Integrate multiple advanced technologies to rebuild a functional tissue with both neurotization and vascularization in the field of tissue engineering.
Based on light-induced anisotropic cell sheets ...(ACS) technology, which enabled the alignment of C2C12 myoblasts on the surface of titanium dioxide nanodots. Then PC12 neural cells were added to co-culture with C2C12s, and the optimal ratio was selected to construct an aligned neuralized muscle structure. Meanwhile, endothelial cells were induced to form the aligned vascular network. High-precision 3d printing technology was used to construct the flexible electrodes, and the above structures were assembled by hydrogel to finally form the composite constructs. The constructs were implanted in nude mice volumetric muscle loss (VML) models for validation, and in vivo electrical stimulation (ES) was performed during recovery. After 4 weeks, gait analysis techniques were used to assess the efficacy of functional recovery according to gait orderliness, print area and intensity. Muscle samples were collected for histology (H&E, MTS) and immunofluorescence staining (MHC, βIIIT, CD31) to evaluate muscle, nerve, and vascular regeneration.
The engineered muscle implanted group showed better muscle, nerve and vascular regeneration ability, and the assistance of electrical stimulation further enhanced muscle functional restoration.
The comprehensive repair strategy of electro-responsive functional neurovascularized engineered muscle (EFNEM) combined with in vivo ES can achieve tissue and functional recovery after VML, providing new insights into the field of tissue reconstruction.
Hydrodenitrogenation (HDN) experiments and density functional theory (DFT) calculations were combined herein to study the substituent effects of the nitrogen heterocycle on the HDN behaviors of ...indole and quinoline. Indole (IND), 2-methyl-indole (2-M-IND), 3-methyl-indole (3-M-IND), quinoline (QL), 2-methyl-quinoline (2-M-QL) and 3-methyl-quinoline (3-M-QL) were used as the HDN reactant on the NiMo/γ-Al
O
catalyst. Some key elementary reactions in the HDN process of these nitrogen compounds on the Ni-Mo-S active nanocluster were calculated. The notable difference between IND and QL in the HDN is that dihydro-indole (DHI) can directly convert to O-ethyl aniline via the C-N bond cleavage, whereas tetrahydro-quinoline (THQ) can only break the C-N single bond via the full hydrogenation saturation of the aromatic ring. The reason for this is that the -NH and C=C groups of DHI can be coplanar and well adsorbed on the Ni-Mo-edge simultaneously during the C-N bond cleavage. In comparison, those of THQ cannot stably simultaneously adsorb on the Ni-Mo-edge because of the non-coplanarity. Whenever the methyl group locates on the α-C or the β-C atom of indole, the hydrogenation ability of the nitrogen heterocycle will be evidently weakened because the methyl group increases the space requirement of the sp
carbon, and the impaction of the C=C groups on the Ni-S-edge cannot provide enough space. When the methyl groups are located on the α-C of quinoline, the self-HDN behavior of 2-M-QL is similar to quinoline, whereas the competitive HDN ability of 2-M-QL in the homologs is evidently weakened because the methyl group on the α-C hinders the contact between the N atom of 2-M-QL and the exposed metal atom of the coordinatively unsaturated active sites (CUS). When the methyl group locates on the β-C of quinoline, the C-N bond cleavage of 3-methyl-quinoline becomes more difficult because the methyl group on the β-C increases the steric hindrance of the C=C group. However, the competitive HDN ability of 3-M-QL is not evidently influenced because the methyl group on the β-C does not evidently hinder the adsorption of 3-M-QL on the active sites.
Keverprazan, a novel potassium-competitive acid blocker, was approved for treating acid-related diseases. This study aimed to analyze the safety, pharmacokinetics (PKs) and pharmacodynamics (PDs) of ...multiple doses of keverprazan. This was a randomized, positive-/placebo-controlled, phase Ic trial. Twenty-six healthy adults were randomized to receive 20 mg/day keverprazan (n = 8), 40 mg/day keverprazan (n = 8), placebo (n = 6), or 20 mg/day vonoprazan (n = 4) for 7 days. Safety, PK and PD assessments were conducted. In the keverprazan, vonoprazan, and placebo groups, adverse events (AEs) were reported in nine (56.25%), two (50.00%), and three (50.00%) subjects, respectively. AEs were mild except a moderate abdominal pain leading to withdraw. No serious AEs occurred. The plasma concentration-time profiles of keverprazan showed rapid absorption (median time to maximum plasma concentration of 1.25-3.0 h). The terminal half-life was 6.23 and 7.01 h for keverprazan 20 and 40 mg groups on day 7. The maximum plasma concentration was 43.1 and 93.2 ng/mL, respectively. There was no apparent accumulation of keverprazan and the major metabolite after 7-day administration. The intragastric pH greater than 5 holding time ratios (HTRs) over 24 h postdose increased from 79.1%, 84.4%, and 84.5% on day 1 to 99.0%, 97.4%, and 100.0% on day 7 in the vonoprazan 20 mg and keverprazan 20 and 40 mg groups, respectively. The intragastric pH greater than 5 HTR of keverprazan reached a plateau at 20 mg. Keverprazan is well-tolerable. A steady-state in exposure was generally reached after 7 days of treatment. A dose of 20 mg/day keverprazan can elicit a significant, stable, and long-lasting gastric acid inhibition effect.
