Mesenchymal stem cells,extracellular vesicles,and transcranial magnetic stimulation for ferroptosis after spinal cord injury

Spinal cord injury is characte rized by diffe rent aetiologies,complex pathogenesis,and diverse pathological changes.Current treatments are not ideal,and prognosis is generally poor.After spinal cord injury,neurons die due to various forms of cell death.Among them,fe rroptosis causes dysfunction after spinal cord injury,and no existing traditional treatments have been indicated to block its occurrence.Meanwhile,emerging therapies using mesenchymal stem cells,extracellular vesicles,and transcranial magnetic stimulation therapy are promising for reve rsing spinal co rd neuronal ferroptosis after spinal cord injury.However,no definitive studies have demonstrated the effectiveness of these approaches.This review summarizes the existing research on the mechanisms of ferroptosis;fe rroptosis after spinal cord injury;treatment of spinal cord injury with mesenchymal stem cells,extracellular vesicles,and transc ranial magnetic stimulation;and treatment of ferroptosis using mesenchymal stem cells,extracellular vesicles,and transc ranial magnetic stimulation.Inhibiting ferroptosis can promote the reversal of neurological dysfunction after spinal cord injury.In addition,mesenchymal stem cells,extracellular vesicles,and transc ranial magnetic stimulation can reve rse adverse outcomes of spinal cord injury and regulate ferroptosis-related fa ctors.Thus,it can be inferred that mesenchymal stem cells,extracellular vesicles,and transcranial magnetic stimulation have the potential to inhibit fe rroptosis after spinal cord injury.This review serves as a reference for future research to confirm these conclusions.

Huangqin flavonoid extraction for spinal cord injury in a rat model

Flavonoids from Huangqin（dried roots of Scutellaria baicalensis Georgi） have anti-inflammatory effects, and are considered useful for treatment of spinal cord injury. To verify this hypothesis, the T9-10 spinal cord segments of rats were damaged using Allen＇s method to establish a rat spinal cord injury model. Before model establishment, Huangqin flavonoid extraction（12.5 g/kg） was administered intragastrically for 1 week until 28 days after model establishment. Methylprednisolone（30 mg/kg） was injected into the tail vein at 30 minutes after model establishment as a positive control. Basso, Beattie, and Bresnahan locomotor scale scores were used to assess hind limb motor function. Hematoxylin-eosin staining was used to detect pathological changes in the injured spinal cord. Immunofluorescence and western blot assays were performed to measure immunoreactivity and expression levels of brain-derived neurotrophic factor, neuronal marker neurofilament protein, microglial marker CD11 b and astrocyte marker glial fibrillary acidic protein in the injured spinal cord. Huangqin flavonoid extraction markedly reduced spinal cord hematoma, inflammatory cell infiltration and cavities and scars, and increased the Basso, Beattie, and Bresnahan locomotor scale scores; these effects were identical to those of methylprednisolone. Huangqin flavonoid extraction also increased immunoreactivity and expression levels of brain-derived neurotrophic factor and neurofilament protein, and reduced immunoreactivity and expression levels of CD11 b and glial fibrillary acidic protein, in the injured spinal cord. Overall, these data suggest that Huangqin flavonoid extraction can promote recovery of spinal cord injury by inducing brain-derived neurotrophic factor and neurofilament protein expression, reducing microglia activation and regulating reactive astrocytes.

Comparison of walking quality variables between incomplete spinal cord injury patients and healthy subjects by using a footscan plantar pressure system

