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A highly efficient, high-voltage power switching technology, the Optical Transconductance Varistor (OTV) is being developed based on the photoconductive property of 6H-SiC. The behavior of the dislocations in 6H-SiC under the application of voltage and laser in such devices is of particular interest. In this study, both ex-situ and in-situ synchrotron X-ray topography were applied to characterize dislocations and investigate their behaviors when the sample was electrically and photonically stressed. Threading dislocations (TDs) and basal plane dislocations (BPDs) were revealed in transmission topographs and grazing topographs. When the samples were connected to external voltage ranging from 1kV to 4kV, there were no observable signs of dislocation movement. This indicates that the energy released from the transitioning of Vanadium states is lower than the activation energy for dislocation gliding.

In 4H-silicon carbide crystals, basal plane slip is the predominant deformation mechanism. However, prismatic slip is often observed in single crystals grown by the physical vapor transport method as the diameter expands to 6 inches or larger. Thermal modeling has shown that occurrence of prismatic slip is attributed to increased radial thermal gradients. While X-ray topography can be used to characterize the presence and extent of prismatic slip, the feasibility of using the chemical etching method to assess the extent of prismatic slip in an industrial setting is investigated. The distribution of scallop shaped etch pits oriented along the directions that correspond to prismatic dislocations, correlate well with the results of the thermal model that predicts the occurrence of prismatic slip dislocations. This capability of the etch pit method to characterize prismatic slip can be used to manage radial thermal gradients during PVT growth.

It has been assumed that patients with strict immunosuppressive treatment after solid organ transplantation have only marginal risk in developing autoimmune encephalitis. We reported a woman in her late 40 s who presented with generalized convulsions and loss of consciousness. After detailed history review, neuropsychological tests, metagenomic next-generation sequencing of serum and cerebrospinal fluid (CSF), magnetic resonance imaging (MRI) brain, and electroencephalogram, she was diagnosed as anti-CASPR2 encephalitis based on the positive anti-CASPR2 auto-antibody in serum and CSF. The patient underwent liver transplantation and has taken lenvatinib for 2 months, in addition to tacrolimus, mycophenotale mofetil, and entecavir administered for half a year. This case was the first report of anti-CASPR2 encephalitis in post-organ transplantation patients. Together with the reports of other encephalitis cases in organ transplantation, it warns the possibility of developing immune-oriented encephalitis in patients undergoing immunosuppression, especially in combination with other treatments of immunomodulatory activity.

Ribonucleases (RNases) play critical roles in RNA metabolism and are collectively essential for cell viability. However, the most knowledge about bacterial RNases comes from the studies on Escherichia coli, very little is known about the RNases in plant pathogens. The crucifer black rot pathogen Xanthomonas campestris pv. campestris (Xcc) encodes fifteen RNases, but none of them has been functionally characterized. Here, we report the physiological function of the exoribonuclease RNase D in Xcc and provide evidences demonstrating that the Xcc RNase D is involved in 5S rRNA degradation and exopolysaccharide (EPS) production. Our work showed that the growth and virulence of Xcc were not affected by deletion of RNase D but were severely attenuated by RNase D overexpression. However, deletion of RNase D in Xcc resulted in a significant reduction in EPS production. In addition, either deletion or overexpression of RNase D in Xcc did not influence the tRNAs tested, inconsistent with the finding in E. coli that the primary function of RNase D is to participate in tRNA maturation and its overexpression degrades tRNAs. More importantly, deletion, overexpression and in vitro enzymatic analyses revealed that the Xcc RNase D degrades 5S rRNA but not 16S and 23S rRNAs that share an operon with 5S rRNA. Our results suggest that Xcc employs RNase D to realize specific modulation of the cellular 5S rRNA content after transcription and maturation whenever necessary. The finding expands our knowledge about the function of the RNase D in bacteria.

Synchrotron monochromatic beam X-ray topography has been widely applied to characterize structural defects in SiC crystals. Using ray tracing simulations, the dislocation contrast in X-ray topography under strong diffraction conditions (diffraction takes place at or near Bragg angle) has been intensively investigated. However, the contrast and the configurations of the dislocation images recorded under weak diffraction conditions have not been fully investigated. Recently, we demonstrated that the contrast of dislocations in synchrotron grazing incidence topography under weak diffraction conditions can also be analyzed and interpreted by applying ray tracing principles. In this study, we have extended the application of the ray tracing method to analyze the dislocation contrast in weak beam synchrotron back reflection and rocking curve topography. The ray tracing method is shown to successfully simulate and correlate the contrast of threading screw dislocations at various positions on the rocking curve and thus allow to determine the signs of Burgers vectors.

