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To evaluate the pharmacokinetics (PK), safety, and bioequivalence of two formulations of apixaban in healthy Chinese subjects under fasting and fed conditions.A single-center, randomized, open, single-dose, two-period crossover PK study was carried out under fasting and fed conditions in 64 healthy subjects enrolled in either the fasting (36 subjects) or the fed (28 subjects) arms of the study. Subjects received a single oral dose of 2.5 mg apixaban tablets as test (T) or reference (R) formulation. The primary PK parameters determined were the area under the plasma concentration-time curve from zero to t and ∞ (AUCA single drop-out in the fed arm of the trial was excluded from the statistical evaluation. The 90% confidence intervals (CIs) for the geometric mean ratio (GMR) for T/R using AUCThe test and reference 2.5 mg apixaban tablets were bioequivalent and both showed good tolerability and safety.

Chinese chestnut shell polyphenol (CSP) reduce inflammation and increase antioxidant capacity, and activating the LEPR-JAK2/STAT3-PTP1B-SOCS-3 signal transduction pathway to alleviate high-fat diet–induced, leptin-resistant obesity in mice.

Cloperastine is a pivotal antibechic widely prescribed to treat cough caused by respiratory diseases. The present trial evaluated the pharmacokinetics (PK), bioequivalence (BE) and safety effects of the generic test (T) tablet of cloperastine after single-dose administration of cloperastine, compared with the original reference (R) tablet of cloperastine.The purpose of this trial was to compare the PK, BE and safety of a test 10 mg versus the reference 10 mg formulation of cloperastine under fasting and postprandial conditions in healthy Chinese volunteers.A single-centre, randomised, open, double-cycle, self-crossover, single oral administration Phase I trial was performed in healthy Chinese volunteers. A total of 60 subjects were enrolled in either the fasting (28 subjects) or the postprandial condition (32 subjects). Subjects randomly received a single dose of the T or R preparation (10 mg dose). Plasma concentrations of cloperastine were analysed by a validated LC-MS/MS method. The primary endpoints of the PK parameters were the area under the plasma concentration-time curve from zero to 72 h (AUCA total of 25 and 30 subjects in the fasting and postprandial conditions completed this clinical trial, respectively. The geometric mean ratio (GMR) of the T/R for the CThe T and R preparations were bioequivalent under both conditions. Food has no significant effect on the absorption of cloperastine. Moreover, T and R preparations were well tolerated. The trial registration number (TRN) and date of registrations were CTR20212515, 13 October 2021.

The hot deformation of TA15 titanium alloy was studied by the hot compression test on the Gleeble-3800 thermal simulation equipment. The true stress-strain curves of TA15 titanium alloy at the temperature of 1123-1223K and the strain rate of 0.001-1s-1 were obtained.. The results show that the flow stress increases with decreasing temperature, and increases as the strain rate increases. And the deformation process is accompanied by work hardening and dynamic recovery and dynamic recrystallization. Based on the true stress-strain curves of TA15 titanium alloy, the Arrhenius-typed constitutive equation was established. The thermal deformation activation energy of TA15 titanium alloy with a strain of 0.2 is 746.27kJ/mol.

Given the afferent functions, sensory nerves recently have been found exerting efferent influences and directly alter organ physiology. Moreover, studies have demonstrated the crucial role of sensory nerves in the physiological function of osteoclasts. However, the direct evidence of whether sensory nerve efferent influences osteoclast, remains lacking. Here, we found abundant efferent signals transported from sensory nerves into osteoclasts; sensory hypersensitivity significantly increased osteoclastic bone resorption; and sensory neurons (SN) directly promote osteoclastogenesis in vitro co-culture system. Then our screening identified a novel neuropeptide Cyp40, is the efferent signal from the sensory nerve and plays a critical role in the osteoclastogenesis, via aryl hydrocarbon receptor (AhR)-Ras/Raf-pErk-NFATc1 pathway. These findings revealed a novel mechanism of sensory nerves on bone regulation: the direct promotion of osteoclastogenesis by secreting Cyp40. Inhibiting the Cyp40 could therefore be a strategy to improve bone quality in osteoporosis and promote bone repair after bone injury.

