ATM-CHK2-Beclin 1 axis promotes autophagy to maintain ROS homeostasis under oxidative stress.

The homeostatic link between oxidative stress and autophagy plays an important role in cellular responses to a wide variety of physiological and pathological conditions. However, the regulatory pathway and outcomes remain incompletely understood. Here, we show that reactive oxygen species (ROS) function as signaling molecules that regulate autophagy through ataxia-telangiectasia mutated (ATM) and cell cycle checkpoint kinase 2 (CHK2), a DNA damage response (DDR) pathway activated during metabolic and hypoxic stress. We report that CHK2 binds to and phosphorylates Beclin 1 at Ser90/Ser93, thereby impairing Beclin 1-Bcl-2 autophagy-regulatory complex formation in a ROS-dependent fashion. We further demonstrate that CHK2-mediated autophagy has an unexpected role in reducing ROS levels via the removal of damaged mitochondria, which is required for cell survival under stress conditions. Finally, CHK2-/- mice display aggravated infarct phenotypes and reduced Beclin 1 p-Ser90/Ser93 in a cerebral stroke model, suggesting an in vivo role of CHK2-induced autophagy in cell survival. Taken together, these results indicate that the ROS-ATM-CHK2-Beclin 1-autophagy axis serves as a physiological adaptation pathway that protects cells exposed to pathological conditions from stress-induced tissue damage.

Antitumor effects of the small molecule DMAMCL in neuroblastoma via suppressing aerobic glycolysis and targeting PFKL.

BACKGROUND: Neuroblastoma (NB) is a common solid malignancy in children that is associated with a poor prognosis. Although the novel small molecular compound Dimethylaminomicheliolide (DMAMCL) has been shown to induce cell death in some tumors, little is known about its role in NB. METHODS: We examined the effect of DMAMCL on four NB cell lines (NPG, AS, KCNR, BE2). Cellular confluence, survival, apoptosis, and glycolysis were detected using Incucyte ZOOM, CCK-8 assays, Annexin V-PE/7-AAD flow cytometry, and Seahorse XFe96, respectively. Synergistic effects between agents were evaluated using CompuSyn and the effect of DMAMCL in vivo was evaluated using a xenograft mouse model. Phosphofructokinase-1, liver type (PFKL) expression was up- and down-regulated using overexpression plasmids or siRNA. RESULTS: When administered as a single agent, DMAMCL decreased cell proliferation in a time- and dose-dependent manner, increased the percentage of cells in SubG1 phase, and induced apoptosis in vitro, as well as inhibiting tumor growth and prolonging survival in tumor-bearing mice (NGP, BE2) in vivo. In addition, DMAMCL exerted synergistic effects when combined with etoposide or cisplatin in vitro and displayed increased antitumor effects when combined with etoposide in vivo compared to either agent alone. Mechanistically, DMAMCL suppressed aerobic glycolysis by decreasing glucose consumption, lactate excretion, and ATP production, as well as reducing the expression of PFKL, a key glycolysis enzyme, in vitro and in vivo. Furthermore, PFKL overexpression attenuated DMAMCL-induced cell death, whereas PFKL silencing promoted NB cell death. CONCLUSIONS: The results of this study suggest that DMAMCL exerts antitumor effects on NB both in vitro and in vivo by suppressing aerobic glycolysis and that PFKL could be a potential target of DMAMCL in NB.

MiR-6869-5p Induces M2 Polarization by Regulating PTPRO in Gestational Diabetes Mellitus.

