview of the metabolic profiles of ribociclib in vitro, which will be of great help in understanding the efficacy and toxicity of this drug.

Percutaneous radiologic gastrostomy via nasopharyngeal intubation for the treatment of patients with complete malignant pharyngoesophageal obstruction.

BACKGROUND/AIMS: For patients with complete malignant pharyngoesophageal obstruction (CMPO), percutaneous radiologic gastrostomy (PRG) under ultrasound/CT guidance can complicate it to cause failure due to unsatisfied stomach filling. In this study, we retrospectively investigated whether PRG via nasopharyngeal intubation is feasible and effective for these patients. METHODOLOGY: PRG via nasopharyngeal intubation was attempted in 21 patients with CMPO (mean 70.8 ± 8.23 years). The technique comprised a dilation of the stomach via nasopharyngeal intubation using a catheter, followed by fluoroscopically guided puncture and gastrostomy tube placement. Complications including hemorrhage, peritonitis, gastrojejunocolic fistula, infection of puncture site, tube blocking and outleakage was observed during and after the procedure. RESULTS: A 5F catheter was successfully inserted to the stomach under fluoroscopical guidance and subsequent PRG was performed in all 21 patients. Minor complications occurred in 14.3% patients including mild infection of the fistula in 1, tube blocking in 1 and unexpected tube drawing out in 1. Follow-up nutrition indexes revealed obvious improved nutrition compared to before PRG (P < 0.05). CONCLUSION: PRG via nasopharyngeal intubation was simple, feasible and effective for patients with CMPO.

Curcumin protects neurons against oxygen-glucose deprivation/reoxygenation-induced injury through activation of peroxisome proliferator-activated receptor-γ function.

The turmeric derivative curcumin protects against cerebral ischemic injury. We previously demonstrated that curcumin activates peroxisome proliferator-activated receptor-γ (PPARγ), a ligand-activated transcription factor involved in both neuroprotective and anti-inflammatory signaling pathways. This study tested whether the neuroprotective effects of curcumin against oxygen-glucose deprivation/reoxygenation (OGD/R)-induced injury of rat cortical neurons are mediated (at least in part) by PPARγ. Curcumin (10 µM) potently enhanced PPARγ expression and transcriptional activity following OGD/R. In addition, curcumin markedly increased neuronal viability, as evidenced by decreased lactate dehydrogenase release and reduced nitric oxide production, caspase-3 activity, and apoptosis. These protective effects were suppressed by coadministration of the PPARγ antagonist 2-chloro-5-nitrobenzanilide (GW9662) and by prior transfection of a small-interfering RNA (siRNA) targeting PPARγ, treatments that had no toxic effects on healthy neurons. Curcumin reduced OGD/R-induced accumulation of reactive oxygen species and inhibited the mitochondrial apoptosis pathway, as indicated by reduced release of cytochrome c and apoptosis-inducing factor and maintenance of both the mitochondrial membrane potential and the Bax/Bcl-2 ratio. Again, GW9662 or PPARγ siRNA transfection mitigated the protective effects of curcumin on mitochondrial function. Curcumin suppressed IκB kinase phosphorylation and IκB degradation, thereby inhibiting nuclear factor-κ B (NF-κB) nuclear translocation, effects also blocked by GW9662 or PPARγ siRNA. Immunoprecipitation experiments revealed that PPARγ interacted with NF-κB p65 and inhibited NF-κB activation. The present study provides strong evidence that at least some of the neuroprotective effects of curcumin against OGD/R are mediated by PPARγ activation.

Construction of bupivacaine-loaded gelatin-based hydrogel delivery system for sciatic nerve block in mice.

Peripheral nerve blockade (PNB) is a common treatment to relieve postoperative pain. However, local anesthetics alone have a short duration of action and severe side effects during postoperative analgesia. In order to overcome these limitations, the present study reported an injectable hydrogel with a drug slow-release profile for regional nerve blockade. The injectable hydrogel was prepared by crosslinking with gelatin and NHS-PEG-NHS, which was degradable in the physiological environment and displayed sustainable release of anesthetics locally, thus improving the disadvantage of the high toxicity of local anesthetics. In this regard, we conducted a series of in vitro characterizations and proved that the hydrogel has a porous three-dimensional mesh structure with high drug loading capability, and sustainable drug release profile. And cytotoxicity experiments confirmed the good biocompatibility of the hydrogel. It was shown that using the animal sciatic nerve block model, the analgesic effect was greatly improved in vivo, and there was no obvious evidence of permanent inflammation or nerve damage in the block site's sections. This locally slow-release platform, combined with local anesthetics, is therefore a promising contender for long-acting analgesia.

The Effects of Processing Parameters during the Wire Arc Additive Manufacturing of 308L Stainless Steel on the Formation of a Thin-Walled Structure.