The sedimentation performance of sludge affects the operation of the entire treatment process. It is important to measure the zone settling velocity accuracy and high efficiency which can reflect the sedimentation performance of sludge. Traditional methods often rely entirely on manual implementation. Long hours of manual measurement work brings physical strain to the operator, low efficiency of the entire measurement work and a large error in the measurement results. Therefore, the method combining image processing and neural network to realize automatic recognition of the scale value of sludge water interface in sludge sedimentation video is proposed. Based on the recognized scale value, overall sedimentation change curve is drew, and the sludge sedimentation rate is calculated. Then, the activated sludge was examined by phase contrast microscope to obtain sludge image. The flocs, filamentous bacteria and other targets in the image are segmented with Labelme, the characteristics of flocs and sedimentation rate of the previous day are taken as input of deep stochastic configuration network, and the calculated sludge sedimentation rate is output for predicting layered sedimentation rate. Through experimental analysis, the prediction error is within a reasonable range. The intelligent prediction of sludge regional sedimentation velocity is realized.

To endow Ti-based orthopedic implants immunomodulatory capability and thus enhanced osseointegration, different amounts of Sr are doped in Na2TiO3 nanorods in the arrays with identical nanotopographic parameters (rod diameter, length and inter-rod spacing) by substitution of Na+ using hydrothermal treatment. The obtained arrays are denoted as STSr2, STSr4, and STSr7, where the arabic numbers indicate the incorporating amounts of Sr in Na2TiO3. The modulation effects of the Sr-doped nanorods arrays on macrophage polarization and osteogenetic functions of osteoblasts are investigated, together with the array without Sr (ST). Moreover, osseointegration of these arrays are also assayed in rat femoral condyles. Sr-doped nanorods arrays accelerate M1 (pro-inflammatory phenotype)-to-M2 (anti-inflammatory phenotype) transformation of the adhered macrophages, enhancing secretion of pro-osteogenetic cytokines and growth factors (TGF-β1 and BMP2), moreover, the Sr doped arrays directly enhance osteogenetic functions of osteoblasts. The enhancement of paracrine of M2 macrophages and osteogenetic function of osteoblasts is promoted with the increase of Sr incorporating amounts. Consequently, Sr doped arrays show significantly enhanced osseointegration in vivo compared to ST, and STSr7 exhibits the best performance. Our work sheds a new light on the design of surface chemical components and structures for orthopedic implants to enhance their osseointegration.

An elderly Chinese male patient was diagnosed with compound heterozygous spinocerebellar ataxia type 8; molecular diagnosis found that the (CTA)n(CTG)n repeat unit of his ATXN8/ATXN8OS gene was 134/93. The patient has a 6-year medical history, mainly manifested by ataxia, dysarthria, abnormal eye movements, and pyramidal signs. Magnetic resonance imaging (MRI) showed no obvious abnormalities in the medulla oblongata and cervical spinal cord except for cerebellar atrophy and sulci enlargement. There are heterozygous SCA8 individuals among his family members, but there are significant differences in their onset age and clinical manifestations.This case reminds us that (CTA)n(CTG)n repeats are very prone to dynamic mutations in intergenerational inheritance, and the ATXN8/ATXN8OS gene penetrance is different in different SCA8 individuals, which suggests that genetic detection is of great importance.

Using nucleophilic, boron-based –CF2Ar reagents, we demonstrate three methods to form C–CF bonds: (1) nucleophilic aromatic substitution, (2) palladium catalyzed cross-coupling, and (3) nucleophilic substitution.

Malignant hyperthermia (MH) is an autosomal dominant genetic condition of the skeletal muscle triggered by inhaled general anesthetic agents or succinylcholine and associated with a hypermetabolic state and skeletal muscle rigidity. Tachycardia, increased carbon dioxide production, hypercarbia, hyperthermia, acidosis, hyperkalemia, cardiac arrhythmias, muscle rigidity, and rhabdomyolysis are common symptoms of MH. As the progression of the syndrome could be rapid or less evident, even experienced physicians have difficulty in diagnosing MH, which can lead to delays in treatment and increased mortality. We report a rare case of a 36-year-old man, who underwent open reduction and internal fixation of the left clavicle after inhaled anesthetics. The patient developed dyspnea, hypotension, unremitting hyperthermia, tachycardia, and elevated serum myoglobin, and finally died of pyemia and disseminated intravascular coagulation. We reviewed the process of disease development, summarized the steps of diagnosis, and improved genetic testing. Exome sequencing revealed a new mutation c.8519G>A (p.arg2840 GLN) in the RYR1 gene that could be associated with MH. The gene mutation was also found in his daughter’s genetic test. This case emphasized the importance of the awareness of MH and its atypical clinical symptoms. The presence of dyspnea, hypotension, unremitting hyperthermia, tachycardia, and raised myoglobin in serum might further strengthen the clinical diagnosis of suspected MH.