The main goal of spinal cord rehabilitation is to restore walking ability and improve walking quality after spinal cord injury(SCI). The spatiotemporal parameters of walking and the parameters of plantar pressure can be obtained using a plantar pressure analysis system. Previous studies have reported step asymmetry in patients with bilateral SCI. However, the asymmetry of other parameters in patients with SCI has not been reported. This was a prospective, cross-sectional study, which included 23 patients with SCI, aged 48.1 ± 14.5 years, and 28 healthy subjects, aged 47.1 ± 9.8 years. All subjects underwent bare foot walking on a plantar pressure measurement device to measure walking speed and spatiotemporal parameters. Compared with healthy subjects, SCI patients had slower walking speed, longer stride time and stance time, larger stance phase percentage, and shorter stride length. The peak pressures under the metatarsal heads and toe were lower in SCI patients than in healthy subjects. In the heel, regional impulse and the contact area percentage in SCI patients were higher than those in healthy subjects. The symmetry indexes of stance time, step length, maximum force, impulse and contact area were increased in SCI patients, indicating a decline in symmetry. The results confirm that the gait quality, including spatiotemporal variables and plantar pressure parameters, and symmetry index were lower in SCI patients compared with healthy subjects. Plantar pressure parameters and symmetry index could be sensitive quantitative parameters to improve gait quality of SCI patients. The protocols were approved by the Clinical Research Ethics Committee of Shengjing Hospital of China Medical University(approval No. 2015 PS54 J) on August 13, 2015. This trial was registered in the ISRCTN Registry(ISRCTN42544587) on August 22, 2018. Protocol version: 1.0.

Novelty phase synthesis mechanism and morphology in resin-bonded Al–Al2O3–TiO2 composites at high temperatures under flowing N2

An Al–AlN core–shell structure is beneficial to the performance of Al–Al2O3 composites. In this paper, the phase evolution and microstructure of Al–Al2O3–TiO2 composites at high temperatures in flowing N2 were investigated after the Al–AlN core–shell structure was created at 853 K for 8 h. The results show that TiO2 can convert Al into Al3Ti(~1685 K), which reduces the content of metal Al and rearranges the structure of the composite. Under N2 conditions, Al3Ti is further transformed into a novelty non-oxide phase, TiCN. The transformation process can be expressed as follows: Al3Ti reacts with C and other carbides(Al4C3 and Al4O4C) to form TiCx(x < 1). As the firing temperature increases, Al3Ti transforms into a liquid phase and produces Ti(g) and TiO(g). Finally, Ti(g) and TiO(g) are nitrided and solid-dissolved into the TiCx crystals to form a TiCN solid solution.

Efficacy and safety of sofosbuvir and daclatasvir in treatment of kidney transplantation recipients with hepatitis C virus infection

AIM To assess the efficacy and safety of sofosbuvir and daclatasvir regimens for kidney transplantation(KT) patients with hepatitis C virus(HCV) infection.METHODS This study enrolled a prospective cohort of consecutive Chinese KT patients with HCV infection. They were given sofosbuvir combined with daclatasvir, with or without ribavirin. They were monitored regularly during and after the treatment. RESULTS Six patients were recruited in our prospective study cohort. All patients were male and naive to directacting antiviral treatment. The treatment duration was 12 wk. Most patients(4/6) were infected with HCV genotype 1b. HCV RNA was undetectable at week 4 after treatment and at the end of treatment in all patients. Sustained virological response rate at 12 wk was 100%(6/6). Two patients had to accept a half dose of sofosbuvir due to serum creatinine elevation during treatment. Kidney function in the remaining patients was stable. No serious adverse events(AEs) were observed. No patient discontinued antiviral therapy due to side effects. CONCLUSION Sofosbuvir and daclatasvir for treatment of KT recipients with HCV infection are highly efficient and safe. Patients tolerated the medications well, and no serious AEs were observed. Larger prospective cohort studies are needed to validate these results.

Activation of the ERK 1/2 and STAT3 signaling pathways is required for 661W cell survival following oxidant injury