The role of microRNA (miRNA) in gestational diabetes mellitus has been widely investigated during the last decade. However, the altering effect of miR-6869-5p on immunity and placental microenvironment in gestational diabetes mellitus is largely unknown. In our study, the expression of miR-6869-5p was documented to be significantly decreased in placenta-derived mononuclear macrophages, which was also negatively related to PTPRO. Besides, PTPRO was negatively regulated by miR-6869-5p in placenta-derived mononuclear macrophages. In vitro, miR-6869-5p inhibited macrophage proliferation demonstrated by EdU and CCK-8 experiments. The inflammatory response in macrophages was also significantly inhibited by miR-6869-5p, which could regulate PTPRO as a target documented by luciferase reporter assay. Moreover, miR-6869-5p promoted M2 macrophage polarization and thus restrain inflammation. Accordingly, miR-6869-5p is involved in maintaining placental microenvironment balance by preventing from inflammation and inducing M2 macrophages in gestational diabetes mellitus.

miR-548c-5p inhibits colorectal cancer cell proliferation by targeting PGK1.

Accumulating studies have implicated that microRNAs (miRNAs) are involved in the pathogenesis of colorectal cancer (CRC). However, the role of miR-548c-5p, a novel identified miRNA in malignancies, in colorectal carcinogenesis remains largely unknown. The present study is aimed to investigate the effect and molecular mechanism of miR-548c-5p in CRC by a sequence of cellular experiments. miR-548c-5p was significantly downregulated, whereas phosphoglycerate kinase 1 (PGK1), a key enzyme for glycolysis, was obviously upregulated in peripheral blood mononuclear cells and cancer tissues from patients with CRC. Besides, miR-548c-5p and PGK1 were negatively associated with each other. The luciferase reporter assay revealed that PGK1 was a targeted gene of miR-548c-5p. Moreover, the proliferation and generation of inflammatory cytokines (TNF-α and IL-6) were significantly inhibited in miR-548c-5p-overexpressed SW480 CRC cells stimulated by lipopolysaccharide (LPS). Accordingly, miR-548c-5p may serve as a cancer suppressor in CRC by targeting PGK1.

Knockdown of periostin attenuates 5/6 nephrectomy-induced intrarenal renin-angiotensin system activation, fibrosis, and inflammation in rats.

To simulate clinical features in human chronic kidney disease (CKD), SD rats were subjected to 5/6 nephrectomy in this study. We found that periostin gene was upregulated in the remnant kidneys using Agilent gene microarrays, and further explored its role via in vivo and in vitro experiments. Intrarenal renin-angiotensin system (RAS) was activated in 5/6 nephrectomized rats and partly deactivated by injection of adenoviruses encoding short hairpin RNA against periostin (sh-periostin). Renal fibrosis in nephrectomized rats and profibrotic transforming growth factor-ß-induced epithelial-mesenchymal transition (EMT) and ERK1/2 activation in NRK-52E cells were suppressed by sh-periostin. Moreover, knockdown of periostin decreased the generation of Interleukin 6 (IL6) and tumor necrosis factor-α (TNF-α) and accelerated p62 degradation in the remnant kidneys. Both HK-2 cells treated with recombinant periostin and NRK-52E cells infected with adenoviruses expressing periostin produced more IL6 and TNF-α than control cells and displayed impaired autophagy as evidenced by inhibition of LC3II to LC3I conversion, Beclin 1 expression, and p62 degradation. By treating cells with rapamycin, an inhibitor of mamalian target of rapamycin known to activate autophagy, we noted that periostin-induced inflammation was inhibited. Additionally, HK-2 cells transfected with periostin overexpression plasmid generated more CCL2 and CXCL10, two important chemotactic factors, than untransfected cells. Conditioned medium from HK-2 cells overexpressing periostin augmented chemotaxis of THP-1 macrophages. Collectively, our work demonstrates that knockdown of periostin attenuates 5/6 nephrectomy-induced intrarenal RAS activation, fibrosis, and inflammation in rats. These findings advance our understanding of periostin's role in CKD induced by nephron loss.

Application potential of bone marrow mesenchymal stem cell (BMSCs) based tissue-engineering for spinal cord defect repair in rat fetuses with spina bifida aperta.