SARS-CoV-2, which likely spilled over from wildlife, is the third highly pathogenic human coronavirus. Being highly transmissible, it is perpetuating a pandemic and continuously posing a severe threat to global public health.

IntroductionInfectious meningitis and encephalitis (ME) are life-threatening conditions are caused by various pathogens. Conventional laboratory tests with low sensitivity and specificity cannot help with early diagnosis.MethodsA prospective study using the novel multiplex PCR detection for 18 pathogens of ME (MME-18) was conducted to investigate the clinical utilization and the epidemiology characteristics of ME in southwestern China. Patients with suspected intracranial infection were recruited between May and October 2019 at West China Hospital of Sichuan University. The MME-18 was used to detect cerebrospinal fluid, and conventional experiments including cryptococcal capsular antigen detection, GeneXpert, real-time PCR, and clinical feedback were used to verify the result of MME-18.ResultsAmong 581 tested patients, 139 eligible individuals were enrolled in the study. Among them, Mycobacterium tuberculosis was the most common pathogen in mono-infection. Viruses and Cryptococcus neoformans were also frequently detected. Of 139 infected patients, 12 cases were diagnosed by MME-18 only, 57 patients by conventional testing only, and 70 cases by both comparator tests and MME-18. There were 96.3% (79/82) diagnoses made by MME-18 had a favorable outcome, and two of twelve diagnoses, made solely by MME-18, had a likely unclear clinical significance.DiscussionThe MME-18 showed satisfactory consistency with expert clinical consensus for patients presenting with ME. Combined with conventional testing and clinical suspicion, MME-18 may help clinicians with the early identification of pathogens.

We outline a new synthetic method to prepare mono- and polyfluoroepoxides from a diverse pool of electrophiles (ketones, acyl chlorides, esters) and fluoroalkyl anion equivalents. The initially formed α-fluoro alkoxides undergo subsequent intramolecular ring closure when heated. We demonstrated the versatility of the method through the isolation of 16 mono- and polyfluoroepoxide products. These compounds provide unique entry points for further diversification via either fluoride migration coupled with ring opening, or defluorinative functionalization reactions, the latter of which can be used as a late-stage method to install select bioactive moieties. The reaction sequences described herein provide a pathway to functionalize the commonly observed products formed from 1,2-addition into carbonyl electrophiles.

Stroke is a fatal neurological disease, which seriously threatens human health and life. Ischemic stroke (IS) is the most common type of stroke in clinic. Its pathogenesis is very complex, mainly caused by nerve damage caused by brain blood supply disorder. Previous studies have confirmed that natural products play important roles in improving neurological disorders. Furthermore, our previous results also suggested that Shenxiong Tongmai granule, a clinically used herbal medicines’ prescription, has a good ameliorating effect on IS. In the present study, we found that Monomethyl lithospermate (MOL), a constituent of Shenxiong Tongmai granule, significantly improved the neurological damage in middle cerebral artery occlusion (MCAO) rats. MOL can significantly improve the neurological deficit score of MCAO rats, and improve the damage of hippocampal neurons caused by ischemia-reperfusion (IR). At the same time, we also found that MOL could reduce the level of oxidative stress in the brain tissues of MCAO rats. Furthermore, the oxygen and glucose deprivation/Reoxygenation (OGD/R)-induced SHSY-5Y cell model was established in vitro to investigate the pharmacological activity and molecular mechanisms of MOL in improving the nerve injury of IS rats. The results showed that MOL could increase the cell viability of SHSY-5Y cells, inhibit the mitochondrial membrane potential (MMOP) collapse and suppress apoptosis. In addition, MOL also ameliorated the elevated oxidative stress level caused by OGR/R treatment in SHSY-5Y cells. Further mechanistic studies showed that MOL could activate the PI3K/AKT pathway via promoting the phosphorylation of PI3K and AKT in MCAO rats and OGR/R-induced SHSY-5Y cells, which could be partially blocked by addition of PI3K/AKT pathway inhibitor of LY294002. Taken together, our current study suggested that MOL exerts a protective effect against neural damage caused by IS in vivo and in vitro by activating the PI3K/AKT pathway.