Synchrotron X-ray topography techniques are used to characterize the microstructures in gallium nitride materials being developed for selective area doping for power electronic applications. Bulk substrates grown by different methods, epitaxial layers that are subject to ion implantation, annealing, etching and regrowth are characterized by X-ray topography in grazing incidence geometry and X-ray rocking curve topography. Strain and tilt maps of ion implanted epitaxial layers and etched and regrown wafers are generated. From the X-ray topographs, it is concluded that ammonothermal grown substrates show the highest quality among other types and most suitable for high-end electronic applications. It is also revealed that epitaxial growth, ion implantation and the annealing process do not change the dislocation distribution, but ion implantation introduces damage, strain and lattice bending effect, which are removed after annealing. Inductively coupled plasma (ICP) etching gives rise to strain variations in the wafer, while using tertiary butyl chloride (TBCl) to etch the wafer does not affect the strain distribution and can remove some damage from a preceding ICP etching process.

Understanding the depth from which contrast from dislocations is still discernible (the effective penetration depth of the X-rays) in grazing-incidence synchrotron monochromatic beam X-ray topography is of great interest as it enables three-dimensional dislocation configuration analysis and accurate density calculations. To this end, systematic analysis has been performed of topographic and ray-tracing simulated contrast of basal plane dislocations with different Burgers vector and line direction combinations, and a universal method to determine the effective penetration depth based on ray tracing has been developed. This study reveals that the observable dislocation contrast depends on the effective misorientation associated with the dislocation modulated by the photoelectric absorption effect. The dislocations with larger effective misorientation tend to have longer projected length and correspondingly deeper effective penetration depths.

4H-SiC wafers with 12 um epilayer were implanted at the Tandem Van de Graaff facility at Brookhaven National Laboratory with tunable energy from 13 MeV up to 66 MeV. Lattice strains introduced by the implantation process were characterized in detail by synchrotron rocking curve X-ray topography (SXRCT) and reciprocal space maps (RSMs). It is observed that the strain levels correlate with the atomic mass and energy of acceleration of the dopant atoms.

Serratus anterior plane block (SAPB) has been proven to be an efficient way to control postoperative pain. This study explored whether the use of continuous SAPB in combination with flurbiprofen could improve early pulmonary function in lung cancer patients undergoing video-assisted thoracoscopic surgery (VATS).From July 2019 to April 2020, patients who scheduled for elective lung resection undergoing VATS were randomly allocated to receive patient-controlled SAPB in combination with intravenous flurbiprofen or patient-controlled intravenous analgesia. Postoperative pulmonary function variables, including forced expiratory volume in 1 second, and forced vital capacity were collected before and 24, 48, and 72 hours after Surgical Procedure. Pain intensity was measured at rest and on coughing. Comfort scores during breathing exercises, postoperative pulmonary complications, and adverse events were recorded.A substantial reduction in lung function was exhibited in both groups after Surgical Procedure (P .001), but lung function variables in the continuous SAPB group were significantly higher (P .001) throughout the postoperative period up to 72 hours, regardless of the surgical procedure type. Meanwhile, there were significant differences of pain intensity at rest and on coughing between the groups (P .001). The incidence of pneumonia, pulmonary atelectasis, hypoxemia, vomiting, and the comfort score in the continuous SAPB group was significantly lower (P.05).Postoperative acute pain treatment with continuous SAPB in combination with flurbiprofen enhanced pulmonary function and reduced postoperative pulmonary complications in lung cancer patients undergoing VATS.