Spina bifida aperta are complex congenital malformations resulting from failure of fusion in the spinal neural tube during embryogenesis. Despite surgical repair of the defect, most patients who survive with spina bifida aperta have a multiple system handicap due to neuron deficiency of the defective spinal cord. Tissue engineering has emerged as a novel treatment for replacement of lost tissue. This study evaluated the prenatal surgical approach of transplanting a chitosan-gelatin scaffold seeded with bone marrow mesenchymal stem cells (BMSCs) in the healing the defective spinal cord of rat fetuses with retinoic acid induced spina bifida aperta. Scaffold characterisation revealed the porous structure, organic and amorphous content. This biomaterial promoted the adhesion, spreading and in vitro viability of the BMSCs. After transplantation of the scaffold combined with BMSCs, the defective region of spinal cord in rat fetuses with spina bifida aperta at E20 decreased obviously under stereomicroscopy, and the skin defect almost closed in many fetuses. The transplanted BMSCs in chitosan-gelatin scaffold survived, grew and expressed markers of neural stem cells and neurons in the defective spinal cord. In addition, the biomaterial presented high biocompatibility and slow biodegradation in vivo. In conclusion, prenatal transplantation of the scaffold combined with BMSCs could treat spinal cord defect in fetuses with spina bifida aperta by the regeneration of neurons and repairmen of defective region.

Sensory neuron differentiation potential of in utero mesenchymal stem cell transplantation in rat fetuses with spina bifida aperta.

BACKGROUND: In previous studies, we found that the deficiency of sensory and motor neurons was a primary defect associated with the spinal malformation. Upon prenatal treatment of spina bifida through in utero stem cell transplantation in a retinoic acid-induced spina bifida rat model, we found that the mesenchymal stem cell (MSCs) survived, migrated, and differentiated into cells of a neural lineage. In the present study, we investigated whether the transplanted MSCs had the potential to differentiate into sensory neurons or to protect sensory neurons in the defective spinal cord. METHODS: Pregnant rats treated with retinoic acid on embryonic day (E) 10, underwent fetal surgery for MSC transplantation on E16. The fetuses were harvested on E20. Immunofluorescence was used to detect the expression of Brn3a protein in the transplanted MSCs and dorsal root ganglion (DRG) neurons in the defective spinal cords. The expression of the transcription factors Brn3a and Runx1 in spinal cords was analyzed using real-time polymerase chain reaction. RESULTS: Some of the transplanted MSCs expressed sensory neuron cell specific phenotypes. The expression of Brn3a and Runx1 was upregulated in the defective spinal cords when compared to controls. The percentage of Brn3a-positive neurons in DRG was also increased after transplantation. CONCLUSION: Our results indicate that the transplantation of MSCs into the spinal cord could promote the transplanted MSCs and the surrounding cells to differentiate toward a sensory neuron cell fate and to play an important role in protecting sensory neurons in DRG. This approach might be of value in the treatment of sensory neuron deficiency in spina bifida aperta.

Different expression patterns of growth factors in rat fetuses with spina bifida aperta after in utero mesenchymal stromal cell transplantation.

BACKGROUND AIMS: In a previous study, we successfully devised a prenatal surgical approach and transplanted mesenchymal stromal cells (MSCs) to fetal rat spinal column to treat retinoic acid-induced neural tube defects in rat. Our results show that MSCs survived, migrated and differentiated into neural lineage cells. We intended to study various growth factor expressions in rat fetal spinal cords with spina bifida aperta after in utero MSC transplantation and the effect of in vivo growth factor introduction for prenatal spina bifida treatment. METHODS: Pregnant rats were treated with retinoic acid on embryonic day 10 and then received fetal surgery for MSC transplantation and/or lentiviral epidermal growth factor (EGF) injection on embryonic day 16; various growth factor expression in spinal cords from embryonic day 20 fetuses were analyzed by means of quantitative reverse transcriptase-polymerase chain reaction. Terminal deoxynucleotidyl transferase dUTP nick end labeling analysis was performed to observe spinal tissue apoptosis. RESULTS: Growth factor expression was dysregulated in spinal cords with spina bifida. After MSC transplantation, we observed significantly increased expression of EGF, fibroblast growth factor (FGF)-8, FGF-2 and FGF-20 in the MSC transplantation group compared with blank injection; Furthermore, EGF expression positively correlated with surviving MSC amounts. Expression of other growth factors was not significantly different. In vivo EGF introduction reduced spinal tissue apoptosis. CONCLUSIONS: Our results suggest that intrinsic EGF and FGF-2, FGF-8 and FGF-20 might affect the in vivo fate of transplanted MSCs in a fetal rat spina bifida model. In vivo EGF introduction together with MSC transplantation might serve as a new strategy for prenatal spina bifida treatment.