The worldwide pandemic of coronavirus disease 2019 (COVID-19) presents us with a serious public health crisis. To combat the virus and slow its spread, wider testing is essential. There is a need for more sensitive, specific, and convenient detection methods of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Advanced detection can greatly improve the ability and accuracy of the clinical diagnosis of COVID-19, which is conducive to the early suitable treatment and supports precise prophylaxis. In this article, we combine and present the latest laboratory diagnostic technologies and methods for SARS-CoV-2 to identify the technical characteristics, considerations, biosafety requirements, common problems with testing and interpretation of results, and coping strategies of commonly used testing methods. We highlight the gaps in current diagnostic capacity and propose potential solutions to provide cutting-edge technical support to achieve a more precise diagnosis, treatment, and prevention of COVID-19 and to overcome the difficulties with the normalization of epidemic prevention and control.

Lysosomes play key roles in different cellular processes such as autophagy, phagocytosis, and apoptosis. Lysosomal dysfunction is related to many diseases. Fluorescence lysosome staining strategy is valuable for the researches on the lysosome involvement in different pathological diagnosis. Here we describe fluorescence lysosome staining methods with carbon dots for the identification of lysosomes in living and fixed cells.

Purpose: To analyze the distribution of fibrovascular proliferative membrane (FVPM) in proliferative diabetic retinopathy (PDR) patients that need treated with pars plana vitrectomy (PPV), and to evaluate the outcomes separately. Methods: Retrospective review of consecutive 25-G PPV cases operated for PDR between September 2018 and April 2020. All FVPMs were outlined and assigned to three groups: arcade type, juxtapapillary type and central type. General characteristics, operation-related variables, best-corrected visual acuity (BCVA) 12 month postoperative and complications were recorded. , All patients were followed up for over one year Results: In total, 93 eyes were recruited. Among them, the FVPMs distribution of nasotemporal and inferiosuperioral were significantly different (both p < 0.01), with 87 (93.55%) FVPMs located in the nasal hemispheres, and 67 (72.04%) in the inferior hemispheres. The eyes with a central FVPM required the longest operation time, with silicon oil used in most patients, generally combined with tractional retinal detachment (RD) and rhegmatogenous RD, as well as the worst postoperative best-corrected visual acuity and the highest rates of recurrent RD and iatrogenic retinal break formation (all p < 0.05). Conclusion: FVPMs were more commonly found in the nasal and inferior mid-peripheral retina in addition to the area of arcade vessels. Performing 25-G PPV for treating PDR eyes with a central FVPM had a relatively worse prognosis.

The activation of ferroptosis is a new effective way to treat drug-resistant solid tumors. Ferroptosis is an iron-mediated form of cell death caused by the accumulation of lipid peroxides. The intracellular imbalance between oxidant and antioxidant due to the abnormal expression of multiple redox active enzymes will promote the produce of reactive oxygen species (ROS). So far, a few pathways and regulators have been discovered to regulate ferroptosis. In particular, the cystine/glutamate antiporter (System Xc−), glutathione peroxidase 4 (GPX4) and glutathione (GSH) (System Xc−/GSH/GPX4 axis) plays a key role in preventing lipid peroxidation-mediated ferroptosis, because of which could be inhibited by blocking System Xc−/GSH/GPX4 axis. This review aims to present the current understanding of the mechanism of ferroptosis based on the System Xc−/GSH/GPX4 axis in the treatment of drug-resistant solid tumors.

Skeletal muscle atrophy is associated with many diseases including cancer, inflammatory diseases, neuromuscular diseases, and acute critical illness.

The purpose of this trial was to evaluate the pharmacokinetics (PK), bioequivalence (BE), and safety of 2 preparations of hydroxychloroquine (200-mg tablet) under fasting and fed conditions. A total of 180 subjects (fasting condition: n = 80; fed condition: n = 100) were randomly enrolled in this randomized, open, single-dose, single-cycle parallel phase Ⅰ clinical study. Under the 2 conditions, the subjects were randomly administered the test (T) or reference (R) tablet, both at a dose of 200 mg (1 tablet). Liquid chromatography-tandem mass spectrometry was used to determine the concentration of hydroxychloroquine in healthy subjects after oral administration of the T or R preparation to evaluate the PK characteristics. In this trial, the T and R preparations of hydroxychloroquine were bioequivalent under both conditions within the range of 80%-125%. No serious adverse events (SAEs) were found in the safety assessments for either condition, and all adverse events (AEs) were mild, except for 2 moderate AEs in the fed condition, indicating good safety.

