Search

Results of both experimental and three-dimensional numerical studies on H2/air continuous rotating detonation are presented. Tangentially injected H2/O2 hotshot jet was used to ignite the engine successfully. Under the condition of air and hydrogen mass flow rates of 265 and 7.7 g/s and the ambient pressure of 11 kPa, H2/air continuous rotating detonation has been realized for about 300 ms. Time–frequency characteristics of the measured results were analyzed by different methods, and the results agreed well with each other. The detonation wave propagated stably during the test, with the propagation frequency variation of 5.35–5.85 kHz. The mean propagation velocity was 1674.3 m/s, which was about 85.0% of the theoretical value. Corresponding three-dimensional numerical simulation was carried out. Flow field structure of the rotating detonation wave was analyzed, and the curvature effect was also considered. Propagation processes of both the experiment and simulation results were compared. The variation of detonation wave propagation frequency of the simulation case was 6.262–6.27 kHz, with the mean propagation velocity of 1870.1 m/s, which was larger than the experiment result. Distribution of the mean combustor pressure along the axis direction was analyzed. Within the heat release zone, the mean pressure decreased greatly, and it changed gently beyond this zone. The changing tendency of both the experimental and numerical results agreed with each other, but there were differences between the pressure values. [ABSTRACT FROM AUTHOR]

Results of experimental studies on a H2/air continuous rotating detonation engine (CRDE) in an annular combustor are presented. A tangentially injected H2/O2 hotshot jet is used to ignite the engine. H2/air continuous rotating detonations are realized at a wide range of total mass flow and equivalence ratio conditions. The detonation propagation modes of all the tests can be divided into four kinds: two-wave, hybrid two/one wave, one-wave, and transient one wave. The mean propagation velocities of the two-wave and one-wave modes are in the range 1365–1476 m/s and 1606–1791 m/s, respectively. The propagation mode and velocity are influenced by both the total mass flow rate and equivalence ratio. Detonation wave propagation processes of the two-wave and one-wave modes are also observed, which further demonstrates the realization of CRDE. [ABSTRACT FROM AUTHOR]

After a primary traumatic injury, spinal cord tissue undergoes a series of pathobiological changes, including compromised blood-spinal cord barrier (BSCB) integrity. These vascular changes occur over both time and space. In an experimental model of spinal cord injury (SCI), longitudinal dynamic contrast-enhanced MRI (DCE-MRI) studies were performed up to 56 days after SCI to quantify spatial and temporal changes in the BSCB permeability in tissue that did not show any visible enhancement on the post-contrast MRI (non-enhancing tissue). DCE-MRI data were analyzed using a two-compartment pharmacokinetic model. These studies demonstrate gradual restoration of BSCB with post-SCI time. However, on the basis of DCE-MRI, and confirmed by immunohistochemistry, the BSCB remained compromised even at 56 days after SCI. In addition, open-field locomotion was evaluated using the 21-point Basso-Beattie-Bresnahan scale. A significant correlation between decreased BSCB permeability and improved locomotor recovery was observed. Copyright © 2008 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Photocatalysis has the advantages of practical, sustainable and environmental protection, so it plays a significant role in energy transformation and environmental utilization. CeO 2 has attracted widespread attention for its unique 4 f electrons, rich defect structures, high oxygen storage capacity and great chemical stability. In this paper, we review the structure of CeO 2 and the common methods for the preparation of CeO 2 -based composites in the first part. In particular, we highlight the co-precipitation method, template method, and sol-gel method methods. Then, in the second part, we introduce the application of CeO 2 -based composites in photocatalysis, including photocatalytic CO 2 reduction, hydrogen production, degradation, selective organic reaction, and photocatalytic nitrogen fixation. In addition, we discuss several modification techniques to improve the photocatalytic performance of CeO 2 -based composites, such as elemental doping, defect engineering, constructing heterojunction and morphology regulation. Finally, the challenges faced by CeO 2 -based composites are analyzed and their development prospects are prospected. This review provides a systematic summary of the recent advance of CeO 2 -based composites in the field of photocatalysis, which can provide useful references for the rational design of efficient CeO 2 -based composite photocatalysts for sustainable development., (© 2024 Wiley-VCH GmbH.)