Background Proton pump inhibitors (PPIs) are widely used to treat digestive system diseases. Previous studies have suggested conflicting results between PPIs treatment and digestive tract cancers (DTCs). We utilized the FDA Adverse Event Reporting System (FAERS) database to assess the effect of PPIs use on DTCs through data mining. Method This study examined the association between six PPI agents and DTCs by mining the FAERS database from January 2004 to September 2021 by using Open Vigil 2.1. The reporting odds ratio (ROR) with 95% confidence intervals (CIs) was used to detect statistically significant associations between PPIs and DTCs. High Level Terms (HLTs) and Preferred Terms (PTs) were defined by the Medical Dictionary for Regulatory Activities 24.0 (MedDRA24.0). Result A total of 2553 DTCs adverse event reports were screened, with positive signals obtained from gastric neoplasms malignant (GNM) (ROR: 1.09, 95% CI: 1.01-1.18) and bile duct neoplasms malignant (BDNM) (ROR: 1.80, 95% CI: 1.44-2.25). Esomeprazole showed the strongest signal (ROR: 1.85, 95% CI: 1.66-2.06) for GNM, while rabeprazole for BDNM (ROR: 2.94, 95% CI: 1.32-6.56), and female PPI users had a higher risk of BDNM (ROR: 2.44, 95% CI: 1.77-3.35). Among Subordinate PTs, adenocarcinoma gastric, and the combination of “bile duct cancer” and “cholangiocarcinoma” were highly associated with PPIs use. Conclusion By mining the FAERS database, we provided important clues for the association between PPIs use and DTCs risk.

Mechanically ventilated patients suffering critical illness are at high risk of developing neurocognitive impairments. Angiotensin type 2 receptor (AGTR2) has been demonstrated to be anti-inflammatory and neuroprotective. The present study thus aimed to investigate whether AGTR2 can alleviate cerebral dysfunction in mice subjected to cochallenge with lipopolysaccharide (LPS) and mechanical ventilation (MV), and to reveal the underlying mechanism. We utilized a mice model that received a single injection of LPS (1 mg/kg, intraperitoneally) followed 2 h later by MV (10 ml/kg, lasting for 2 h). Pretreatment with the AGTR2 pharmacological agonist C21 (0.03, 0.3, and 3 mg/kg, intraperitoneally, once daily, lasting for 10 days). Locomotor activity and behavioral deficits were evaluated 24 h post-MV by open-field and fear-condition tests. Brain hippocampus and prefrontal cortex tissues were collected for immunofluorescence staining and western blotting to evaluate the resulting impacts on microglia, including morphological traits, functional markers, synaptic engulfment, superoxide production, and signaling molecules. Compared with vehicle-control, pre-administrated C21 reduced the branch endpoints and length of microglia processes in a dose-dependent manner in mice subjected to LPS/MV. The neuroprotective effect of AGTR2 was behaviorally confirmed by the improvement of memory decline in LPS/MV-treated mice following C21 pretreatment. In addition to morphological alterations, C21 reduced microglial functional markers and reduced microglial-dendrite contact and microglial engulfment of synaptic protein markers. In terms of the underlying molecular mechanism, AGTR2 stimulation by C21 leads to activation of protein phosphatase 2A, which subsequently mitigates microglial PKCδ and NF-κB activation, and inhibites NOX2-derived ROS production. The AGTR2 agonist C21 alleviates behavioral deficits in those mice subjected to LPS/MV, via mechanisms that involve reactive microglia and abnormal synaptic plasticity in NOX2-derived ROS and the PKCδ-NFκB pathway.

Context Icariin (ICA) is the main active ingredient of Epimedium brevicornu Maxim (Berberidaceae), which is used in the immune, reproductive, neuroendocrine systems, and anti-aging. Objective To evaluate the effect of ICA on natural aging rat. Materials and methods 16-month-old Sprague–Dawley (SD) rats were randomly divided into aging, low and high-dose ICA groups (n = 8); 6-month-old rats were taken as the adult control (n = 8). Rats were fed regular feed (aging and adult control) or feed containing ICA (ICA 2 and 6 mg/kg group) for 4 months. HE and Nissl staining were used to assess pathological changes. Western blot was used to test the expression of autophagy (LC3B, p62, Atg5, Beclin1) and p-AMPK, p-mTOR and p-ULK1 (ser 757). Immunofluorescence was used to detect the co-localization of LC3 and neurons. Results ICA improved neuronal degeneration associated with aging and increased the staining of Nissl bodies. Western blot showed that ICA up-regulated autophagy-related proteins LC3B (595%), Beclin1 (73.5%), p-AMPK (464%) protein (p