Effects of mesenchymal stem cells transplanted at different time points in a rat remnant kidney model.

AIMS: The optimal time for mesenchymal stem cell (MSCs) transplantation remains an unresolved issue. We compared the effects of MSCs on a rat remnant kidney model. METHODS: Male Sprague-Dawley rats were randomly divided and treated with a corresponding reagent at 4, 8, 12 and 16 weeks, respectively. A remnant kidney model was established and MSCs were injected into rats. The migration of MSCs was then assessed by using cell-tracking experiments. Renal function and histological analyses were performed 4 weeks after MSC transplantation. Immunohistochemistry, Western blotting and real-time polymerase chain reaction were used to detect the TGF-ß1 and α-SMA levels. RESULTS: Four weeks after MSC injection, MSCs were found to migrate to the injured kidney. Significant histological damage improvement was observed after the treatment of MSCs at 4 and 8 weeks. The functional benefits of MSC treatment were observed in the 5/6 nephrectomy (Nx) + MSC group and the benefits were significantly higher at 4 and 8 weeks than at other time points (p < 0.05). Meanwhile, serum creatinine and urea levels as well as glomerular sclerosis and tubulointerstitial injury indexes were decreased at 4 and 8 weeks. Compared with the 5/6 Nx + PBS group, TGF-ß1 and α-SMA levels were decreased in the 5/6 Nx + MSC group. CONCLUSION: These data can be used to optimize the MSC transplantation time point as a therapeutic modality.

[Expert survey for Chinese medicine syndrome characteristics of different clinical types of coronary artery disease based on the Delphi method].

OBJECTIVE: To carry out expert survey for traditional Chinese medicine (TCM) syndrome characteristics of different clinical types of coronary artery disease (CAD). METHODS: By using Delphi method, we carried out two rounds of nationwide expert surveys for modern TCM characteristics of syndrome elements and syndrome types of CAD. RESULTS: Based on expert consensus, qi deficiency, blood stasis, phlegm turbidity, qi deficiency blood stasis, and intermingled phlegm and blood stasis are common TCM syndromes for different clinical types of CAD. Of them, qi stagnation, blood stasis, phlegm turbidity, heat accumulation, cold coagulation, yang deficiency, deficiency of both qi and yang were more often seen in patients with unstable angina than in those with stable angina. Qi deficiency, yin deficiency, and deficiency of both qi and yin were less seen. We could see more excess syndrome and less deficiency syndrome (such as qi deficiency, yin deficiency, etc.) in acute ST-segment elevation myocardial infarction (STEMI) than acute non-ST-segment elevation myocardial infarction (NSTEMI). Qi deficiency, blood stasis, water retention, yang deficiency, phlegm turbidity, yin deficiency, Xin-qi deficiency, and qi deficiency blood stasis induced water retention are the most common TCM syndrome types of CAD heart failure (HF). Blood deficiency, yin deficiency, heat accumulation, deficiency of both Xin and Pi, deficiency of both qi and blood, deficiency of both qi and yin, yin deficiency and fire hyperactivity were more often seen in CAD arrhythmias. CONCLUSIONS: TCM syndrome distributions of different clinical types of CAD have common laws and individual characteristics. Results based on the expert consensus supplied evidence and support for clinical diagnosis and treatment of CAD.