Based on a typical ozone （O 3 ） pollution process in Jinan City from June 16 to 26, 2021, the variation characteristics of O 3 and its precursor volatile organic compounds （VOCs） during different pollution periods （clean period （CP）, pollution rise period （PRP）, heavy pollution period （HPP）, and pollution decline period （PDP）） in the urban area were analyzed. Both positive matrix factorization （PMF） and an observation-based model （OBM） were used to identify the main sources of VOCs, O 3 production mechanisms, and sensitive species. The results showed that the average value of ρ （O 3 -8h） during the HPP period in the urban area was （246.67±11.24） μg·m -3 , and ρ （O 3 -1h） had a peak value of 300 μg·m -3 . The volume fractions of VOCs and NO 2 concentration were affected by the decrease in planetary boundary layer and wind speed, which were 76.99%-145.36% and 127.78%-141.18% higher than those in the other three periods, respectively, and were the main reasons for the aggravation of O 3 pollution. Alkanes, oxygenated volatile organic compounds （OVOCs）, and halogenated hydrocarbons accounted for 43.81%, 20.98%, and 17.43% of VOCs in urban areas, respectively. All of them showed significant growth during the HPP period, with acetone, propane, and ethane being the top three species by volume in each stage and isopentane showing the highest growth during the HPP period. Alkene, alkanes, and aromatic hydrocarbons accounted for 40.19%, 28.06%, and 21.92% of the ozone generation potential （OFP）. 1-butene, toluene, isopentane, and isoprene were the species with higher OFP. Isoprene had the highest OFP during the PRP phase, and 1-butene had the highest OFP during the HPP phase. The volume fraction of isopentane significantly increased OFP. The correlation coefficient between VOCs and CO preliminarily indicated that motor vehicle exhaust and oil and gas volatilization were the main sources of VOCs during the HPP period. Further use of PMF revealed that solvent use sources, combustion sources, motor vehicle exhaust+oil and gas volatilization sources, industrial emission sources, and plant sources were important sources of VOCs in urban areas. The contribution of motor vehicle exhaust+oil and gas volatilization sources in the HPP period to VOCs was 3.09-14.72 times higher than that in other periods. The contribution of solvent use sources to VOCs was approximately 2.50 times higher than that in the CP and PRP periods. The main sources of VOCs volume fraction increase were motor vehicle exhaust, oil and gas volatilization sources, and solvent use sources. Potential sources and concentration weight analysis found that VOCs were also affected by the transmission of VOCs to Binzhou and Dongying in the northeast direction. The OBM results indicated that the main pathway of O 3 formation in urban areas was the reaction of peroxide hydroxyl radicals （HO 2 ·） and methyl peroxide radicals （CH 3 O 2 ·） with NO, and the net ozone generation rate during the HPP phase [ P （O 3 ） net ] was 24×10 -9 h -1 . Based on the sensitivity experiment results, the alkene components of 1-butene, propylene, cis-2-butene, and ethylene were the dominant species for O 3 production.

The placenta plays a crucial role in successful mammalian reproduction. Ruminant animals possess a semi-invasive placenta characterized by a highly vascularized structure formed by maternal endometrial caruncles and fetal placental cotyledons, essential for full-term fetal development. The cow placenta harbors at least two trophoblast cell populations: uninucleate (UNC) and binucleate (BNC) cells. However, the limited capacity to elucidate the transcriptomic dynamics of the placental natural environment has resulted in a poor understanding of both the molecular and cellular interactions between trophoblast cells and niches, and the molecular mechanisms governing trophoblast differentiation and functionalization. To fill this knowledge gap, we employed Stereo-seq to map spatial gene expression patterns at near single-cell resolution in the cow placenta at 90 and 130 days of gestation, attaining high-resolution, spatially resolved gene expression profiles. Based on clustering and cell marker gene expression analyses, key transcription factors, including YBX1 and NPAS2, were shown to regulate the heterogeneity of trophoblast cell subpopulations. Cell communication and trajectory analysis provided a framework for understanding cell-cell interactions and the differentiation of trophoblasts into BNCs in the placental microenvironment. Differential analysis of cell trajectories identified a set of genes involved in regulation of trophoblast differentiation. Additionally, spatial modules and co-variant genes that help shape specific tissue structures were identified. Together, these findings provide foundational insights into important biological pathways critical to the placental development and function in cows.