GH2132 superalloy performances excellent properties, such as the good rupture strength and yield strength below 923K, the fine processing plasticity and the good welding properties. The warm working behavior of GH2132 superalloy at 673 K – 773K is investigated by a thermal simulator in this paper. The results show that the worm working effects at the center of specimen is the most significant compared with other positions. The deformation temperature and strain rate is the key parameters significantly affecting the warm working behavior. The increase of the temperature enhances the recovery softening effect, which reduces the stress and the work hardening effect slightly. The deformation heat is significant with the increasing strain rate, which results in the work hardening behavior does not change markedly. This study provides an important reference for the worm forming of GH2132 superalloy.

To increase the correction effectiveness of full-order aberration, a control system based on a magnetic fluid flexible mirror with dual-layer actuators is presented. The combined magnetic field created by the Maxwell coil and the double-layer driving coils controls the geometry of the magnetic fluid surface. A model-based optical sensorless control approach for lower layer coils is developed and aimed to enable high magnitude restoration of lower-order aberrations. An adaptive important factor that causes on Youla parameterization, on the other hand, is developed for the upper coils to rectify higher-order residual aberrations. Matlab is used to simulate the algorithm in order to test its performance in full-order aberration correction, and the results reveal that the approach has good correction performance.

A straightforward method for the undirected trifluoromethylation of unactivated methylene units was developed. The reaction proceeds in aqueous acetonitrile with Grushin's reagent, bpyCu(CF3)3, under broad-spectrum white-light irradiation. The trifluoromethylation tolerates a wide range of functional groups including ketones, esters, nitriles, amides, alcohols, and carboxylic acids. The C-H cleavage step is performed via intermolecular H atom abstraction, and the selectivities across a range of methylene units are reported. Mechanistic studies offer a general reaction coordinate for the overall transformation.

Malignant tumor is a major killer that seriously endangers human health. At present, the methods of treating tumors include surgical resection, chemotherapy, radiotherapy and immunotherapy. However, the survival rate of patients is still very low due to the complicated mechanism of tumor occurrence and development and high recurrence rate. Individualized treatment will be the main direction of tumor treatment in the future. Because only by understanding the molecular mechanism of tumor development and differentially expressed genes can we carry out accurate treatment and improve the therapeutic effect. MicroRNA (miRNA) is a kind of small non coding RNA, which regulates gene expression at mRNA level and plays a key role in tumor regulation. Ferroptosis is a kind of programmed death caused by iron dependent lipid peroxidation, which is different from apoptosis, necrosis and other cell death modes. Now it has been found that ferroptosis plays an important role in the occurrence and development of tumors and drug resistance. More and more studies have found that miRNAs can regulate tumor development and drug resistance through ferroptosis. Therefore, in this review, the mechanism of ferroptosis is briefly outlined, and the relationship between miRNAs and ferroptosis in tumors is reviewed.

Microswimmers such as bacteria exhibit large speed fluctuation when exploring their living environment. Here, we show that the bacterium Escherichia coli with a wide range of length speeds up beyond its free-swimming speed when passing through narrow and short confinement. The speedup is observed in two modes: for short bacteria with L20 μm, the maximum speed occurs when the cell body leaves the confinement, but a flagellar bundle is still confined. For longer bacteria (L ≥ 20 μm), the maximum speed occurs when the middle of the cell, where the maximum number of flagellar bundles locate, is confined. The two speed-up modes are explained by a vanishing body drag and an increased flagella drag-a universal property of an "ideal swimmer." The spatial variance of speed can be quantitatively explained by a simple model based on the resistance matrix of a partially confined bacterium. The speed change depends on the distribution of motors, and the latter is confirmed by fluorescent imaging of flagellar hooks. By measuring the duration of slowdown and speedup, we find that the effective chemotaxis is biased in filamentous bacteria, which might benefit their survival. The experimental setup can be useful to study the motion of microswimmers near surfaces with different surface chemistry.