Wire arc additive manufacturing (WAAM) excels in producing medium to large components with a high deposition rate. Process optimization is crucial for uniform, defect-free components. This research employs orthogonal experimental design and response surface methodology (RSM) to control TIG WAAM-ed 308L stainless steel components. Varied parameters, including tungsten electrode angle, welding current, and speed, target weld bead attributes. Analysis of variance (ANOVA) evaluates multi-processing parameter influence on weld bead formation. Comparison with experimental results confirms accurate modeling of the relationship between parameters and bead attributes. The study optimizes process parameters and swing to enhance dimensional accuracy in single-layer and multi-layer components, improving precision, quality, and accuracy in thin-walled structures.

Transport of influenza virus neuraminidase (NA) to host cell surface is regulated by ARHGAP21 and Cdc42 proteins.

Influenza virus neuraminidase (NA) is transported to the virus assembly site at the plasma membrane and is a major viral envelope component that plays a critical role in the release of progeny virions and in determination of host range restriction. However, little is known about the host factors that are involved in regulating the intracellular and cell surface transport of NA. Here we identified the Cdc42-specific GAP, ARHGAP21 differentially expressed in host cells infected with influenza A virus using cDNA microarray analysis. Furthermore, we have investigated the involvement of Rho family GTPases in NA transport to the cell surface. We found that expression of constitutively active or inactive mutants of RhoA or Rac1 did not significantly affect the amount of NA that reached the cell surface. However, expression of constitutively active Cdc42 or depletion of ARHGAP21 promoted the transport of NA to the plasma membranes. By contrast, cells expressing shRNA targeting Cdc42 or overexpressing ARHGAP21 exhibited a significant decrease in the amount of cell surface-localized NA. Importantly, silencing Cdc42 reduced influenza A virus replication, whereas silencing ARHGAP21 increased the virus replication. Together, our results reveal that ARHGAP21- and Cdc42-based signaling regulates the NA transport and thereby impacts virus replication.

DNA vaccines targeting the encoded antigens to dendritic cells induce potent antitumor immunity in mice.

BACKGROUND: Although DNA vaccine holds a great potential for cancer immunotherapy, effective long-lasting antitumoral immunity sufficient to induce durable responses in cancer patients remains to be achieved. Considering the pivotal role of dendritic cells (DC) in the antigen processing and presentation, we prepared DC-targeting DNA vaccines by fusing tumor-associated antigen HER2/neu ectodomain to single chain antibody fragment (scFv) from NLDC-145 antibody specific for DC-restricted surface molecule DEC-205 (scFvNLDC-145), and explored its antitumoral efficacy and underlying mechanisms in mouse breast cancer models. RESULTS: In vivo targeting assay demonstrated that scFvNLDC-145 specifically delivered DNA vaccine-encoded antigen to DC. Compared with untargeted HER2/neu DNA vaccines, vaccination with scFvNLDC-145-HER2/neu markedly promoted the HER2/neu-specific cellular and humoral immune responses with long-lasting immune memory, resulting in effective protection against challenge of HER2/neu-positive D2F2/E2 breast tumor while ineffective in parental HER2/neu-negative D2F2 breast tumor. More importantly, in combination with temporary depletion of regulatory T cells (Treg) by low-dose cyclophosphamide, vaccination with scFvNLDC-145-HER2/neu induced the regression of established D2F2/E2 breast tumor and significantly retarded the development of spontaneous mammary carcinomas in transgenic BALB-neuT mice. CONCLUSION: Our findings demonstrate that DC-targeted DNA vaccines for in vivo direct delivery of tumor antigens to DC could induce potent antigen-specific cellular and humoral immune responses and, if additional combination with systemic Treg depletion, was able to elicit an impressively therapeutic antitumoral activity, providing a rationale for further development of this approach for cancer treatment.

Synthesis and biological studies of neopetrosiamides as inhibitors of cancer cell invasion.

The tricyclic peptides neopetrosiamides A and B, isolated from the marine sponge Neopetrosia sp., are potential antimetastatic agents that inhibit tumour cell invasion by both amoeboid and mesenchymal migration pathways. They differ in the stereochemistry of the methionine sulfoxide at position 24. Our previously reported syntheses using an orthogonal sulfur protection strategy established the critical connectivity of the three disulfide bonds. In this report, fifteen analogues of neopetrosiamide A and B, six which replace selected disulfide bonds and nine which replace the diastereomeric methionine sulfoxide, have been prepared using Fmoc solid-phase peptide chemistry. Disulfide replacement analogues were shown to lose activity, and only one of the methionine sulfoxide analogues retained full bioactivity in morphological studies.

The Way to Spend a Workday Matters in School Principals' Somatic and Psychological Discomfort.

BACKGROUND: School principals usually have to sacrifice health and family obligations to obtain sufficient work time. This study investigates school principals' somatic and psychological discomfort related to their time allocation to diverse work contexts and life domains, so as to test the optimal allocation of time to each context and domain. METHODS: This study is based on survey data of 347 school principals, from the preexisting 2021 Survey of School Teachers' Living Conditions in Shanghai. Generalized linear regression modeling was adopted to analyze the data according to the research purpose. RESULTS: This study finds that school principals' daily time spent on work at home, sleep, breakfast, exercise, and family obligations significantly predict their somatic or psychological discomfort. However, their time spent on work at school, daytime napping, lunch, and dinner are not of significance. CONCLUSIONS: This study reveals several unhealthy ways of working and lifestyle habits among school principals from a perspective of time allocation, such as extended periods working at home, sleep deficits, hurried breakfast, lack exercise, and failure to meet familial obligations.