Objective: Numerous observational investigations have documented a correlation between asthma and ulcerative colitis(UC). In this Mendelian Randomization (MR) study, we utilized extensive summary data from Genome-Wide Association Studies (GWAS) to further estimate the association between adult-onset asthma and the risk of UC, and to investigate the role of Interleukin-18 (IL-18) as a potential mediator., Materials and Methods: A two-step, two-sample MR study was conducted through mediation analysis. For this study, we employed a two-sample MR analysis using the inverse variance-weighted (IVW), weighted median, weighted mode, and MR-Egger regression techniques. We utilized publicly accessible summary statistics from a GWAS meta-analysis of adult-onset asthma in the UK Biobank (n=327,253; cases=26,582; controls=300,671) as the exposure factor. The outcomes were derived from GWAS data of individuals with European ancestry (n=26,405; cases=6,687; controls=19,718). GWAS data for IL-18 were obtained from individuals of European ancestry (n=9,785,222; cases=3,636; controls=9,781,586)., Results: The MR analysis indicates that adult-onset asthma is associated with an increased risk of UC, with an odds ratio (OR) of 1.019 (95% CI 1.001-1.045, P=0.006). However, there is no strong evidence to suggest that UC significantly impacts the risk of adult-onset asthma. IL-18 may act as a potential mediator in the causal relationship between adult-onset asthma and UC, with a mediation proportion of 3.9% (95% CI, 0.6%-6.9%)., Conclusion: In summary, our study established a causal relationship between asthma and UC, in which IL-18 contributes to a small extent. However, the primary factors underlying the influence of asthma on UC remain unclear. Future research should focus on identifying other potential mediators. In clinical practice, it is important to pay greater attention to intestinal lesions in patients with asthma., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zou, Lu, Liao, Liu and Dai.)

Meteorological conditions play a key role in the occurrence and evolution of atmospheric complex pollution. Considering the different pollution formation mechanisms of PM 2.5 and O 3 , statistical calculation and in-depth learning methods were used to construct the PM 2.5 and O 3 meteorological condition indexes based on long-term pollution meteorological observation data. A research method was developed to study the meteorological characteristics and impact contribution of atmospheric complex pollution by using the meteorological condition index, and quantitative analysis of the distribution and variation of pollution excluding the influence of regional meteorological differences was also conducted. The results showed that in the summer of 2021, the pollution meteorological conditions in the key regions in central and eastern China were generally worse in the north and better in the south(index:"2+26" cities>the border area of Jiangsu, Anhui, Shandong, and Henan>the Yangtze River Delta) and the worst in June and the best in July. The "double high" pollution began to appear when the PM 2.5 meteorological condition index>30 and O 3 meteorological condition index>100; meanwhile, the unfavorable meteorological conditions for O 3 also promoted the increase in PM 2.5 concentration, resulting in the frequency of "double high" increases with the increase in O 3 meteorological condition index. Compared with that during the same period last year, ρ (PM 2.5 ) of each region decreased by 3.9 μg·m -3 , 3.3 μg·m -3 , and 1.4 μg·m -3 due to the contribution of the improvement in the pollution meteorological conditions, which is nearly 58.5% on average of the total decrease in PM 2.5 concentration. However, the change in O 3 pollution meteorological conditions was better in the north and worse in the south, and the overall deterioration in the Yangtze River Delta Region led to approximately 2.8 μg·m -3 growth for the O 3 concentration. The PM 2.5 and O 3 concentrations after excluding the impact of meteorological differences showed different distribution characteristics from the air quality monitoring, in which the high concentrations of PM 2.5 were distributed along the Bohai Sea, the inter-provincial border, and the south of the region, whereas the high concentrations of O 3 were concentrated along the Taihang Mountains, around Mount Tai, and in parts of the Yangtze River Delta. The daily concentration variations in a single city during a specific pollution control period could be used as a basis for evaluating the effectiveness of local supervision and control, which will provide a reference for the dynamic supervision and daily scheduling of local control management.

In this study, taking the Beijing-Tianjin-Hebei region as an example, CMAQ and BETR models were constructed to carry out numerical simulation for the pyrene (Pyr) and benzo[a] pyrene (BaP) in 2014. The model results were compared and evaluated for the atmospheric transportation and transformation of PAHs. Additionally, the XGBoost model was used to identify the key atmospheric physicochemical processes and parameters that affect the environmental behavior of PAHs in the CMAQ. The results showed that the ratio of the simulated value of BETR and annual average value of CMAQ to the measured annual average value was between 1/2 and 2, and the seasonal trend of the simulated concentrations of Pyr and BaP from the CMAQ model were basically consistent with the measured values, which verified the reliability of the two types of models. At the same time, the simulated concentration of the CMAQ model averaged from 9 km grid to 27 km grid and was comparable to the BETR concentration. The results showed that the average concentrations of Pyr and BaP in the BETR model were approximately 1.59 and 1.38 times those of the CMAQ simulation concentrations, respectively, indicating that the two models had good comparability in terms of average annual concentration level and spatial distribution. The SHAP-based variable importance on the XGBoost model showed that boundary layer height was the most significant meteorological factor affecting the transportation and transformation of Pyr and BaP, accounting for 22%-35% of all factors, and sometimes even exceeded the emissions for certain cities and pollutants. The boundary layer height was significantly negatively correlated with the concentration of PAHs. Wind speed was a secondary factor affecting the concentration of PAHs and was negatively correlated with the PAHs, whereas the influence of wind direction on the concentration of PAHs varied.