Alpinia oxyphylla Miq. (Zingiberaceae) extract exerts protective activity against tert-butyl hydroperoxide-induced toxicity in HepG2 cells, and the antioxidant response element (ARE) luciferase activity increased 6-fold at 30 μg/mL in HepG2 cells transiently transfected with ARE-luciferase. To identify active molecules, activity-guided isolation of the crude extract led to four sesquiterpenes (1, 2, 5, 6) and two diarylheptanoids (3 and 4) from an n-hexane extract and six sesquiterpenes (7–12) from an ethyl acetate extract. Chemical structures were elucidated by one-dimensional, two-dimensional nuclear magnetic resonance (1D-, 2D-NMR), and mass (MS) spectral data. Among the isolated compounds, eudesma-3,11-dien-2-one (2) promoted the nuclear accumulation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and increased the promoter property of the ARE. Diarylheptanoids, yakuchinone A (3), and 5′-hydroxyl-yakuchinone A (4) showed radical scavenging activity in 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 3-ethylbenzothiazoline-6-sulphonic acid (ABTS) assays. Furthermore, optimization of extraction solvents (ratios of water and ethanol) was performed by comparison of contents of active compounds, ARE-inducing activity, radical scavenging activity, and HepG2 cell protective activity. As a result, 75% ethanol was the best solvent for the extraction of A. oxyphylla fruit. This study demonstrated that A. oxyphylla exerted antioxidant effects via the Nrf2/HO-1 (heme oxygenase-1) pathway and radical scavenging along with active markers eudesma-3,11-dien-2-one (2) and yakuchinone A (3).

Endoscopic resection for early esophageal cancer has a risk of residual margins. The risk these residual margins pose have not been fully evaluated. The present study aimed to investigate the associated risk factors and prognosis of residual margins following the endoscopic resection of early esophageal squamous cell carcinoma. In total, 369 patients (381 lesions) with early esophageal squamous cell carcinoma treated in the Fourth Hospital of Hebei Medical University (Shijiazhuang, China) with endoscopic resection were retrospectively analyzed. Sex, age, location, tumor diameter, depth of tumor invasion, endoscopic treatment, endoscopic ultrasonography (EUS) before resection, work experience of endoscopists and the degree of tumor differentiation were all evaluated as potential risk factors. In addition, the prognosis of patients with positive margins were analyzed. A total of 73 patients (73/381, 19.2%) had positive margins after endoscopic resection. Amongst the 65 patients who were successfully followed up, five patients succumbed to cardiovascular and cerebrovascular diseases, one patient received radiotherapy, two patients received radiotherapy and chemotherapy whilst one patient received chemotherapy. By contrast, 12 patients received surgery and 20 patients received additional endoscopic mucosal resection or endoscopic submucosal dissection. The other 29 patients were followed up regularly and no recurrence could be found. Univariate analysis revealed that tumor diameter, endoscopic treatment, depth of invasion, EUS before resection, degree of tumor differentiation and direction of invasion were all associated with the positive margin. Multivariate logistic regression analysis then found that EUS before resection, degree of tumor differentiation and depth of tumor invasion are independent risk factors for positive margins after endoscopic resection. These results suggest that poorly differentiated lesions and deeper invasion depth can increase the risk of positive margin after endoscopic resection. As a result, EUS evaluation before resection may reduce the risk of invasion depth. In addition, for poorly differentiated lesions, more aggressive treatment regimens may be recommended for preventing recurrence.

Background: Cloperastine is a preferred pivotal antibechic drug, mainly used for the cough caused by respiratory diseases. Previous studies have proved that it is effective and safe in the patients. Methods: The present phase I trial was designed to evaluate the pharmacokinetics (PK), bioequivalence (BE) and safety of 10 mg cloperastine in Chinese healthy subjects after single-dose administration under the fasting and postprandial conditions. A total of 60 subjects were enrolled in either the fasting (28 subjects) or postprandial group (32 subjects). A two-cycle test was carried out with an interval of 7 days. The whole blood samples were collected for the PK and BE analysis before and after administration (0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 24, 36, 48 h). The primary endpoints of the PK parameters for BE trial were the area under the plasma concentration time curve from zero to t and 72 h (AUC0-t), the maximal plasma concentration (Cmax), and the safety parameters as secondary endpoints were mainly the occurrence of adverse events (AE), vital signs, physical examination, electrocardiogram, and laboratory tests before and after the trial. Results: A total of 25 and 30 subjects in the fasting and postprandial groups completed this clinical trial, respectively. The geometric mean ratio (GMR) of test/reference (T/R) for Cmax and AUC0-72h were 102.05 % and 103.80 % in the fasting trial, respectively. And their 90% confidence interval (CI) were 93.63 %~111.22 % and 95.74 %~112.54 %, respectively. In the postprandial condition, the GMR of T/R for Cmax and AUC0-72h were 94.20 % and 98.78 %, respectively. And their 90 % CI were 87.44 %~101.49 % and 93.53 %~104.33 %, respectively. All the values were fell within the range of 80.00 %~125.00 %. Furthermore, no adverse reactions (ADR) and serious adverse events (SAE) occurred during the whole clinical trial. Conclusions: The results of this trial showed that the T and R tablets were bioequivalent under both conditions. Moreover, both preparations were tolerated well.Clinical Trial Registration: http://www.chinadrugtrials.org.cn/m_index.html, CTR20212515