[Expression of endogenous leukemia inhibitory factor in neonatal rats with periventricular leukomalacia].

OBJECTIVE: To study the changes of endogenous leukemia inhibitory factor (LIF) in neonatal rats with periventricular leukomalacia (PVL). METHODS: A PVL model of 3-day-old Wistar rats was prepared by left carotid artery ligation followed by 6% oxygen for 4 hours. The rats were sacrificed at 1, 3, 7, 14 and 28 days of hypoxia ischemia (HI), and the brain tissues were sampled. Real-Time PCR and Western blot methods were applied to analyze the expression of LIF mRNA and protein. Double staining immunofluorescence was used to detect the co-expression of LIF and GFAP. RESULTS: At 1, 3 and 7 days of HI, LIF protein level in the PVL group was higher than in the control group (P<0.01). In the PVL group, the LIF protein level on the third day after HI reached a peak and was higher than the other time points (P<0.01). The change of LIF mRNA expression showed the same tendency with LIF protein. The double staining immunofluorescence showed a co-expression of LIF and GFAP. CONCLUSIONS: LIF mRNA and LIF protein expression in astrocytes show a trend of initial increase followed by steady decline in neonatal rats with PVL, suggesting that endogenous LIF may participate in the repair of PVL.

The role of CD44-hyaluronic acid interaction in exogenous mesenchymal stem cells homing to rat remnant kidney.

BACKGROUND/AIMS: The aim of our study was to reveal the role of CD44-Hyaluronic acid (HA) in the homing and improving renal function of systemically transplanted MSCs in chronic renal failure. METHODS: First, a remnant kidney model was established in rats and the expression of HA was determined using immunohistochemistry (IHC) and western blotting. Next, chemotaxis assay using flow cytometry, and cell migration assay of MSCs were performed in vitro. Then, MSCs were transplanted into rats, thus, sprague-Dawley (SD) rats were randomly divided into sham group, 5/6 nephrectomy (5/6 Nx) group, MSC group and MSC/Anti-CD44 group (n = 8 for all groups). Migration of MSCs to the kidney in these rats was assessed by using cell tracking experiments, and tissue damage was evaluated by morphological analysis using Masson's trichrome staining and periodic acid Schiff staining. RESULTS: HA was significantly observed in 5/6 Nx group, but not in sham group. Meanwhile, HA was discovered induced MSCs migration remarkably (p < 0.05) and anti-CD44 antibody inhibited the migration significantly (p < 0.05) in vitro. In vivo, the GFP-MSCs were observed in MSC group and the cells reduced in MSC/Anti-CD44 groups, especially, in the tubulointerstitium. CONCLUSION: Our findings reveal that CD44-HA has the potential to induce MSCs homing to injured tissue, while its effect on the ability of MSCs, improving tissue function, is not significant.

Determination and Prediction of Time-Varying Parameters of Mooney-Rivlin Model of Rubber Material Used in Natural Rubber Bearing under Alternating of Aging and Seawater Erosion.

In this paper, we examined the parameters of the Mooney-Rivlin model based on the effects of alternative aging and sea corrosion tests for natural rubber bearings and rubber materials in seawater. The model parameters for rubber material used in natural rubber bearings were determined using the least-squares method. Meanwhile, the time-varying law formula of the Mooney-Rivlin model parameters of rubber were fitted, and the fitting and calculated values were compared. Both fitting values and calculated values coincide with each other well. Then, the rubber material parameters were predicted based on the calculated results and combined with nonlinear auto-regressive (NAR). The predicted values were compared with both the fitting and calculated values. The average deviations between predicted and fitting values for C10 and C01 were 2.6% and 5.1%, respectively, and average deviations between predicted and calculated values for C10 and C01 were 5.2% and 4.1%. Compared results show that the predicted values are in good agreement with both the fitting and calculated values; meanwhile, the proposed time-varying law formula of the Mooney-Rivlin model parameters of rubber material have been well verified.