Context Panax japonicus is the dried rhizome of Panax japonicus C.A. Mey. (Araliaceae). Saponins from Panax japonicus (SPJ) exhibit anti-inflammatory and antioxidative effects. Objective To explore the neuroprotective effect of SPJ on natural ageing of rat. Materials and methods Sprague-Dawley (SD) rats 18-month-old were divided into ageing control, ageing treated with SPJ 10 or 30 mg/kg (n = 8). Five-month-old rats were taken as the adult control (n = 8). Rats were fed regular feed or feed containing SPJ for 4 months. Cognitive level was evaluated by Morris water maze (MWM) test. The mechanisms of SPJ's neuroprotection were evaluated by transmission electron microscope, western blot analysis, and immunofluorescence in vivo and in vitro. Results SPJ attenuated ageing-induced cognitive impairment as indicated by elevated number of times crossing the target platform (from 1.63 to 3.5) and longer time spent in the target platform quadrant (from 1.33 to 1.98). Meanwhile, SPJ improved the morphology of microglia and synapse, and activated M2 microglia polarisation including increased hippocampus levels of CD206 (from 0.98 to 1.47) and YM-1 (from 0.67 to 1.1), and enhanced autophagy-related proteins LC3B (from 0.48 to 0.82), Beclin1 (from 0.32 to 0.51), Atg5 (from 0.22 to 0.89) whereas decreased p62 level (from 0.71 to 0.45) of ageing rats. In vitro study also showed that SPJ regulated the microglial polarisation and autophagy. Discussion and conclusions SPJ improved cognitive deficits of ageing rats through attenuating microglial inflammation and enhancing microglial autophagy, which could be used to treat neurodegenerative disorders.

Sawing concrete with diamond saw blade is a complex process with alternating loading. However, due to the poor working conditions of the thin circular blade made of high manganese steel core, and the lack of research on its failure mechanism, a large number of used blade are abandoned every year in China and all over the world without steel core reused. Therefore, exploring the failure mechanism of diamond saw blade can improve the cutting quality and efficiency, and extend the service life of the saw blade. In this paper, the failure mechanism of diamond saw blade sawing concrete was analyzed through segment wear experiment and microstructure observation of segments and steel core of failed sawblade. The results showed that the stress concentration exited at the bottom of slot, where it became the most dangerous section. The crack at the bottom of the cooling hole caused the saw blade to deviate violently and bear unevenly. The microstructure is great different along the outer to the center of the steel core. The closer to the teeth of the saw blade, the more obvious the microstructure change, while the central core still retains the original structure. Under the same sawing area of 0.01m2, the stable dust adhesion of plain concrete is less than that of the steel fiber concrete. However, when the dust adhesion increases to more than the stable adhesion, the phenomenon of blockage will occur. Therefore, deflection, crack, wear and burn were the main failure reasons of diamond saw blade when sawing concrete.

Valganciclovir (VGCV) is the prodrug of ganciclovir (GCV). The objective of this study was to establish a population pharmacokinetic model (PPK) of GCV to investigate the PK characteristics of GCV after administration of VGCV in adult Chinese renal allograft recipients. Seventy Chinese renal allograft recipients were given 450 mg (n = 41) or 900 mg (n = 29) VGCV daily. Blood samples were drawn 0-24 hours after 5 days' therapy, and GCV plasma levels were determined. The PPK model was constructed using nonlinear mixed-effects modeling, and the Bayesian estimation of AUC0-24h was constructed for an individual patient based on limited plasma samples. The PK of GCV was best described by a 2-compartment model with a first-order absorption process. The CL/F, V2 /F, Q/F, V3 /F, Ka , and lag time of GCV were 15.8 ± 0.71 L/h, 10.9 ± 2.38 L, 3.98 ± 0.40 L/h, 167 ± 44.0 L, 0.23 ± 0.0078 1/h, and 0.93 ± 0.017 hours, respectively. Clearance of creatinine was found to have a significant impact on the CL/F of GCV (P < .01). Sampling strategies consisted of plasma concentrations 0 and 2 and 0, 2, and 4 hours after VGCV administration were shown to be suitable for the estimation of the GCV AUC0-24h . The PPK model was acceptable and can describe the PK of GCV in Chinese renal transplant patients administered VGCV. The AUC0-24h of GCV in Chinese renal transplant patients can be calculated by a limited sampling strategy method.