The activation of ferroptosis is a new effective way to treat drug-resistant solid tumors. Ferroptosis is an iron-mediated form of cell death caused by the accumulation of lipid peroxides. The intracellular imbalance between oxidant and antioxidant due to the abnormal expression of multiple redox active enzymes will promote the produce of reactive oxygen species (ROS). So far, a few pathways and regulators have been discovered to regulate ferroptosis. In particular, the cystine/glutamate antiporter (System X

Monitoring cell viability plays a vital role in fundamental aspects of pathology, medicine, and biology. Mitochondria and the nucleolus are involved in regulating cell viability in many biological ...

Purpose: To investigate the neuroprotective effect of Shenxiong Drop Pill (SXDP) pretreatment on rats with middle cerebral artery occlusion (MCAO) in rats, and the mechanism involved.Methods: Ninety-nine SD rats were randomly assigned to 4 groups: control group, MCAO group, shamoperated group and SXDP group. The MCAO model was established via thread occlusion. Rats in the SXDP group was administered SXDP 7 days before induction of MCAO. Neurological deficit score (NDS) was determined using Bederson's neurological behavioral scoring method, while cerebral infarction volume was measured using TTC staining. Integrated optical density (IOD) of Nissl Body was evaluated via Nissl staining. Brain water content was measured using dry-wet method. The expression level of AQP4 in brain tissues was determined using immunocytochemistry.Results: The SXDP treatment resulted in significant reduction in NDS, marked improvement in IOD of Nissl Body, and significant reductions in cerebral infarction volume, brain water content, and expression level of AQP4, relative to control (p< 0.05).Conclusion: These results suggest that SXDP pretreatment exerts neuroprotective effect against cerebral ischemia in rats by decreasing in cerebral edema through a mechanism involving downregulation of the expression of AQP4. Keywords: Middle cerebral artery occlusion, Cerebral ischemia, Aquaporins-4, Cerebral edema, Neuroprotection

Bone defect repair at load-bearing sites is a challenging clinical problem for orthopedists. Defect reconstruction with implants is the most common treatment; however, it requires the implant to have good mechanical properties and the capacity to promote bone formation. In recent years, the piezoelectric effect, in which electrical activity can be generated due to mechanical deformation, of native bone, which promotes bone formation, has been increasingly valued. Therefore, implants with piezoelectric effects have also attracted great attention from orthopedists. In this study, we developed a bioactive composite scaffold consisting of BaTiO3, a piezoelectric ceramic material, coated on porous Ti6Al4V. This composite scaffold showed not only appropriate mechanical properties, sufficient bone and blood vessel ingrowth space, and a suitable material surface topography but also a reconstructed electromagnetic microenvironment. The osteoconductive and osteoinductive properties of the scaffold were reflected by the proliferation, migration, and osteogenic differentiation of mesenchymal stem cells. The ability of the scaffold to support vascularization was reflected by the proliferation and migration of human umbilical vein endothelial cells and their secretion of VEGF and PDGF-BB. A well-established sheep spinal fusion model was used to evaluate bony fusion in vivo. Sheep underwent implantation with different scaffolds, and X-ray, micro-computed tomography, van Gieson staining, and elemental energy-dispersive spectroscopy were used to analyze bone formation. Isolated cervical angiography and visualization analysis were used to assess angiogenesis at 4 and 8 months after transplantation. The results of cellular and animal studies showed that the piezoelectric effect could significantly reinforce osteogenesis and angiogenesis. Furthermore, we also discuss the molecular mechanism by which the piezoelectric effect promotes osteogenic differentiation and vascularization. In summary, Ti6Al4V scaffold coated with BaTiO3 is a promising composite biomaterial for repairing bone defects, especially at load-bearing sites, that may have great clinical translation potential.