AIM: To evaluate the influence of hydrogen peroxide (H2O2) on mouse photoreceptor-derived 661W cell survival and to determine the effect of PD98059, an inhibitor for MEK1 (the direct upstream activator of ERK1/2), and S3I201, a STAT3-specific inhibitor on 661W cell survival after H2O2 exposure. METHODS: The mouse photoreceptor-derived 661W cells were cultured. 661W cells were treated for 12 hours with different concentrations (0, 0.25, 0.50, 0.75, 1mmol/L) of H2O2 and cell viability was determined by 3- (4, 5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide) (MTT) assay. 661W cells were treated with different concentrations H2O2 (0, 5, 10, 50, 500, 1000 mu mol/L) for 15 minutes or 1mmol/L H2O2 for different time points (0,5,10,15,30 minutes), and p-Tyr705-STAT3, STAT3, Phospho-p44/42 MAPK (Thr202/Tyr204), ERK1/2 were surveyed by immunoblot analysis. After treatment with 50 mu mol/L PD98059, or S3I201 for 1 hour, the inhibition efficiency of cell signal pathways was analyzed by immunoblot analysis and the effects of inhibitors on cell viability were determined by MTT. RESULTS: After treating with different concentrations of H2O2 for 12 hours, the cell viability of 661W cells decreased in concentration-dependent manner (P<0.05). Moreover, H2O2 induced phosphorylation of ERK1/2 and STAT3 in 661W cells (P <0.05). After pretreatment with 50 mu mol/L PD98059 or S3I201 for 1 hour, H2O2-induced phosphorylation of ERK1/2 or STAT3 was suppressed separately (P<0.05). Using PD98059 or S3I201 to inhibit ERK1/2 or STAT3 signal pathway, the cell viability of 661W cells decreased significantly (P<0.05). CONCLUSION: We demonstrated that the exposure of 661W cells to H2O2 increased the activation of ERK1/2 and STAT3 signal pathways. Activation of these pathways is required for 661W cell survival following oxidant injury.

Exploration of nucleos(t)ide analogs cessation in chronic hepatitis B patients with hepatitis B e antigen loss

BACKGROUND Nucleos(t)ide analogs(NAs)cessation in chronic hepatitis B(CHB)patients remains a matter of debate in clinical practice.Current guidelines recommend that patients with hepatitis B e antigen(HBeAg)seroconversion discontinue NAs after relatively long-term consolidation therapy.However,many patients fail to achieve HBeAg seroconversion after the long-term loss of HBeAg,even if hepatitis B surface antigen(HBsAg)loss occurs.It remains unclear whether NAs can be discontinued in this subset of patients.AIM To investigate the outcomes and factors associated with HBeAg-positive CHB patients with HBeAg loss(without hepatitis B e antibody)after cessation of NAs.METHODS We studied patients who discontinued NAs after achieving HBeAg loss.The Cox proportional hazards model was used to identify predictors for virological relapse after cessation of NAs.The cut-off value of the consolidation period was confirmed using receiver operating characteristic curves;we confirmed the cut-off value of HBsAg according to a previous study.The log-rank test was used to compare cumulative relapse rates among groups.We also studied patients with CHB who achieved HBeAg seroconversion and compared their cumulative relapse rates.Propensity score matching analysis(PSM)was used to balance baseline characteristics between the groups.RESULTS We included 83 patients with HBeAg loss.The mean age of these patients was 32.1±9.5 years,and the majority was male(67.5%).Thirty-eight patients relapsed,and the cumulative relapse rate at months 3,6,12,24,36,60,120,and 180 were 22.9%,36.1%,41.0%,43.5%,45.0%,45.0%,45.0%,and 52.8%,respectively.Twentysix(68.4%)patients relapsed in the first 3 mo after NAs cessation,and 35 patients(92.1%)relapsed in the first year after NAs cessation.Consolidation period(≥24 mo vs<24 mo)(HR 0.506,P=0.043)and HBsAg at cessation(≥100 IU/mL vs<100 IU/mL)(HR 14.869,P=0.008)were significant predictors in multivariate Cox regression.In the PSM cohort,which included 144 patients,there were lower cumulative relapse rates in patients with HBeAg seroconversion(P=0.036).CONCLUSION HBeAg-positive CHB patients with HBeAg loss may be able to discontinue NAs therapy after long-term consolidation,especially in patients with HBsAg at cessation<100 IU/mL.Careful monitoring,especially in the early stages after cessation,may ensure a favorable outcome.

