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Four air-stable cyclometalated half-sandwich iridium complexes 1–4 with C,N-donor Schiff base ligands were prepared through C–H activation in moderate-to-good yields. These complexes have been well...

Dental pulp stem cells (DPSCs) are ideal seed cells for the regeneration of dental tissues. However, DPSC senescence restricts its clinical applications. Metformin (Met), a common prescription drug for type 2 diabetes, is thought to influence the aging process. This study is aimed at determining the effects of metformin on DPSC senescence. Young and aging DPSCs were isolated from freshly extracted human teeth. Flow cytometry confirmed that DPSCs expressed characteristic surface antigen markers of mesenchymal stem cells (MSCs). Cell Counting Kit-8 (CCK-8) assay showed that a concentration of 100 μM metformin produced the highest increase in the proliferation of DPSCs. Metformin inhibited senescence in DPSCs as evidenced by senescence-associated β-galactosidase (SA-β-gal) staining and the expression levels of senescence-associated proteins. Additionally, metformin significantly suppressed microRNA-34a-3p (miR-34a-3p) expression, elevated calcium-binding protein 39 (CAB39) expression, and activated the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) signaling pathway. Dual-luciferase reporter assay confirmed that CAB39 is a direct target for miR-34a-3p. Furthermore, transfection of miR-34a-3p mimics promoted the senescence of DPSCs, while metformin treatment or Lenti-CAB39 transfection inhibited cellular senescence. In conclusion, these results indicated that metformin could alleviate the senescence of DPSCs by downregulating miR-34a-3p and upregulating CAB39 through the AMPK/mTOR signaling pathway. This study elucidates on the inhibitory effect of metformin on DPSC senescence and its potential as a therapeutic target for senescence treatment.

Pediatric obsessive-compulsive disorder (OCD) sometimes appears rapidly, even overnight, often after an infection. Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections, or PANDAS, describes such a situation after infection withBinding of IgG to specific neurons in human and mouse brain slices was evaluated ex vivo after incubation with serum from 27 children with rigorously characterized PANDAS, both at baseline and after intravenous immunoglobulin (IVIG) treatment, and 23 matched control subjects. Binding was correlated with symptom measures. Neural activity after serum incubation was assessed in mouse slices using molecular markers and electrophysiological recording.IgG from children with PANDAS bound to CINs, but not to several other neuron types, more than IgG from control subjects, in three independent cohorts of patients. Post-IVIG serum had reduced IgG binding to CINs, and this reduction correlated with symptom improvement. Baseline PANDAS sera decreased activity of striatal CINs, but not of parvalbumin-expressing GABAergic interneurons, and altered their electrophysiological responses, in acute mouse brain slices. Post-IVIG PANDAS sera and IgG-depleted baseline sera did not alter the activity of striatal CINs.These findings provide strong evidence for striatal CINs as a critical cellular target that may contribute to pathophysiology in children with rapid-onset OCD symptoms, and perhaps in other conditions.

The preparation technology of micro-nano structure on copper surface is studied and optimized. Aqueous solution containing sodium carbonate and sodium molybdate is used as electrolyte, and the copper sample is anodized at a constant voltage to form a layer of oxidation on the copper surface. Then, the copper surface is treated with aqueous solution containing phosphate and sodium dihydrogen phosphate as corrosion solution to obtain a micro-nano structure on the copper. The surface is observed by using a scanning electron microscope. Finally, the analysis software is used to analyze the scanning electron microscope image to calculate the micro-nano structure pores on the copper surface. The results show that when the anodizing voltage is 15 V, the anodizing time is 20 min, the phosphoric acid mass fraction is 20%, and the corrosion time is 30 min, the copper surface is relatively smooth, and the porosity reaches 25.77%. Orthogonal experiments demonstrate that the type, concentration of the corrosive solution, and etching time have a great effect, while the anodizing electrolyte, voltage and electrolysis have no significant effect on the porosity. Using a combination of anodic oxidation and chemical corrosion, micro and nano junctions with uniform and high porosity can be prepared on the copper surface.