Critical analysis on the transformation and upgrading strategy of Chinese municipal wastewater treatment plants: Towards sustainable water remediation and zero carbon emissions.

In the light of circular economy aspects, processing of large-scale municipal wastewater treatment plants (WWTPs) needs reconsideration to limit the overuse of energy, implement of non-green technologies and emit abundant greenhouse gas. Along with the huge increase in the worldwide population and agro-industrial activities, global environmental organizations have issued several recent roles to boost scientific and industrial communities towards sustainable development. Over recent years, China has imposed national and regional standards to control and manage the discharged liquid and solid waste, as well as to achieve carbon peaking and carbon neutrality. The aim of this report is to analyze the current state of Chinese WWTPs routing and related issues such as climate change and air pollution. The used strategies in Chinese WWTPs and upgrading trends were critically discussed. Several points were addressed including the performance, environmental impact, and energy demand of bio-enhanced technologies, including hydrolytic acidification pretreatment, efficient (toxic) strain treatment, and anaerobic ammonia oxidation denitrification technology, as well as advanced treatment technologies composed of physical and chemical treatment technologies, biological treatment technology and combined treatment technology. Discussion and critical analysis based on the current data and national policies were provided and employed to develop the future development trend of municipal WWTPs in China from the construction of sustainable and "Zero carbon" WWTPs.

[Effects of the proliferation state of the endothelial progenitor cells preconditioned with salvianolic acid B and bone marrow mesenchymal stem cells transplanted in acute myocardial infarction rats].

OBJECTIVE: To observe the proliferation state of transplanted cells in acute myocardial infarction (AMI) rats, and the endothelial progenitor cells (EPCs) preconditioned by salvianolic acid B in different ratios with the bone mesenchymal stem cells (BMSCs). METHODS: The cultivation and purification of EPCs were performed by density-gradient centrifugation and plastic adherence method. Two types of cells were identified by immunocytochemical method (CD34, CD133, and CD44). The rat model of AMI was prepared by ligation of left anterior descending artery. The EPCs were pre-treated with the optimal concentration of salvianolic acid B (8 microg/ mL). They were mixed with BMSCs in different proportions (EPCs/BMSCs in the ratio of 1:1, 2:1, 4:1, and 8:1, respectively). BMSCs and EPCs were injected into the myocardial infarction area. The infarcted area was determined by the N-BT staining and hematoxylin-eosin staining. The expression of Ki-67 was detected by immunohistochemical assay. RESULTS: Compared with the model group (19.60% +/- 3.23%), the myocardial infarction area of each implanted group obviously decreased (P < 0.05). Of them, the decrease was most obvious in the 4:1 group (11.37% +/- 2.18%) and the 8:1 group (9.23% +/- 2.35%, P < 0.05). Compared with the model group (cell/high magnification, 5.17 +/- 2.31), the Ki-67 positive cell number of each implanted groups significantly increased (P < 0.05). Of them, the Ki-67 positive cell number was obviously higher in the 8:1 group (15.00 +/- 3.16, P < 0.05). CONCLUSIONS: EPCs pretreated by salvianolic acid B combined with BMSCs could reduce the myocardial infarcted area, improve the proliferation of BMSCs in the peripheral infarction and local ischemia. Besides, along with the increase of the implant proportion of EPCs, the infarct area was gradually reduced, and the proliferative expression was gradually enhanced.

Electrocoagulation coupled with conductive ceramic membrane filtration for wastewater treatment: Toward membrane modification, characterization, and application.