Clinical patterns and characteristics of uveitis in a secondary hospital in southern China

AIM: To investigate the characteristics of uveitis in a secondary hospital in southern China.METHODS: We reviewed all records of patients with uveitis at Hengli Hospital from January 2008 to December2011. Demographic data, past history, ophthalmic examinations and other laboratory tests were analyzed.RESULTS: One hundred and ninety-nine uveitis patients were enrolled in this study, including 134(67.3%) males and 65 females(32.7%) with an average age of 41.0 ±15.1y. The anatomical distribution included103(51.8%) cases of anterior uveitis, followed by panuveitis(65, 32.7%), posterior uveitis(29, 14.6%) and intermediate uveitis(2, 1.0%). Of the 98(49.2%) non-idiopathic cases, there were 10.1% Behcet’s disease,9.5% Vogt-Koyanagi-Harada(VKH) syndrome, 7.5%infectious uveitis, 7.5% traumatic uveitis and 3.5%postoperative uveitis.CONCLUSION: Idiopathic anterior and posterior uveitis,Behcet’s disease, VKH syndrome, infectious uveitis and traumatic uveitis are the most common uveitis entities in a secondary hospital in southern China. Additional measures should be taken to prevent infectious and traumatic uveitis.

Multi-arm covariate-adaptive randomization

Simultaneously investigating multiple treatments in a single study achieves considerable efficiency in contrast to the traditional two-arm trials.Balancing treatment allocation for influential covariates has become increasingly important in today’s clinical trials.The multi-arm covariate-adaptive randomized clinical trial is one of the most powerful tools to incorporate covariate information and multiple treatments in a single study.Pocock and Simon’s procedure has been extended to the multi-arm case.However,the theoretical properties of multi-arm covariate-adaptive randomization have remained largely elusive for decades.In this paper,we propose a general framework for multi-arm covariate-adaptive designs which also includes the two-arm case,and establish the corresponding theory under widely satisfied conditions.The theoretical results provide new insights into the balance properties of covariate-adaptive randomization procedures and make foundations for most existing statistical inferences under two-arm covariate-adaptive randomization.Furthermore,these open a door to study the theoretical properties of statistical inferences for clinical trials based on multi-arm covariateadaptive randomization procedures.

Evaluation of microRNA expression profiles in human sperm frozen using permeable cryoprotectant-free droplet vitrification and conventional methods

For sperm cryopreservation,the conventional method,which requires glycerol,has been used for a long time.In addition,the permeable cryoprotectant-free vitrification method has been continuously studied.Although the differences of cryopreservation effects between the two methods have being studied,differences in microRNA(miRNA)profiles between them remain unclear.In this study,we investigated the differences in miRNA expression profiles among conventional freezing sperm,droplet vitrification freezing sperm and fresh human sperm.We also analyzed the differences between these methods in terms of differentially expressed miRNAs(DEmiRs)related to early embryonic development and paternal epigenetics.Our results showed no significant differences between the cryopreservation methods in terms of sperm motility ratio,plasma membrane integrity,DNA integrity,mitochondrial membrane potential,acrosome integrity,and ultrastructural damage.However,sperm miRNA-sequencing showed differences between the two methods in terms of the numbers of DEmiRs(28 and 19 with vitrification using a nonpermeable cryoprotectant and the conventional method,respectively)in postthaw and fresh sperm specimens.DEmiRs related to early embryonic development and paternal epigenetics mainly included common DEmiRs between the groups.Our results showed that the differences between conventional freezing and droplet vitrification were minimal in terms of miRNA expression related to embryonic development and epigenetics.Changes in sperm miRNA expression due to freezing are not always detrimental to embryonic development.This study compared differences in miRNA expression profiles before and after cryopreservation between cryopreservation by conventional and vitrification methods.It offers a new perspective to evaluate various methods of sperm cryopreservation.

Donsker’s Invariance Principle Under the Sub-linear Expectation with an Application to Chung’s Law of the Iterated Logarithm

We prove a new Donsker’s invariance principle for independent and identically distributed random variables under the sub-linear expectation.As applications,the small deviations and Chung’s law of the iterated logarithm are obtained.