In this work, we calculate the local slip resistances (LSRs) in equal-molar MoNbTi multi-principal element alloy via molecular static simulations. We consider dislocations of either screw or edge character gliding on four types of slip planes, {110}, {112}, {123}, and {134}, in either forward or backward sense of the 111 slip direction. As references, we also compute the Peierls stresses of the same dislocations in two natural reference metals, Mo and Nb, and a synthetic one, the mean-field, A -atom potential-based MoNbTi. Further, we compare the LSRs with the corresponding ideal shear strengths that do not account for the lattice distortions induced by dislocation cores. We show that for neither dislocation character is the LSR on the {110} plane the lowest in MoNbTi, in contrast to Mo and Nb. For edge dislocations, slip on the {134} plane is the easiest, but for the screw dislocations, it is the hardest. For screw dislocations, the {112} glide plane is the most favored, while for edge dislocations, it is the least favored. We also find that the screw-to-edge ratio in the slip resistance is reduced by one order of magnitude in MoNbTi compared to that of any pure reference metal for the same type of slip plane. These results suggest that, in contrast to pure body-centered cubic (BCC) metals, BCC MPEAs could deform by a multiplicity of slip modes due to the lower screw-to-edge ratios and the lower LSRs for edge dislocations on the three higher order planes.

The new schemes of calculation of double integrals and triple integrals are proposed in this paper. The formulas in which the double integral is converted into a line integral with respect to the arc length, and the triple integral is converted into a surface integral with respect to the area or a line integral with respect to the arc length are given separately. The effectiveness of the proposed methods is verified by several examples. Under certain conditions, these methods become the normal iterated integrals in Cartesian coordinate system or polar coordinate system, and the commonly used triple iterated integrals in Cartesian coordinate system, Cylindrical coordinate system or Spherical coordinate system. The transformation calculation method promoted in this paper points out the intrinsic relationship among double integral, triple integral, line integral and surface integral, which further enriches the theories of multivariate integrals.

Most metal sites and some non-metallic sites such as carbon and nitrogen are usually considered to be traditional active sites during peroxymonosulfate (PMS) activation. However, as an important non-metallic element, the actual role of silicon (Si) in PMS activation still remains unclear. In this work, taking iron silicate (FeSi) as an example, the role of the Si region in PMS activation was clearly revealed. The experiments and density functional theory (DFT) calculation results showed that besides the traditional Fe sites, the Si also played a non-negligible role during PMS activation. In FeSi containing oxygen vacancies (Ovac), Fe-Si was the active site instead of Fe-Fe. The Bard charge results implied that the presence of Ovac tuned the electronic properties of FeSi, making the Si participate in PMS activation. This work deepened understanding of the role of Si in silicates for PMS activation and provided a theoretical basis for the development of excellent Si-based catalysts.

Concrete structures can be degraded by exposure to environmental stressors such as freeze–thaw cycling and salt corrosion. Magnesium potassium phosphate cement (MKPC) mortar is useful for the rapid repair of such structures but must acquire environmental resistance rapidly. In this study, the freeze–thaw resistance of MKPC mortar specimens of different hydration ages was tested in water and a 5% Na2SO4 solution. The strength, volume deformation, and water absorption rates were compared with those of full-age MKPC mortar specimens (28 d). The phase composition and microscopic morphology of the MKPC mortar specimens before and after corrosion were observed, and the corrosion-resistance mechanism was analyzed. After 225 freeze–thaw cycles in water and sulfate solution, the strength residual rates of the early-age specimen (1 d) were higher than those of the full-age specimen (28 d). The degree of strength attenuation in the 1 d specimen was lower in the sulfate environment than in the water environment. After 225 freeze–thaw cycles, the volume expansion rates of 1 d specimens in water or sulfate were 0.487% and 0.518%, respectively, while those of 28 d specimens were 0.963% and 1.308%. The comparison shows that the 1 d specimen had significantly better deformation resistance under freeze–thaw than the 28 d specimen. After 225 freeze–thaw cycles, the water absorption rates of 1 d specimens were 1.95% and 1.64% in water and sulfate solution, respectively, while those of 28 d specimens were 2.20% and 1.83%. This indicates that freeze–thaw cycling has a greater effect on the pore structure of fully aged mortar than on early-age mortar (1 d). Therefore, MKPC mortar is suitable for the rapid repair of concrete structures in harsh environments. The results form a theoretical basis for winter emergency repair projects. They also further the understanding of the application of MKPC-based materials in extreme environments.