Background: Mitochondrial transplantation (MT) is a new technology developed in recent years, which injects healthy mitochondria directly into damaged tissues or blood vessels to play a therapeutic role. It has been studied in many animal models of various diseases, such as myocardial ischemia, cerebral stroke, liver and lung injury, and even has been successfully used in the treatment of childhood heart disease. MT can quickly improve tissue function within a few minutes after injection. This fast response is what is frequently questioned, for it is hard to understand how the whole mitochondria transport to the damaged sites, enter cells and function within such a short period of time. Are there any small molecules of mitochondrial component rather than the whole mitochondria that being responsible for the function of MT? To test this hypothesis, we established a much simple ultra-violet (UV)-irradiated HeLa cell model instead of the more complex animal models.Results: The results of colony formation, sulforhodamine B (SRB), and Hoechst 33342/PI double staining assay strongly indicated that MT exhibited a significant protective effect on UV irradiation damage. The UV irradiation-induced cell cycle arrest at S phase, apoptosis, mitochondrial membrane potential (MMP) decreasing, and the related apoptosis signalling factors p-IKKα, p-p65, I-κB and the activation of caspase3 were all reversed by MT treatments to some extent. Furthermore, mechanisms of MT were evaluated through comparing the effect of thermal inactivation, ultrasonic crushing, and repeated freezing and thawing treatments on MT function. The results denied the above hypothesis that mitochondrial component may function to MT, excluded the function of ATP, mtDNA and other small molecules, and indicated that the mitochondria structural integrity is essential.Conclusions: Our data support a potent anti-UV irradiation effect of MT, and structural integrity of mitochondria is critical for its function.

Context Panax japonicus is the dried rhizome of Panax japonicus C.A. Mey. (Araliaceae). Saponins from Panax japonicus (SPJ) exhibit anti-inflammatory and antioxidative effects. Objective To explore the neuroprotective effect of SPJ on natural ageing of rat. Materials and methods Sprague-Dawley (SD) rats 18-month-old were divided into ageing control, ageing treated with SPJ 10 or 30 mg/kg (n = 8). Five-month-old rats were taken as the adult control (n = 8). Rats were fed regular feed or feed containing SPJ for 4 months. Cognitive level was evaluated by Morris water maze (MWM) test. The mechanisms of SPJ’s neuroprotection were evaluated by transmission electron microscope, western blot analysis, and immunofluorescence in vivo and in vitro. Results SPJ attenuated ageing-induced cognitive impairment as indicated by elevated number of times crossing the target platform (from 1.63 to 3.5) and longer time spent in the target platform quadrant (from 1.33 to 1.98). Meanwhile, SPJ improved the morphology of microglia and synapse, and activated M2 microglia polarisation including increased hippocampus levels of CD206 (from 0.98 to 1.47) and YM-1 (from 0.67 to 1.1), and enhanced autophagy-related proteins LC3B (from 0.48 to 0.82), Beclin1 (from 0.32 to 0.51), Atg5 (from 0.22 to 0.89) whereas decreased p62 level (from 0.71 to 0.45) of ageing rats. In vitro study also showed that SPJ regulated the microglial polarisation and autophagy. Discussion and conclusions SPJ improved cognitive deficits of ageing rats through attenuating microglial inflammation and enhancing microglial autophagy, which could be used to treat neurodegenerative disorders.

Summary Osteoarthritis is the most common form of joint disease and is one of the leading causes of chronic pain. Given the multi-factorial nature, numerous efforts have been made to clarify the multiple factors impacting the pain symptoms and joint pathology, including synovial macrophages in particular. Accumulating evidence from studies involving human participants and experimental animal models suggests that accumulating macrophages in synovial tissue are implicated in peripherally mediated pain sensitization of affected joints in osteoarthritis. Crosstalk between synovial macrophages and the innervating primary nociceptive neurons is thought to contribute to this facilitated pain processing by the peripheral nervous system. Due to high plasticity and complexity of synovial macrophages in the joint, safe therapies targeting single cells or molecules are currently lacking. Using advanced technologies (such as single-cell RNA sequencing and mass cytometry), studies have shown that diverse subpopulations of synovial macrophages exist in the distinct synovial microenvironments of specific osteoarthritis subtypes. Considerable progress has been made in delineating the molecular mechanisms of various subsets of synovial macrophages in the development of osteoarthritis. To develop a novel intra-articular treatment paradigm targeting synovial macrophages, we have summarized in this review the recent advances in identifying the functional consequences of synovial macrophage sub-populations and understanding of the molecular mechanisms driving macrophage-mediated remodeling.