To investigate the pollution characteristics and sources of atmospheric brown carbon (BrC) in Chongming Island, a background site of the Yangtze River Delta (YRD) region in China, PM 2.5 samples collected from December 2018 to January 2019 were analyzed to determine their chemical compositions and optical properties. The results showed that the light absorption coefficient (Abs 365,M ) of BrC extracted by methanol at 365 nm was (5.39±3.33) M -1 ·m -1 , which was 1.3 times of the water extracted BrC. Both increased significantly with the increase of pH values, suggesting that less acidic conditions can enhance the light absorption ability of BrC. In winter, both Abs 365 and MAE 365 (mass absorption efficiency) were higher in the nighttime than in the daytime. A strong linear correlation observed between Abs 365 and levoglucosan ( R 2 =0.72) indicated that many light absorbing substances in Chongming Island were derived from biomass burning emissions. During the campaign, nitro-aromatic compounds (NACs) and PAHs accounted for (1.5±1.1) ng·m -3 and (8.3±4.7) ng·m -3 , respectively, contributing to 0.1% and 0.067% of the absorption of the total BrC at 365 nm, respectively. Positive matrix factorization (PMF) analysis further showed that biomass and fossil fuel combustions were the main sources of BrC in Chongming Island in winter, accounting for 56% of the total BrC, followed by secondary formation, accounting for 24% of the total BrC, with road dust contributing only 6%.

Baduanjin exercise is a traditional Chinese health Qigong routine created by an ancient physician for health promotion. Its mild-to-moderate exercise intensity is suitable for individuals with medical conditions. Recently, a large number of trials have been conducted to investigate the effects of Baduanjin exercise in patients with chronic obstructive pulmonary disease (COPD). It remains to be determined whether Baduanjin exercise prescription is beneficial for the management of COPD patients. Thus, we conducted a systematic review to objectively evaluate the existing literature on this topic. We searched six databases (PubMed, Web of Science, Cochrane Library, Scopus, China National Knowledge Infrastructure, and Wanfang) from inception until early May 2018. The adapted Physical Therapy Evidence Database (PEDro) scale was used for study quality assessment of all randomized controlled trials (RCTs). Based on 95% confidence interval (CI), the pooled effect size (Hedge's g) of exercise capability (6-Minute Walking Test, 6-MWT), lung function parameters (forced expiratory volume in one second, FEV₁; forced volume vital capacity, FVC; FEV₁/FVC ratio), and quality of life were calculated based on the random-effects model. Twenty RCTs ( n = 1975 COPD patients) were included in this review, with sum scores of the adapted PEDro scale between 5 and 9. Study results of the meta-analysis indicate that Baduanjin is effective in improving exercise capability (Hedge's g = 0.69, CI 0.44 to 0.94, p < 0.001, I ² = 66%), FEV₁ (Hedge's g = 0.47, CI 0.22 to 0.73, p < 0.001, I ² = 68.01%), FEV₁% (Hedge's g = 0.38, CI 0.21 to 0.56, p < 0.001, I ² = 54.74%), FVC (Hedge's g = 0.39, CI 0.22 to 0.56, p < 0.001, I ² = 14.57%), FEV₁/FVC (Hedge's g = 0.5, CI 0.33 to 0.68, p < 0.001, I ² = 53.49%), and the quality of life of COPD patients (Hedge's g = -0.45, CI -0.77 to -0.12, p < 0.05, I ² = 77.02%), as compared to control groups. Baduanjin exercise as an adjunctive treatment may potentially improve exercise capability and pulmonary function of COPD patients as well as quality of life. Baduanjin exercise could be tentatively prescribed for COPD in combination with the conventional rehabilitation program to quicken the process of recovery. To confirm the positive effects of Baduanjin exercise for COPD patients, future researchers need to consider our suggestions mentioned in this article.

Tracking transplanted stem cells is necessary to clarify cellular properties and improve transplantation success. In this study, we designed and synthesized melanin-based gadolinium 3+ (Gd 3+ )-chelate nanoparticles (MNP-Gd 3+ ) of ∼7 nm for stem cell tracking in vivo. MNP-Gd 3+ possesses many beneficial properties, such as its high stability and sensitivity, shorter T1 relaxation time, higher cell labeling efficiency, and lower cytotoxicity compared with commercial imaging agents. We found that the T1 relaxivity (r 1 ) of MNP-Gd 3+ was significantly higher than that of Gd-DTPA; the nanoparticles were taken up by bone mesenchymal stem cells (BMSCs) via endocytosis and were broadly distributed in the cytoplasm. Based on an in vitro MTT assay, no cytotoxicity of labeled stem cells was observed for MNP-Gd 3+ concentrations of less than 800 µg/mL. Furthermore, we tracked MNP-Gd 3+ -labeled BMSCs in vivo using 3.0T MRI equipment. After intramuscular injection, MNP-Gd 3+ -labeled BMSCs were detected, even after four weeks, by 3T MRI. We concluded that MNP-Gd 3+ nanoparticles at appropriate concentrations can be used to effectively monitor and track BMSCs in vivo. MNP-Gd 3+ nanoparticles have potential as a new positive MRI contrast agent in clinical applications. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 131-137, 2017., (© 2016 Wiley Periodicals, Inc.)