Self-Normalized Moderate Deviation and Laws of the Iterated Logarithm Under G-Expectation

The sub-linear expectation or called G-expectation is a non-linear expectation having advantage of modeling non-additive probability problems and the volatilityuncertainty in finance.Let{Xn;n≥1}be a sequence of independent random vari-ables in a sub-linear expectation space(Ω,H,E^(^)).Denote S_(n)=∑_(k=1)^(n)Xk and=V_(n)^(2)=∑_(k=1)^(n)X_(k)^(2).In this paper,a moderate deviation for self-normalized sums,thatis,the asymptotic capacity of the event{Sn/Vn≥x_(n)}for x_(n)=o(√n),is found both for identically distributed random variables and independent but not necessarilyidentically distributed random variables.As an application,the self-normalized lawsof the iterated logarithm are obtained.A Bernstein's type inequality is also establishedfor proving the law of the iterated logarithm.

Lindeberg's central limit theorems for martingale-like sequences under sub-linear expectations

The central limit theorem of martingales is the fundamental tool for studying the convergence of stochastic processes,especially stochastic integrals and differential equations.In this paper,the central limit theorem and the functional central limit theorem are obtained for martingale-like random variables under the sub-linear expectation.As applications,the Lindeberg's central limit theorem is obtained for independent but not necessarily identically distributed random variables,and a new proof of the Lévy characterization of a GBrownian motion without using stochastic calculus is given.For proving the results,Rosenthal's inequality and the exponential inequality for the martingale-like random variables are established.

Phosphate limitation increases coenzyme Q10 production in industrial Rhodobacter sphaeroides HY01

Coenzyme Q10(CoQ10)is an important component of the respiratory chain in humans and some bacteria.As a high-value-added nutraceutical antioxidant,CoQ10 has excellent capacity to prevent cardiovascular disease.The content of CoQ10 in the industrial Rhodobacter sphaeroides HY01 is hundreds of folds higher than normal physiological levels.In this study,we found that overexpression or optimization of the synthetic pathway failed CoQ10 overproduction in the HY01 strain.Moreover,under phosphate-limited conditions(decreased phosphate or in the absence of inorganic phosphate addition),CoQ10 production increased significantly by 12%to220 mg/L,biomass decreased by 12%,and the CoQ10 productivity of unit cells increased by 27%.In subsequent fed-batch fermentation,CoQ10 production reached 272 mg/L in the shake-flask fermentation and 1.95 g/L in a 100-L bioreactor under phosphate limitation.Furthermore,to understand the mechanism associated with CoQ10 overproduction under phosphate-limited conditions,the comparatve transcriptome analysis was performed.These results indicated that phosphate limitation combined with glucose fed-batch fermentation represented an effective strategy for CoQ10 production in the HY01.Phosphate limitation induced a pleiotropic effect on cell metabolism,and that improved CoQ10 biosynthesis efficiency was possibly related to the disturbance of energy metabolism and redox potential.

On the laws of the iterated logarithm under sub-linear expectations

In this paper,we establish some general forms of the law of the iterated logarithm for independent random variables in a sub-linear expectation space,where the random variables are not necessarily identically distributed.Exponential inequalities for the maximum sum of independent random variables and Kolmogorov’s converse exponential inequalities are established as tools for showing the law of the iterated logarithm.As an application,the sufficient and necessary conditions of the law of the iterated logarithm for independent and identically distributed random variables under the sub-linear expectation are obtained.In the paper,it is also shown that if the sub-linear expectation space is rich enough,it will have no continuous capacity.The laws of the iterated logarithm are established without the assumption on the continuity of capacities.