Although magnesium and its alloys are candidates for orthopedic implants, they can effectively promote osteogenesis and angiogenesis. However, due to the degradability of magnesium, different concentrations of magnesium ions have different effects on cells, which affects the safety of magnesium implants. The cellular and molecular mechanisms by which magnesium promotes osteogenesis and angiogenesis are still unclear, which further affects its clinical use. In this study, HUVECs were treated with different concentrations of magnesium ions, and the concentration between 1 and 5 mM, especially 5 mM, was most suitable for cultivation of HUVECs. Using gene sequencing, RT-PCR, ELISA and Western blot analysis, we found that magnesium can promote MC3T3-E1 expression and secretion of PDGF-BB. Then, osteogenesis-related tests and angiogenesis-related tests found that magnesium promotes the secretion of PDGF-BB by MC3T3-E1 not only to improve the osteogenic differentiation ability of osteoblasts but also to effectively promote the angiogenic ability of HUVECs.

Porous titanium scaffolds can provide sufficient mechanical support and bone growth space for large segmental bone defect repair. However, they fail to restore the physiological environment of bone tissue. Barium titanate (BaTiO3) is considered a smart material that can produce an electric field in response to dynamic force. Low-intensity pulsed ultrasound stimulation (LIPUS), as a kind of micromechanical wave, can not only promote bone repair but also induce BaTiO3 to generate an electric field. In our studies, BaTiO3 was coated on porous Ti6Al4V and LIPUS was externally applied to observe the influence of the piezoelectric effect on the repair of large bone defects in vitro and in vivo. The results show that the piezoelectric effect can effectively promote the osteogenic differentiation of bone marrow stromal cells (BMSCs) in vitro as well as bone formation and growth into implants in vivo. This study provides an optional alternative to the conventional porous Ti6Al4V scaffold with enhanced osteogenesis and osseointegration for the repair of large bone defects.

This paper reports new geochronological (U–Pb) and isotope (C, O, and S) data to investigate the timing of mineralization and mode of ore genesis for the recently discovered Changtuxili Mn–Ag–Pb–Zn deposit, located on the western slopes of the southern Great Hinggan Range in NE China. The mineralization is hosted by intermediate–acidic lavas and pyroclastic rocks of the Baiyingaolao Formation. Three stages of mineralization are identified: quartz–pyrite (Stage I), galena–sphalerite–tetrahedrite–rhodochrosite (Stage II), and quartz–pyrite (Stage III). δ13C and δ18O values for carbonate from the ore vary from −8.51‰ to −4.96‰ and 3.97‰ to 15.90‰, respectively, which are indicative of a low-temperature alteration environment. δ34SV-CDT values of sulfides range from −1.77‰ to 4.16‰ and show a trend of equilibrium fractionation (δ34SPy ​> ​δ34SSp ​> ​δ34SGn). These features indicate that pyrite, sphalerite, and galena precipitated during the period of mineralization. The alteration mineral assemblage and isotope data indicate that the weakly acidic to weakly alkaline ore-forming fluid was derived largely from meteoric water and the ore-forming elements C and S originated from magma. During the mineralization, a geochemical barrier was formed by changes in the pH of the ore-forming fluid, leading to the precipitation of rhodochrosite. On the basis of the mineralization characteristics, new isotope data, and comparison with adjacent deposits, we propose that the Changtuxili Mn–Ag–Pb–Zn deposit is an intermediate-to low-sulfidation epithermal deposit whose formation was controlled by fractures and variability in the pH of the ore-forming fluid. The surrounding volcanic rocks yield zircon U–Pb ages of 160−146 ​Ma (Late Jurassic), indicating that the mineralization is younger than 146 ​Ma.

Pedicle screw and rod instrumentation based on titanium can produce satisfying strength and stiffness for spinal fusion. However, excessive stiffness produced by titanium rods may cause stress shielding. Thus, polyetheretherketone (PEEK) rods with a low modulus of elasticity were introduced as substitutes for titanium rods. The purpose of this paper is to compare the effectiveness of PEEK rods versus titanium alloy rods in anterior spinal fusion with a new sheep model. Sheep models of anterior–posterior cervical fusion were innovatively adopted in our study. Twenty-four sheep were randomly divided into a control group and a treatment group that received anterior–posterior cervical fixation with titanium rods or PEEK rods, respectively. Then, surgical segments were harvested and assessed by X-ray, micro-CT and histological examination to evaluate the efficiency of bone fusion. No complications related to fixation were found during the research process. The results of the X-ray showed a stronger spinal fusion in the PEEK rod groups than in the titanium rod group at 12 weeks postoperatively, and both groups underwent bone fusion at 24 weeks postoperatively. The results of micro-CT showed that fixation with PEEK rods achieved better bone ingrowth at an early postoperative stage (12 weeks) compared to fixation with titanium rods (bone volume fraction (BVF): 20.26 ± 4.36% vs 14.48 ± 3.49%, p