Objective: To observe the effect of psoralidine in rats with ovariectomy, and preliminarily study its mechanism., Method: Sixty female Sprague-Dawley rats were divided into 5 groups: the sham operation group, the model group, the psoralidine low-dose group (4 mg x kg(-1)), the psoralidine high-dose group (16 mg x kg(-1)) and the Zhuangguzhitong capsule group, with 12 rats in each group. Thirteen weeks later, their blood and bone samples were collected to detect bone density, bone biochemistry, pathomorphology, serum E2 and CT., Result: Psoralidine could up-regulate the bone density of lumbar vertebra and thighbone of rats with ovariectomy (P < 0.05), the maximum bending strength of thighbone (P < 0.05), and serum E2 and CT (P < 0.05)., Conclusion: Psoralidine has a good active effect on postmenopausal antiosteoporosis. Its mechanism may be related to such pathways as E2 and CT.

alpha-Amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors (AMPARs) are key regulators of synaptic function and cognition. In Alzheimer's disease (AD), cell-surface AMPARs are downregulated, however the reason for this downregulation is not clear. In the present study, we found that Abeta significantly decreased levels of the cell-surface AMPA-type glutamate receptor subunit 2 (GluR2), and increased the concentration of free cytosolic calcium ion ([Ca2+]i) in hippocampal neurons. Ion channel blockers (nifedipine, tetrodotoxin, SKF96365) decreased [Ca2+ and increased the level of cell-surface GluR2, whereas Bay K 8644, an activator of L-type voltage-gated calcium channels increased [Ca2+]i and decreased cell-surface GluR2. Abeta and Bay K 8644 increased phosphorylation of serine-880 (S880) on GluR2, whereas the nifedipine. tetrodotoxin and SKF96365 decreased S880 phosphorylation. Finally, we found that bisindolylmeimide I (GF 109203X, GFX), an inhibitor of protein kinase C (PKC) blocked both the decrease in cell-surface GluR2 and the increase in phospho-S880 induced by Abeta and Bay K 8644. Taken together, these results demonstrate that Abeta decreases cell-surface GluR2 by increasing PKC-mediated phosphorylation of S880. Our study supports the view that a rise in cytosolic [Ca2+]i induced by Abeta could impair synaptic function by decreasing the availability of AMPARs at the synapse. This decrease in AMPARs may contribute to the decline in cognitive function seen in AD.

One of the pathological feathers of Alzheimer's disease (AD) is neurofibrillary tangles (NFTs), which consist of paired helical filaments (PHFs) formed by hyperphosphorylated microtubule-associated protein tau. To study the role of mitogen-activated protein kinase (MAPK) in tau hyperphosphorylation and the underlying mechanism, wild type mouse neuroblastoma cells (N2a) were dealt with different concentrations (0.1 microg/mL, 0.2 microg/mL and 0.4 microg/mL) of anisomycin (an activator of MAPK) for 6 h. The relationship between MAPK activity and tau phosphorylation at some Alzheimer-sites was analyzed, and the activities of protein kinase A (PKA) and glycogen synthase kinase-3 (GSK-3) were detected. The results showed that anisomycin activated MAPK in a dose-dependent manner, but tau hyperphosphorylation at Ser-198/199/202 and Ser-396/404 sites was only observed when the concentration of anisomycin was at the level of 0.4 microg/mL, and the alteration of tau phosphorylation at Ser-214 showed no significant difference in different groups. 0.2 microg/mL and 0.4 microg/mL of anisomycin led to an increase in the activity of GSK-3, respectively, but had no effect on the activity of PKA. Lithium chloride, a specific inhibitor of GSK-3, completely abolished the anisomycin-induced elevation of tau phosphorylation without any effect on the activity of MAPK. In conclusion, overactivation of MAPK up to a certain degree induces tau hyperphosphorylation at Ser-198/199/202 and Ser-396/404 sites, and this is probably related to the effect of activated GSK-3 by MAPK.