Objectives: This study aimed to determine the effect of intraoperative administration of flurbiprofen on postoperative levels of programmed death 1 (PD-1) in patients undergoing thoracoscopic surgery. Materials and Methods: In this prospective double-blind trial, patients were randomized to receive intralipid (control group, n = 34, 0.1 mL/kg, i.v.) or flurbiprofen axetil (flurbiprofen group, n = 34, 50 mg, i.v.) before induction of anesthesia. PD-1 levels on T cell subsets, inflammation, and immune markers in peripheral blood were examined before the induction of anesthesia (T0) and 24 h (T1), 72 h (T2), and 1 week (T3) after surgery. A linear mixed model was used to determine whether the changes from baseline values (T0) between groups were significantly different. Results: The increases in the percentage of PD-1(+)CD8(+) T cells observed at T1 and T2 in the control group were higher than those in the flurbiprofen group (T1: 12.91 ± 1.65 vs. 7.86 ± 5.71%, p = 0.031; T2: 11.54 ± 1.54 vs. 8.75 ± 1.73%, p = 0.004), whereas no differences were observed in the changes in the percentage of PD-1(+)CD4(+) T cells at T1 and T2 between the groups. Moreover, extensive changes in the percentage of lymphocyte subsets and inflammatory marker concentrations were observed at T1 and T2 after surgery and flurbiprofen attenuated most of these changes. Conclusions: Perioperative administration of flurbiprofen attenuated the postoperative increase in PD-1 levels on CD8(+) T cells up to 72 h after surgery, but not after this duration. The clinical relevance of changes in PD-1 levels to long-term surgical outcome remains unknown.

Two new diphenyl ethers (1 and 2) were isolated from the fermentation products of an endophytic fungus Phomopsis asparagi. Their structures were elucidated by spectroscopic methods, including extensive 1D and 2D NMR techniques. Compounds 1 and 2 were evaluated for their anti-methicillin-resistant Staphylococcus aureus (anti-MRSA) activity. The results revealed that compounds 1 and 2 showed good inhibition with IZD 10.8 ± 2.0 and 11.4 ± 1.8 mm, respectively.

The first addition-elimination of nitroalkanes to 3-phenacylideneoxindoles was developed, affording the corresponding 3-alkenylphenacylidene-oxindoles with high yields.The addition-elimination mechanism of 3-phenacylideneoxindoles with nitroalkanes and removable NO2 group in concert guarantees the high regioselectivity.

Valganciclovir (VGCV) treatment is recommended for the prevention of cytomegalovirus (CMV) infection in renal allograft recipients. The aim of the present study is to investigate the pharmacokinetic characteristics of ganciclovir (GCV) after administration of VGCV in Chinese adult renal allograft recipients and estimate the exposure to GCV using limited sampling strategy (LSS). Forty Chinese renal allograft recipients were given 450 mg or 900 mg VGCV daily. Blood samples were drawn before treatment and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 h after 5 days of VGCV therapy, and the plasma concentrations of VGCV and GCV were determined using a liquid chromatography-mass spectrometry assay. The major pharmacokinetic parameters for GCV and VGCV were determined using a noncompartmental assay. Multiple stepwise linear regression analysis was conducted to establish a model equation for the estimation of the GCV AUC0–24 h in Chinese patients using LSS. In the 450 and 900 mg groups, the Cmax for VGCV was 0.2 ± 0.10 and 0.4 ± 0.16 mg/L, respectively; the Cmax for GCV was 4.2 ± 1.1 and 8.6 ± 1.6 mg/L, respectively; and the AUC0–24 h for GCV was 28.4 ± 8.4 and 60.7 ± 17.5 mg·h/L, respectively. For the establishment of LSS models, 40 patients were divided into the training group (n = 24) and validation group (n = 16). The model equations used for the calculation of AUC0–24 h for GCV were established in the training group by using multiple linear regression assay. Equations including AUC = 8.1 + 29.7 × C0 + 5.7 × C4 (r2 = 0.91) and AUC = − 0.4 + 11.0 × C0 + 2.1 × C2 + 13.7 × C8 (r2 = 0.98) were acceptable. The %MPE and %MAPE values obtained from the validation group for the two model equations were 5.89 ± 14.5% and 12.1 ± 9.53%, and − 1.30 ± 4.40% and 3.28 ± 3.11%, respectively. The LSS models that included C0 and C4 or C0, C2, and C8 in the estimation of AUC0–24 h for GCV had favorable performance and can be used for therapeutic drug monitoring in the prevention of CMV infection using VGCV in Chinese renal allograft recipients.