Membrane separation is an effective solution for pollutant removal, however, achieving high permeability and antifouling ability remains a pressing challenge for its widespread application. In this study, a novel method of coating flat ceramic membranes (CMs) with a conductive film (Sb-SnO2) was developed to enhance the filtration and antifouling performance of CMs when the membrane filtration was coupled with electrocoagulation. After comparing the parameters, including the film sheet resistance and pure water flux, with those of other coating methods (i.e., gel coating and immersion hydrolysis), a well-fixed conductive coating with optimal permeability and stability was generated using spray pyrolysis with a substrate ceramic membrane surface temperature of 475 °C, precursor concentration of 0.5 M (calculate as SnO2), and spraying amount of 50 mL (120 cm2), during membrane modification. Batch filtration experiments using wastewater from the mechanical industry demonstrated that the conductive ceramic membrane (CCM) cathode integrated with electrocoagulation at an electric field of 2.8 V/cm (3.0 mA/cm2) achieved permeate fluxes that were 0.34, 0.70, 0.75 and 1.41 times higher than those of sole CM separation after four cycles. Moreover, the membrane separation process was dominated by the standard pore-blocking model, and its correlation coefficient decreased with the exertion of the electric field, indicating that membrane filtration fouling changed from irreversible to reversible. This CCM combined with electrocoagulation exhibited significant potential for alleviating membrane fouling and widespread application, and could act as a promising technology for industrial wastewater treatment.

Experimental Investigation of Pre-Flawed Rocks under Dynamic Loading: Insights from Fracturing Characteristics and Energy Evolution.

Different fractures exist widely in rock mass and play a significant role in their deformation and strength properties. Crack rocks are often subjected to dynamic disturbances, which exist in many fields of geotechnical engineering practices. In this study, dynamic compression tests were carried out on rock specimens with parallel cracks using a split hopkinson pressure bar apparatus. Tests determined the effects of strain rate and crack intensity on dynamic responses, including progressive failure behavior, rock fragmentation characteristics, and energy dissipation. Based on the crack classification method, tensile-shear mixed cracking dominates the failure of rock specimens under the action of impact loading. Increasing the flaw inclination angle from 0°-90° changes the predominant cracking mechanism from tensile cracking to mixed tensile-shear cracking. The larger the loading rate, the more obvious the cracking mechanism, which indicates that the loading rate can promote the cracking failure of rock specimens. The fragmentation analysis shows that rock samples are significantly broken at higher loading rates, and higher loading rates lead to smaller average fragment sizes; therefore, the larger the fractal dimension is, the more uniform the broken fragments of smaller sizes are. Energy utilization efficiency decreases while energy dissipation density increases with increasing strain rate. For a given loading rate, the energy absorption density and energy utilization efficiency first decrease and then increase with increasing flaw inclination, while the rockburst tendency of rock decreases initially and then increases. We also find that the elastic-plastic strain energy density increases linearly with the total input energy density, confirming that the linear energy property of granite has not been altered by the loading rate. According to this inherent property, the peak elastic strain energy of the crack specimen can be calculated accurately. On this basis, the rockburst proneness of granite can be determined quantitatively using the residual elastic energy index, and the result is consistent with the intensity of actual rockburst for the specimens.

Association of Static Posturography With Severity of White Matter Hyperintensities.

Background: Impaired gait and balance are associated with severity of leukoaraiosis. Evaluation of balance is based on neurological examination using Romberg's test with bipedal standing, assessment scale, and posturographic parameters. The goal of this study was to determine the relationship between static equilibrium and grades of white matter hyperintensities (WMHs) using static posturography as a quantitative technical method. Method: One hundred and eighteen (118) patients with lacunar infarct were recruited and assessed on MRI with Fazekas's grading scale into four groups. On admission, age, gender, height, weight, Berg Balance Scale (BBS), mini-mental state examination (MMSE), and static posturography parameters were recorded, and their correlations with WMHs were determined. Results: Age was significantly and positively correlated with severity of WMHs (r = 0.39, p < 0.05). WMH score was negatively correlated with BBS score (r = -0.65, p < 0.05) and MMSE score (r = -0.79, p < 0.05). There was a significant positive correlation between track length anteroposterior (AP, with eyes closed) and severity of WMHs (r = 0.70, p < 0.05). Partial correlation analysis and multiple logistic regression analysis indicated that track length AP with eyes closed, was a predictor for the severity of WMHs (p< 0.05). Conclusion: The severity of WHMs is associated with age, cognitive decline, and impairment in balance. Posturography parameter in track length in AP direction with eyes closed in relation to cognition and balance, may be a potential marker for disease progression in WMHs.