Purpose
Ensartinib is a novel, potent and highly selective inhibitor of anaplastic lymphoma kinase (ALK) that has promising clinical activity and low toxicity in patients with ALK-positive non-small ...cell lung cancer. This study was conducted to investigate the pharmacokinetics, metabolism and excretion of ensartinib following a single 200 mg/100 μCi oral dose of radiolabeled ensartinib to healthy subjects.
Methods
Six healthy male subjects were enrolled and administrated an oral suspension in a fasted state. Blood, urine and feces were collected. Radioactivity concentrations were measured by liquid scintillation counting and plasma concentrations of ensartinib by liquid chromatography-tandem mass spectrometry. Both techniques were applied for metabolite profiling and characterization.
Results
The mean total recovery was 101.21% of the radiolabeled dose with 91.00% and 10.21% excreted in feces and urine, respectively. Unchanged ensartinib was the predominant drug-related component in urine and feces, representing 4.39% and 38.12% of the administered dose, respectively. Unchanged ensartinib and its metabolite M465 were the major circulating components, accounting for the same 27.45% of the plasma total radioactivity (AUC
0–24h
pool), while other circulating metabolites were minor, accounting for less than 10%. Mean
C
max
, AUC
0–∞,
T
1/2
and
T
max
values for ensartinib in plasma were 185 ng/mL, 3827 h ng/mL, 18.3 h and 3.25 h, respectively. The total radioactivity in plasma was cleared with terminal half-life of 27.2 h. Treatment with ensartinib was well tolerated, and no serious adverse events were reported.
Conclusion
It was well tolerated in the six healthy male subjects following a single oral administration of 200 mg/100 μCi dose of ensartinib. Besides unchanged ensartinib, metabolite of M465 was the predominant circulating drug-related component. The drug was primarily eliminated in feces.
Clinical trial registration
ClinicalTrials.gov NCT03804541.
The long-range transport of biomass burning pollutants from Southeast Asia has a significant impact on air quality in China. In this study, the Moderate Resolution Imaging Spectroradiometer (MODIS) ...fire data and aerosol optical depth (AOD) products and the Tropospheric Monitoring Instrument (TROPOMI) carbon monoxide (CO) data were used to analyze the impact of air pollution caused by biomass burning in Southeast Asia on southern China. Results showed that Yunnan, Guangdong and Guangxi were deeply affected by biomass burning emissions from March to April during 2016–2020. Comparing the data for fires on the Indochinese Peninsula and southern provinces of China, it is obvious that the contribution of pollutants emitted by local biomass burning in China to air pollution is only a small possibility. The distribution of CO showed that the overall emissions increased greatly from March to April, and there was an obvious transmission process. In addition, the MODIS AOD in areas close to the national boundary of China is at a high level (>0.6), and the AOD in the southwest of Guangxi province and the southeast of Yunnan Province is above 0.8. Combined with a typical air pollution event in southern China, the UVAI combined with wind direction and other meteorological data showed that the pollutants were transferred from the Indochinese Peninsula to southern China under the southwest monsoon. The PM2.5 data from ground-based measurements and backward tracking were used to verify the pollutant source of the pollution event, and it was concluded that the degree of pollution in Yunnan, Guangxi and Guangdong provinces was related to the distance from the Indochinese Peninsula. Results indicate that it is necessary to carry out in-depth research on the impact of cross-border air pollution transport on domestic air quality as soon as possible and to actively cooperate with foreign countries to carry out pollution source research and control.
Mechanical cues are widely used for regulating cell behavior because of their overarching, extensive, and non‐invasive advantages. However, unlike chemical cues, mechanical cues are not efficient ...enough to determine cell fate independently and improving the mechanosensitivity of cells is rather challenging. In this study, the combined effect of chemical and mechanical cues on the osteogenic differentiation of human mesenchymal stem cells is examined. These results show that chemical cues such as the presence of an osteogenic medium, induce cells to secrete more collagen, and induce integrin for recruiting focal adhesion proteins that mature and cascade a series of events with the help of the mechanical force of the scaffold material. High‐resolution, highly ordered hollow‐micro‐frustum‐arrays using double‐layer lithography, combined with modified methacrylate gelatin loaded with pre‐defined soluble chemicals to provide both chemical and mechanical cues to cells. This approach ultimately facilitates the achievement of cellular osteodifferentiation and enhances bone repair efficiency in a model of femoral fracture in vivo in mice. Moreover, the results also reveal these pivotal roles of Integrin α2/Focal adhesion kinase/Ras homolog gene family member A/Large Tumor Suppressor 1/Yes‐associated protein in human mesenchymal stem cells osteogenic differentiation both in vitro and in vivo. Overall, these results show that chemical cues enhance the microtopographical sensitivity of cells.