Hyperphosphorylated tau is the major protein subunit of neurofibrillary tangles in Alzheimer's disease (AD) and related tauopathies. It is not understood, however, why the neurofibrillary tangle-containing neurons seen in the AD brains do not die of apoptosis but rather degeneration even though they are constantly awash in a proapoptotic environment. Here, we show that cells overexpressing tau exhibit marked resistance to apoptosis induced by various apoptotic stimuli, which also causes correlated tau hyperphosphorylation and glycogen synthase kinase 3 (GSK-3) activation. GSK-3 overexpression did not potentiate apoptotic stimulus-induced cell apoptosis in the presence of high levels of tau. The resistance of neuronal cells bearing hyperphosphorylated tau to apoptosis was also evident by the inverse staining pattern of PHF-1-positive tau and activated caspase-3 or fragmented nuclei in cells and the brains of rats or tau-transgenic mice. Tau hyperphosphorylation was accompanied by decreases in beta-catenin phosphorylation and increases in nuclear translocation of beta-catenin. Reduced levels of beta-catenin antagonized the antiapoptotic effect of tau, whereas overexpressing beta-catenin conferred resistance to apoptosis. These results reveal an antiapoptotic function of tau hyperphosphorylation, which likely inhibits competitively phosphorylation of beta-catenin by GSK-3beta and hence facilitates the function of beta-catenin. Our findings suggest that tau phosphorylation may lead the neurons to escape from an acute apoptotic death, implying the essence of neurodegeneration seen in the AD brains and related tauopathies.

We describe a new test of vibrissae-elicited forelimb placing ability that allows testing of sensorimotor integration across the midline. Rats were given unilateral brain lesions using one of three methods: (1) middle cerebral artery occlusion (MCAo) causing significant damage to the cortex and striatum, (2) aspiration lesions to remove tissue from the sensorimotor cortex, and (3) infusions of the catecholamine neurotoxin 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle, producing a parkinsonian syndrome. Application of the new test to these animals revealed that with some lesion types, the ability of vibrissae on the unimpaired side of the body to trigger placing in the functionally impaired forelimb recovers before vibrissae on the impaired side can elicit placing. This occurs despite the lack of any apparent vibrissae sensory deficit, since the contralesional vibrissae maintained the ability to trigger placing in the unimpaired forelimb in all lesions studied. Chronically, MCAo-lesioned rats do not place the impaired forelimb upon stimulation of the impaired-side vibrissae, but do place if the vibrissae on the good side are stimulated (i.e., when the placing is triggered "across the midline"). This is in contrast to 6-OHDA-lesioned rats which, consistent with parkinsonian akinesia, cannot place the impaired limb regardless of sensory trigger. Also, differences in the pattern of recovery between MCAo- and aspiration-lesioned rats suggest a possible anatomical substrate for cross-midline placing ability and its recovery. Unlike other tests, cross-midline placing methods can readily distinguish between severe stroke and severe parkinsonism in rats.

Background and Purpose: Insulin-like growth factor-1 (IGF-1) and caffeinol are both neuroprotective and probably have different mechanisms of action; therefore, they may be more effective in combination., Methods: We tested the N-terminal tripeptide of IGF-1, Gly-Pro-Glu (GPE), and its analogue, G2MePE, alone and with caffeinol in a rat middle cerebral artery (MCA) suture occlusion model. We randomly assigned rats to 6 groups of 8 to 12 animals: (1) control; (2) GPE, 3 mg/kg per hour; (3) G2MePE, 0.3 mg/kg per hour; (4) caffeinol, a mixture of caffeine (10 mg/kg) with ethanol (0.32 g/kg); (5) GPE with caffeinol (combination of group 2 with 4); and (6) G2MePE with caffeinol (combination of group 3 with 4). Drugs were started 75 minutes after suture occlusion, at the start of reperfusion. Three days after MCA occlusion, neurological deficit (Neurological Deficit Score [NDS]) and lesion volume were measured., Results: GPE and caffeinol improved NDS by 34% and 36%, respectively (P<0.01), and also decreased cortical but not striatal lesion volume compared with control (GPE cortex, 121 mm3; caffeinol cortex, 134 mm3; and control, 221 mm3; P<0.01). GPE plus caffeinol did not have more efficacy than either GPE or caffeinol alone. G2MePE slightly improved NDS (19.7%, P=0.05) but not lesion volume. However, G2MePE plus caffeinol very significantly improved NDS (64%) and lesion volume in both cortex (combination 95 mm3 versus control 221 mm3) and striatum (combination 74 mm3 versus control 110 mm3) (P<0.001), and was significantly more effective than either caffeinol or G2MePE alone., Conclusions: Both GPE and caffeinol significantly protect cortex after MCA occlusion. At the doses used in this study, the GPE analogue G2MePE by itself had minimal protective effects, but when combined with caffeinol, it demonstrated robust beneficial effects on cortical and subcortical lesion size and behavioral deficit. Further study of this combination appears justified.