Nicotinamide Improves Cognitive Function in Mice With Chronic Cerebral Hypoperfusion.

Normal brain function requires steady blood supply to maintain stable energy state. When blood supply to the brain becomes suboptimal for a long period of time, chronic cerebral hypoperfusion (CCH) and a variety of brain changes may occur. CCH causes white matter injury and cognitive impairment. The present study investigated the effect of nicotinamide (NAM) on CCH-induced cognitive impairment and white matter damage in mice. Male C57Bl/6J mice aged 10-12 weeks (mean age = 11 ± 1 weeks) and weighing 24 - 29 g (mean weight = 26.5 ± 2.5 g) were randomly assigned to three groups (eight mice/group): sham group, CCH group and NAM group. Chronic cerebral hypoperfusion (CCH) was induced using standard methods. The treatment group mice received intraperitoneal injection of NAM at a dose of 200 mg/kg body weight (bwt) daily for 30 days. Learning, memory, anxiety, and depression-like behaviors were measured using Morris water maze test (MWMT), open field test (OFT), sucrose preference test (SPT), and forced swim test (FST), respectively. White matter damage and remodeling were determined via histological/ immunohistochemical analyses, and western blotting, respectively. The results showed that the time spent in target quadrant, number of crossings and escape latency were significantly lower in CCH group than in sham group, but they were significantly increased by NAM (p < 0.05). Mice in NAM group moved significantly faster and covered longer distances, when compared with those in CCH group (p < 0.05). The percentage of time spent in open arms and the number of entries to the open arms were significantly lower in CCH group than in NAM group (p < 0.05). Moreover, anhedonia and histologic scores (index of myelin injury) were significantly higher in CCH group than in sham group, but they were significantly reduced by NAM (p < 0.05). The results of immunohistochemical staining and Western blotting showed that the protein expressions of 2', 3'-cyclic-nucleotide 3'-phosphodiesterase (CNPase) and synaptophysin were significantly downregulated in CCH group, relative to sham group, but they were significantly upregulated by NAM (p < 0.05). These results indicate that NAM improves cognitive function in mice with CCH.

Association of RAGE with acute ischemic stroke prognosis in type 2 diabetes.

BACKGROUND: In experimental models, the receptor for advanced glycation end products (RAGE) has been reported as a key mediator in cerebral ischemia. In this study, the clinical significance of serum RAGE levels in acute ischemic stroke patients with type 2 diabetes was determined. METHOD: Three hundred seven patients (165 patients without diabetes and 142 patients with diabetes) with acute cerebral infarction (ACI) were enrolled over 3 consecutive months. On admission, their National Institute of Health Stroke Scale (NIHSS) scores were recorded. The clinical laboratory data of all subjects were collected, and their serum levels of RAGE were assayed using enzyme-linked immunosorbent assay (ELISA). On admission and 3 months after stroke, the clinical outcomes were assessed using the Barthel index (BI) and modified Rankin scale (mRS). RESULTS: Patients with diabetes (PwD) had significantly higher levels of triglycerides (TGs), RAGE, fasting blood glucose (FBG), glycosylated hemoglobin A1c (HbA1c), and worse stroke prognosis than patients without diabetes (p < 0.05). Hypertension history, RAGE, and FBG in patients without diabetes in ischemic stroke were increased, relative to stroke prognosis. Weight, RAGE, and FBG data showed significant correlation with stroke outcome in PwD (p < 0.05). Multiple logistic regression analysis indicated that the RAGE level was an independent risk factor for poor prognosis of stroke, especially in PwD with ACI (p < 0.05). CONCLUSION: Acute ischemic stroke is associated with elevated serum RAGE level, which, at admission, is an independent predictor of poor outcome for stroke in type 2 diabetes.