Photosynthetic Properties of Photosystem Ⅱ in Arabidopsis thaliana Ipa1 Mutant

In a previous study, we characterized a high chlorophyll fluorescence Ipal mutant of Arabidopsis thallana, in which approximately 20% photosystem （PS） Ⅱ protein is accumulated. In the present study, analysis of fluorescence decay kinetics and thermoluminescence profiles demonstrated that the electron transfer reaction on either the donor or acceptor side of PSII remained largely unaffected in the Ipa1 mutant. In the mutant, maximal photochemical efficiency （Fv/Fm, where Fm is the maximum fluorescence yield and Fv is variable fluorescence） decreased with increasing light intensity and remained almost unchanged in wildtype plants under different light conditions. The Fv/Fm values also increased when mutant plants were transferred from standard growth light to low light conditions. Analysis of PSll protein accumulation further confirmed that the amount of PSll reaction center protein is correlated with changes in Fv/Fm in Ipal plants. Thus, the assembled PSll in the mutant was functional and also showed increased photosensitivity compared with wild-type plants.

Convergence to a self-normalized G-Brownian motion

G-Brownian motion has a very rich and interesting new structure that nontrivially generalizes the classical Brownian motion.Its quadratic variation process is also a continuous process with independent and stationary increments.We prove a self-normalized functional central limit theorem for independent and identically distributed random variables under the sub-linear expectation with the limit process being a G-Brownian motion self-normalized by its quadratic variation.To prove the self-normalized central limit theorem,we also establish a new Donsker’s invariance principle with the limit process being a generalized G-Brownian motion.

Detection of dopamine using self-assembled diazoresin/single-walled carbon nanotube modified electrodes

Ultrathin films of diazoresin （DR）/single-walled carbon nanotube （SWNT） were fabricated on thioglycollic acid （TGA） decorated gold （Au） electrodes by the self-assembly method combined with the photocrosslinking technique. The electrochemical behavior of dopamine （DA） at the DR/SWNT modified electrodes was studied using the cyclic voltammetry （CV） and differential pulse voltammetry （DPV） methods. Under the optimal conditions, a linear CV response to DA concentration from 1 p, mol/L to 40 μmol/L was observed, and the detection limit of DA was 2.1 ×10-3 μmol/L via the DPV method in the presence of 10μmol/L of uric acid （UA） or 2.5 × 10-3 μmol/L via the DPV method in the presence of 10 μmol/L of ascorbic acid （AA）. Moreover, the modified electrodes exhibited good reproducibility and sensitivity, demonstratinz its feasibilitv for analytical ourooses.

A theoretical study of step edge geometry on sapphire(0001) and its effect on ZnO nucleation

Step-edge-induced nucleation plays a key role in controlling the growth of novel nanostructures and low-dimensional mat erials. However, it is difficult to experimentally determine the step edge structures of complex metal oxides. In this work, we present a detailed theoretical study of the stability of stoichiometTic steps on sapphire(OOOl). Based on first-principles calculations and excess charge computation by Finnis1 approach, a pair of non-polar step edges are determined to be the most stable. By studying the adsorption characteristics of ZnO and combining previous works, we successfully explained how growth temperature and deposition rate affect the in-plane orientation of ZnO grown on sapphire(OOOl). The knowledge on the step edge structures and nucleation patterns would benefit the study on step-edge-guided nanostruc ture grow th.

Decrease of Photosystem Ⅱ Photochemistry in Arabidopsis ppt1 Mutant Is Dependent on Leaf Age

In the present study, we compared the effect of leaf age at one development stage on the photosynthetic behavior of a T-DNA-tagged allele of the pptl mutant. Chlorophyll fluorescence （Fv/Fm, where Fm is the maximum fluorescence yield and Fv is variable fluorescence） and fluorescence decay kinetics of the pptl mutant were different in leaves of different ages. The steady state levels of thylakoid membrane proteins in 40-day-old leaves were decreased compared with those in 20-day-old leaves and changes in photosystem （PS） II proteins were correlated with those of the F,/Fm ratio in the pptl mutant. Increased accumulation of leaf sugars was accompanied by decreased photosynthetic gene transcripts and protein content in 40- day-old leaves of the mutant. Thus, the results of the present study provide evidence for the phosphate translocator in maintaining normal photosynthesis at a late leaf age.