Microtubule-associated protein tau is abnormally hyperphosphorylated in Alzheimer's disease (AD) and other tauopathies and is believed to lead to neurodegeneration in this family of diseases. Here we show that infusion of forskolin, a specific cAMP-dependent protein kinase A (PKA) activator, into the lateral ventricle of brain in adult rats induced activation of PKA by severalfold and concurrently enhanced the phosphorylation of tau at Ser-214, Ser-198, Ser-199, and or Ser-202 (Tau-1 site) and Ser-396 and or Ser-404 (PHF-1 site), which are among the major abnormally hyperphosphorylated sites seen in AD. PKA activation positively correlated to the extent of tau phosphorylation at these sites. Infusion of forskolin together with PKA inhibitor or glycogen synthase kinase-3 (GSK-3) inhibitor revealed that the phosphorylation of tau at Ser-214 was catalyzed by PKA and that the phosphorylation at both the Tau-1 and the PHF-1 sites is induced by basal level of GSK-3, because forskolin activated PKA and not GSK-3 and inhibition of the latter inhibited the phosphorylation at Tau-1 and PHF-1 sites. Inhibition of cdc2, cdk5, or MAPK had no significant effect on the forskolin-induced hyperphosphorylation of tau. Forskolin inhibited spatial memory in a dose-dependent manner in the absence but not in the presence of R(p)-adenosine 3',5'-cyclic monophosphorothioate triethyl ammonium salt, a PKA inhibitor. These results demonstrate for the first time that phosphorylation of tau by PKA primes it for phosphorylation by GSK-3 at the Tau-1 and the PHF-1 sites and that an associated loss in spatial memory is inhibited by inhibition of the hyperphosphorylation of tau. These data provide a novel mechanism of the hyperphosphorylation of tau and identify both PKA and GSK-3 as promising therapeutic targets for AD and other tauopathies.

Aim: To explore the protective effects of melatonin (Mel) on the abnormal phosphorylation of neuronal cytoskeletal proteins., Methods: We generated a neuroblastoma (SH-SY5Y) cell system in which cytoskeletal proteins are abnormally phosphorylated resulting in microtubule disruption due to the marked inhibition of protein phosphatase activities by okadaic acid (OA)., Results: OA-induced declines in cell viability and mitochondrial metabolic activity were remarkably prevented by Mel. In addition, the hyperphosphorylation/accumulation of neurofilament-(NF-) H/M subunits and the disruption of microtubules, induced by OA, were significantly inhibited by Mel., Conclusion: Our results suggest multiple protective functions of Mel against a series of pathological lesions known to culminate in AD, including abnormal phosphorylation of cytoskeletal proteins, microtubule disassembly and mitochondrion-initiated cell toxicity.

Neurofibrillary tangles (NFTs) consisting of the hyperphosphorylated microtubule-associated protein tau are a defining pathological characteristic of Alzheimer's disease (AD). Hyperphosphorylation of tau is hypothesized to impair the microtubule stabilizing function of tau, leading to the formation of paired helical filaments and neuronal death. Glycogen synthase kinase-3 (GSK-3) has been shown to be one of several kinases that mediate tau hyperphosphorylation in vitro. However, molecular mechanisms underlying overactivation of GSK-3 and its potential linkage to AD-like pathologies in vivo remain unclear. Here, we demonstrate that injection of wortmannin (a specific inhibitor of phosphoinositol-3 kinase) or GF-109203X (a specific inhibitor of protein kinase C) into the left ventricle of rat brains leads to overactivation of GSK-3, hyperphosphorylation of tau at Ser 396/404/199/202 and, most significantly, impaired spatial memory. The effects of wortmannin and GF-109203X are additive. Significantly, specific inhibition of GSK-3 activity by LiCl prevents hyperphosphorylation of tau, and spatial memory impairment resulting from PI3K and PKC inhibition. These results indicate that in vivo inhibition of phosphoinositol-3 kinase and protein kinase C results in overactivation of GSK-3 and tau hyperphosphorylation and support a direct role of GSK-3 in the formation of AD-like cognitive deficits.