Chemical cues enhance the mechanical sensitivity of mesenchymal stem cells through Integrin α2/Focal adhesion kinase/Ras homolog gene family member A/Large Tumor Suppressor 1/Yes‐associated protein pathway. Further, double‐layer lithography and anisotropic etching is used to fabricate high‐resolution, highly ordered 3D hollow‐micro‐frustum‐arrays, combined with modified methacrylate gelatin loaded with pre‐defined soluble chemicals to provide both chemical and mechanical cues to cells to achieve osteogenic differentiation.
Congenital cavitary optic disc anomalies (CODA) is clinically typified by an enlarged excavation of optic disc in diverse degrees. Here, we report the clinical and genetic findings in a ...four-generation Chinese family with a complicated form of autosomal dominant CODA. Cardinal manifestations included bilateral excavated optic disc with multiple cilioretinal vessels emerging and bilateral retinoschisis with great variability in the range of extension and severity. Other intra-familial phenotypic diversities were also noted, including severity in retinal atrophy, onset age of visual impairment and presence of congenital nystagmus and strabismus. Genome-wide linkage analysis and fine mapping mapped a novel locus for CODA to a 34.3 cM interval between D14S972 and D14S139 at 14q12-q22.1. A maximum multi-point log odds score of 3.901 was reached at D14S275. However, no mutation was identified by exome sequencing or direct sequencing of PAX6 and PAX2 genes, suggesting that the mutation may reside within a regulatory element. In conclusion, we find retinoschisis as a necessary consequence of optic nerve head (ONH) anomalies. The complicated phenotype observed in the family provided additional insights into the inherited ONH anomalies. Mapping of a novel locus, 14q12-q22.1, implies a new disease-causing gene and potential distinct pathogenesis for CODA.
In response to pathological stimulation, methylation status conversion of the genome drives changes of cell feature and is able to promote disease development. Yet the role of methylation in the ...development of thyroid-associated ophthalmopathy (TAO) remains to be evaluated. Overexpansion of orbital tissue is the key feature of TAO. In this study, the methylation profile of orbital adipose/connective tissue from TAO patients and normal individuals were compared. After screening 3,739 differentially methylated probes, the distribution and properties of these probes were analyzed. Furthermore, enriched biological functions of these genes associated with differential methylation and the relationship between their methylation status and expression profile were also identified, including PTPRU and VCAM-1. According to our results, methylation was involved in disregulated immune response and inflammation in TAO and might contribute to activation of fibroblast and adipogenesis, leading to the expansion of orbital tissue. Neuropathy and neurobehavioral symptoms were also potentially associated with methylation. These results may help to extend the understanding of methylation in TAO and provide more insights into diagnosis and treatment of patients.
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•Establish and calculate the finite CoMoS model with corner structures.•Analyze the MoS bond and hydrogen dissociation on Mo-edge and Co-mixed Mo-edge.•Predict the steady state of ...Corner site under HDS reaction conditions.•Analyze the superiority of Corner site in thiophene HDS.
A non-periodic computational CoMoS model consisting of un-promoted Mo-edge (Mo-E), Co-mixed Mo-edge (Mo-X), Co-edge (Co-E) and corner (Corner) sites was used to examine the structural effect of CoMoS nanocluster on its hydrodesulfurization (HDS) reaction activity. A density functional theory (DFT) with numerical atomic functions was used to predict the fine structures of Mo-E, Mo-X, Co-E and Corner under common HDS condition. The elementary thiophene HDS reactions on Mo-X, Co-E and Corner sites were compared. The results show that the Mo-E has short and long MoS bonds; the former is more stable. The hydrogen dissociation on short MoS bond is endothermic and with high activation energy, whereas the hydrogen dissociation on long MoS bond is just the opposite. The Mo-X has only short MoS bonds. The Co atoms on the Mo-X and Corner exhibit a square planar coordinated structure with four sulfur atoms with a CoMo atom pair. The CoMo atom pair can easily form coordinatively unsaturated active site (CUS) by H2S desorption. The CUSs on the Mo-X and Corner sites preferably bond with radical containing sulfides to spin-restricted sulfides, leading to high hydrogenolysis activity of the CS bonds. The di-sulfur atom pairs on the Co-E and Corner sites are effective to dissociate the hydrogen molecule and reduce steric hindrance from adsorbing sulfur intermediates during HDS, leading to high hydrogenation activity at the Co-E and Corner sites. Thiophene HDS reactions can process completely on the Corner site which contains CoMo and di-sulfur atom pairs. Hence, increasing Corner sites in CoMoS is effective and beneficial to HDS catalysis.
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