Effect of oval foramen restriction and premature contraction of the arterial catheter on right heart function of fetuses and infants.

Objective: The effect of fetal oval foramen restriction and premature contraction of the arterial catheter for the right heart function of fetuses and infants was studied by evaluating the right and left ventricular (RV/LV) ratios, the tricuspid annular plane systolic excursion (TAPSE) value, and the Tei index of right heart function parameters. Methods: This study was approved by the Ethics Committee of First Affiliated Hospital of Hebei North University (K20190116). We collected 257 fetuses between March 2020 and December 2021. Among these, 98 fetuses that did not have any heart abnormalities were assigned to group A, 91 fetuses with restriction of the left and right atrial channels were assigned to group B, and 68 fetuses with premature contraction of the arterial catheter were assigned to group C. The ventricular transverse diameter, the right heart TAPSE value and the Tei index of fetuses in late pregnancy and 90 days after birth were measured in the three groups, and the diagnostic value of each index for the right heart function injury was evaluated. P < 0.05 indicates significant. Results: The P-value of the TAPSE value and Tei index of infants in BC and AC groups and postnatal infants were less than 0.05, which was significant. In the BC group, the RV/LV ratio of fetuses was compared when P > 0.05, which was not significant; however, P < 0.05 after birth was considered significant. For fetuses and postnatal infants in the BC group, the RV/LV ratio was negatively associated with the TAPSE value. However, it was positively associated with the Tei index; Diagnostic test results. To predict impaired right heart function after birth, TAPSE had low diagnostic value, RV/LV and Tei index had high diagnostic value. Conclusions: Oval foramen restriction and premature contraction of the arterial catheter may affect the right heart function after birth and be related to the degree of the right heart enlargement. Although TAPSE prediction of the fetal and postnatal right heart function is limited, the RV/LV ratio and the Tei index can be used to predict impaired right heart function after birth.

Hydrolysis of Carbonyl Sulfide in Blast Furnace Gas Using Alkali Metal-Modified γ-Al2O3 Catalysts with High Sulfur Resistance.

A carbonyl sulfide (COS) hydrolysis catalyst can play an efficient role in blast furnace gas (BFG), but the life of the catalyst is greatly shortened due to the presence of O2 and H2S in the atmosphere, so improving the sulfur resistance of the catalyst is the key to application. In this work, alkali metals Na and K modified γ-Al2O3 catalysts to improve COS hydrolysis efficiency and sulfur resistance by adding an alkaline center. Compared with γ-Al2O3 catalysts, the COS hydrolysis efficiency of the modified catalysts in the experiment was improved by 12% in the presence of H2S and O2. The main cause of catalyst sulfur poisoning is the presence of O2, which intensifies both the total amount of sulfur deposition and the proportion of sulfate. It is found that the NaOH/Al2O3 catalyst shows better sulfur resistance than the KOH/Al2O3 catalyst for two reasons: first, the support of Na can significantly improve the medium-strong alkaline site, which is the adsorption site of H2S. This is equivalent to increasing the "sulfur capacity" of H2S adsorption and reducing the impact of sulfur deposition on the main reaction. Second, the elemental sulfur is more easily produced on the NaOH/Al2O3 catalyst, but the sulfur is further oxidized to sulfate and sulfite on the KOH/Al2O3 catalyst. The molecular diameter of elemental sulfur is smaller than that of sulfate. Therefore, the NaOH/Al2O3 catalyst has better sulfur resistance.

Dabigatran etexilate tetra-hydrate.

In the title compound, C34H41N7O5·4H2O (systematic name: ethyl 3-{[2-({4-[(Z)-amino-(hexyl-oxycarbonyl-imino)-meth-yl]anilino}meth-yl)-1-meth-yl-benzimidazole-5-carbon-yl]pyridin-2-yl-amino}-propano-ate tetra-hydrate), the benzene and pyridine rings form dihedral angles of 5.4 (1) and 43.8 (1)°, respectively, with the benzimidazole mean plane. The terminal butyl group is disordered over two conformations in a 0.756 (10):0.244 (10) ratio. There is an intramolecular N-H⋯O hydrogen bond present. In the crystal, the water mol-ecules are involved in the formation of O-H⋯O, O-H⋯N and N-H⋯O hydrogen bonds, which link the components into layers parallel to the ab plane.

Expeditious synthesis of tetrasubstituted helical alkenes by a cascade of palladium-catalyzed C-H activations.

Twisted molecules: A modular approach for the synthesis of tetrasubstituted helical alkenes by a palladium-catalyzed norbornene-mediated domino reaction is presented. This intermolecular domino process allows the formation of three C-C bonds in one operation through a C-H activation/carbopalladation/C-H activation sequence.