Mitochondrial transplantation (MT) is a new technology developed in recent years, which injects healthy mitochondria directly into damaged tissues or blood vessels to play a therapeutic role. This technology has been studied in many animal models of various diseases including myocardial ischemia, cerebral stroke, liver and lung injury, and even has been successfully used in the treatment of childhood heart disease. MT can quickly improve tissue function within a few minutes after injection. The speed with which MT improves tissue function is frequently questioned, for it is hard to understand how the whole mitochondrion transports to the damaged sites, enters cells and functions within such a short period of time. Are there small molecules of mitochondrial component responsible for the function of MT? To test this hypothesis, we established an ultra-violet (UV)-irradiated HeLa cell model. The results of colony formation, sulforhodamine B (SRB), and Hoechst 33342/PI double staining assay strongly indicated that MT exhibited a significant protective effect against UV irradiation damage. The UV irradiation-induced cell cycle arresting at S phase, apoptosis, mitochondrial membrane potential (MMP) decreasing, and the related apoptosis signaling factors p-IKKα, p-p65, I-κB and the activation of caspase3 were all reversed by MT treatments to some extent. The mechanisms of MT were evaluated through comparing the effect of thermal inactivation, ultrasonic crushing, and repeated freezing and thawing treatments on MT function. These results denied the above hypothesis that mitochondrial component may be responsible for MT, excluded the function of ATP, mtDNA and other small molecules, and indicated that the mitochondria structural integrity is essential. We also evaluated the effect of Ca

Primary and secondary hyperalgesia develop in response to chronic joint inflammation due to peripheral and central mechanisms. Synovial macrophage and spinal microglia are involved in pain sensitization in arthritis. The level of angiotensin II type 2 receptor (AT

Reactive oxygen species (ROS) are either toxic in excess or essential for redox signalling at the physiological level, which is closely related to the site of generation. Xanthohumol (XN) is an important natural product of hops (Humulus lupulus L.) and was reported to induce ROS in mitochondria. While in the present study, our data indicate that NADPH oxidase (NOX) is another site. In human acute myeloid leukemia HL-60 cells, we first identified that cell proliferation was inhibited by XN without affecting viability, and this could be alleviated by the antioxidant N-acetyl-L-cysteine (NAC); cell cycles were blocked at G1 phase, apoptosis was induced in a dose-dependent manner, and malondialdehyde (MDA) content was upregulated. XN-induced ROS generation was detected by flow cytometry, which can be inhibited by diphenyleneiodonium chloride (DPI, a NOX inhibitor), while not by NG-methyl-L-arginine acetate (L-NMMA, a nitric oxide synthase inhibitor). The involvement of NOX in XN-induced ROS generation was further evaluated: immunofluorescence assay indicated subunits assembled in the membrane, and gp91phox knockdown with siRNA decreased XN-induced ROS. Human red blood cells (with NOX, without mitochondria) were further selected as a cell model, and the XN-induced ROS and DPI inhibiting effects were found again. In conclusion, our results indicate that XN exhibits antiproliferation effects through ROS-related mechanisms, and NOX is a source of XN-induced ROS. As NOX-sourced ROS are critical for phagocytosis, our findings may contribute to the anti-infection and anti-inflammatory effect of XN.

Chronic pain in osteoarthritis (OA) is characterized by pain sensitization, which involves both peripheral and central mechanisms. Studies suggest synovial macrophage and spinal microglia are implicated in pain sensitization in OA. We, therefore, reviewed the evidence of whether synovial macrophage and spinal microglia facilitated pain sensitization at diverse levels and how this event occurred in OA. Peripherally, joint inflammation is now believed to be a source of OA-related pain. Synovial macrophages accumulate in OA inflamed synovium and display a pro-inflammatory phenotype. Abundant macrophage-derived pro-inflammatory cytokines and other pain-causing substance facilitate hyperexcitation of primary sensory neuron in OA-related pain. Thus, activated synovial macrophage was considered a predictor for phenotyping of OA pain clinically. In response to affected joint-derived strong nociception, aberrant neuronal excitability is often associated with the hyperactivity of microglia in the spinal dorsal horn, thereby leading to central sensitization. Hyperactivity of synovial macrophage and spinal microglia underlies the mechanisms of pain sensitization at the peripheral and central level in OA. This concept provides not only a clinically relevant strategy for identifying the phenotype of OA-related pain but also has the potential to develop individualized interventions for OA, particularly in those patients with hyperactivity of macrophage and microglia.