Calpain is a calcium-activated protease and has two ubiquitously distributed mammalian isoforms, namely calpain 1 (calpain I, mu-calpain and CAPN1) and calpain 2 (calpain II, m-calpain and CAPN2). Calpains regulate the function of many proteins by limited proteolysis. To determine the nature of different subtypes of calpain on degradation of microtubule-associated protein tau, the rat cortex extracts were incubated with 0.2 mmol/L, 1 mmol/L, 3 mmol/L and 5 mmol/L of CaCl(2 )for 15 min at 37 degrees C, respectively, and it was found that Ca(2+) treatment at concentrations 1-5 mmol/L led to significant proteolysis of the tau protein and this degradation was blocked by calpain inhibitor, calpeptin. In addition, when the extracts containing 1 mmol/L CaCl(2 )were treated with mu-calpain inhibitor (0.05 micromol/L of calpastatin) or m-calpain inhibitor (100 micromol/L calpain inhibitor IV) or both, the Ca(2+)-induced degradation of tau protein was blocked to about 8.6% 92.5% and 97.8% compared with the group with 1 mmol/L CaCl(2), respectively. These data suggest that both mu-calpain and m-calpain in brain cortex extracts are activated by Ca(2+) and both of them degraded tau protein, although, m-calpain plays a more important role in proteolysis of the tau protein.

Aim: To explore the relationship between cocaine-induced cyclin-dependent kinase-5 (CDK5) overexpression or overactivation and Alzheimer-like hyperphosphorylation of cytoskeletal protein., Methods: Cocaine was injected (ip, 20 mg/kg/d) into rats and the phosphorylation of neuronal cytoskeletal proteins was measured by Western blotting., Results: The levels of phosphorylated tau at PHF-1 epitope and phosphorylated neurofilament determined by SMI31 were elevated in rat brain hippocampus, cortex, and caudatoputamen on d 8 and d 16 after the injection of cocaine, when compared with saline control rat at the same brain regions. On the other hand, the levels of tau non-phosphorylated at tau-1 site and non-phosphorylated neurofilament determined by SMI32 were decreased in same brain regions at the same time points examined. No significant difference of phosphorylated tau and neurofilament at those epitopes was seen on d 4. Although cocaine injection could induce significant hyperphosphorylation of neuronal cytoskeletal proteins, the overexpression of CDK5 and p35 was not detected., Conclusion: Peritoneal injection of cocaine induces Alzheimer-like hyperphosphorylation of tau and neurofilament in rat brain, and the effect may be not relevant to an increase in overexpression or overactivation of CDK5.

By computerized static posturography with sway frequency analysis, subclinical effects of lead on postural balance was examined in 29 female workers (lead workers) employed at a glass factory for 3-17 (mean 7.9) years in Beijing, China, in relation to brainstem function assessed by brainstem auditory evoked potential (BAEP). Their blood lead concentrations ranged from 26 to 79 (mean 55.7) microg/dl; ages were 21-30 (mean 28) years. Control subjects, aged 22-29 (mean 27.0) years, were 14 healthy female workers at a textile factory located in the same district. With eyes closed, power of the sway of high (2-4 Hz) and low (1 Hz or less) frequencies in lead workers was significantly larger than that in controls; with eyes open, their power of the sway of low frequency was significantly larger (p<0.05). The multiple regression analysis showed that the power of high frequency sway with eyes closed and of low and high frequencies with eyes open were significantly related to blood lead concentrations in lead workers (p<0.05). On the other hand, no significant differences in BAEP latencies between lead workers and controls were observed. The low frequency sway with eyes open was significantly correlated with the high frequency sway with eyes closed in the lead workers. The pattern of changes in postural balance suggested that the anterior cerebellar lobe, vestibulo-cerebellar and spinocerebellar afferent systems were affected asymptomatically in female lead workers; the sway of vestibulo-cerebellar and anterior cerebellar lobe types were simultaneously affected by lead. It appears that a computerized static posturography with sway frequency analysis is useful technique for assessment of subclinical lead neurotoxicity.

Aim: To investigate the in vivo induction of Alzheimer-like tau phosphorylation by wortmannin and the attenuation by melatonin., Methods: Stereotaxic technique was used for administrating wortmannin or melatonin into rat lateral ventricle. The phosphorylation of tau was analyzed by immunocytochemistry and Western blot, and ultrastructural alteration in neuronal processes was detected by electron microscopy., Results: Level of phosphorylated tau at paired helical filament-1 (PHF-1) epitope was elevated at 1 h, peaked at 6 h, and then decreased at 12 h and 24 h after injection of wortmannin 10 mumol/L. The increased tau phosphorylation at particular epitope determined at 6 h was arrested by preinjection of melatonin 10 mumol/L or 100 mumol/L for 12 h. The wortmannin-induced hyperphosphorylation of tau was mainly detected in pyramidal neuron of hippocampus, and swelled axons and depredated myelin sheaths were also seen in the same region of the brain., Conclusion: Wortmannin induced in vivo Alzheimer-like hyperphosphorylation of tau at Ser396/404, and melatonin inhibited partially the pathological processes.