Purpose/Background: Monoacylglycerol lipase (MAGL) is a 33 kDa serine protease that hydrolyses 2-arachidonoylglycerol (2-AG) to arachidonic acid in the mammalian central nervous system (CNS). Given that arachidonic acid and its eicosanoid metabolites induce inflammation and promote neurodegeneration, selective inhibition of MAGL constitutes a promising therapeutic strategy for neurodegenerative diseases. To date, several 11C- or 18F-labeled MAGL PET agents have been developed. While most of them bind to MAGL via an irreversible mechanism, only a limited number of reversible PET ligands have been disclosed. Herein, we report the design and synthesis of multiple reversible MAGL inhibitors based on a piperazinyl azetidine scaffold. Based on a structure-activity relationship study, the best performing reversible MAGL inhibitors, namely, target compounds 10 and 15 were labeled with fluorine-18 for further evaluations by autoradiography and PET imaging in rodents and non-human primates. Both [18F]10 and [18F]15 ([18F]MAGL-2102) exhibited favorable brain uptakes, heterogeneous radioactivity distribution, good specific binding, and adequate brain kinetics. Methods: A series of piperazinyl azetidine based MAGL inhibitor candidates were designed and synthesized (Fig. 1A). An initial screening was carried out with all inhibitor candidates in human MAGL inhibitor screening assay (Fig. 1B), and the potencies of the most promising irreversible inhibitor 10 and 15 were determined (Fig. 1C). The selectivity for MAGL over other serine hydrolases was assessed by activity-based protein profiling assays (ABPP) (Fig. 1D). The radiosyntheses of [18F]10 and [18F]15 were achieved via the Cu-mediated 18F-fluorination of the corresponding borate precursor with [18F]Et4NF in DMA/nBuOH at 110 ℃ for 20 min (Fig. 1E). In vitro autoradiography studies with were performed with [18F]10 (Fig. 1F) and [18F]15 on sagittal rat brain sections (Fig. 1G). Dynamic PET imaging studies were conducted with [18F]10 (Fig. 1H) and [18F]15 in rodents (Fig. 1I) and non-human primates (Fig. 1J). Results: All Candidates were obtained in 21-61% yields (Fig. 1A). Only 10 and 15 exhibited above 50% inhibition of MAGL at 9.26 nM (Fig. 1B) and their potencies (IC50: 4.2 and 4.6 nM, respectively) were measured (Fig. 1C). Both 10 and 15 exhibited excellent selectivity for MAGL over other lipid hydrolases (Fig. 1D). Ligands [18F]10 and [18F]15 were obtained in high radiochemical yields (57% and 53%, respectively, decay-corrected) and high molar activities (37 and 63 GBq/µmol, respectively) (Fig. 1E). Ligands [18F]10 and [18F]15 exhibited high radioactivity accumulation in the hippocampus, cortex, thalamus, striatum and cerebellum in both autoradiography and PET studies on rats and rhesus (Fig. 1F-1J). The reversible MAGL inhibitor, JNJ-42226314, remarkably diminished the radioactivity in MAGL-rich regions and abolished the regional heterogeneity (Fig. 1F-1J). Conclusion: We have designed and synthesized a novel panel of reversible candidate MAGL inhibitors based on a piperazinyl azetidine scaffold. Compounds 10 and 15 were identified as best-in-class MAGL inhibitors with excellent potencies and MAGL selectivities by in vitro pharmacological evaluations. A robust radiolabeling procedure was established for [18F]10 and [18F]15. Further evaluations of [18F]10 and [18F]15 in autoradiography and dynamic PET imaging studies in rodents and non-human primates demonstrated that both [18F]10 and [18F]15 had heterogenous regional brain distribution, which was consistent with known MAGL-expression patterns, and reversible binding in vivo. Specific MAGL binding was demonstrated for [18F]10 and [18F]15 on the rodent brain in vitro as well as in vivo. Notably, [18F]15 exhibited superior performance characteristics by means of a higher general brain uptake and enhanced in vivo specificity. In conclusion, [18F]15 ([18F]MAGL-2102) constitutes a promising reversible PET ligand for visualization of MAGL, which holds promise for clinical translation., SNMMI2022