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This study compares how a modified distributed Bragg reflector (DBR) and yellow color filter (Y-CF) increase the color purity, viewing angle, and brightness of the quantum dot color conversion layer (QDCC) for micro-LED displays. We designed and built a 53-layer high-performance modified DBR with almost total blue leakage filtering (T %: 0.16 %) and very high G/R band transmittance (T %: 96.97 %) for comparison. We also use a Y-CF that filters blue light (T %: 0.84 %) and has good G/R band transmittance (T %: 94.83 %). Due to DBR's angle dependency effect, the modified DBR/QDCC structure offers a remarkable color gamut (117.41 % NTSC) at the forward viewing angle, but this rapidly diminishes beyond 30°. The Y-CF/QDCC structure retains 116 % NTSC color at all viewing angles. Because of its consistent color performance at all viewing angles, sufficient brightness, and outstanding color gamut, the Y-CF/QDCC structure is the best option for contemporary QDCC-based micro-LED displays., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

The transmembrane protein TMEM206 was recently identified as the molecular basis of the extracellular proton-activated Cl - channel (PAC), which plays an essential role in neuronal death in ischemia-reperfusion. The PAC channel is activated by extracellular acid, but the proton-sensitive mechanism remains unclear, although different acid-sensitive pockets have been suggested based on the cryo-EM structure of the human PAC (hPAC) channel. In the present study, we firstly identified two acidic amino acid residues that removed the pH-dependent activation of the hPAC channel by neutralization all the conservative negative charged residues located in the extracellular domain of the hPAC channel and some positively charged residues at the hotspot combined with two-electrode voltage-clamp (TEVC) recording in the Xenopus oocytes system. Double-mutant cycle analysis and double cysteine mutant of these two residues proved that these two residues cooperatively form a proton-sensitive site. In addition, we found that chloral hydrate activates the hPAC channel depending on the normal pH sensitivity of the hPAC channel. Furthermore, the PAC channel knock-out (KO) male mice (C57BL/6J) resist chloral hydrate-induced sedation and hypnosis. Our study provides a molecular basis for understanding the proton-dependent activation mechanism of the hPAC channel and a novel drug target of chloral hydrate. SIGNIFICANCE STATEMENT Proton-activated Cl - channel (PAC) channels are widely distributed in the nervous system and play a vital pathophysiological role in ischemia and endosomal acidification. The main discovery of this paper is that we identified the proton activation mechanism of the human proton-activated chloride channel (hPAC). Intriguingly, we also found that anesthetic chloral hydrate can activate the hPAC channel in a pH-dependent manner. We found that the chloral hydrate activates the hPAC channel and needs the integrity of the pH-sensitive site. In addition, the PAC channel knock-out (KO) mice are resistant to chloral hydrate-induced anesthesia. The study on PAC channels' pH activation mechanism enables us to better understand PAC's biophysical mechanism and provides a novel target of chloral hydrate., (Copyright © 2023 the authors.)

The invention of laser cooling has fundamentally influenced the research frontier of atomic physics and quantum physics, and recently an intense focus has been on the studies of cold atom physics in microgravity environments. Herein, we report the results of our laser cooling experiment in TianGong-2 space lab, which operated for 34 consecutive months in orbit. Over such an extended operation time, the quality of laser cooling did not experience any significant decline, while the properties of laser cooling in orbital microgravity were systematically studied. In particular, we demonstrate magneto-optical trapping and polarization-gradient cooling in orbit and carefully examine their performances. A comparison of the in-orbit and on-ground results indicates that a higher cooling efficiency exists in microgravity, including a smaller loss rate during the trapping and cooling process and lower ultimate temperature of laser-cooled atoms. Our progress has laid the technical foundations for future applications of cold atoms in space missions with operation times of the order of years., (© The Author(s) 2022. Published by Oxford University Press on behalf of China Science Publishing & Media Ltd.)

Background: It is well known that obstructive jaundice could affect the pharmacodynamics of some anesthetics, and the sensitivity of some anesthetics would increase among icteric patients. Remimazolam is a new ultra-short-acting intravenous benzodiazepine sedative/anesthetic, which is a high-selective and affinity ligand for the benzodiazepine site on the GABAA receptor. However, no study has reported the pharmacodynamics of remimazolam in patients with obstructive jaundice. We hypothesize that obstructive jaundice affects the pharmacodynamics of remimazolam, and the sensitivity of remimazolam increases among icteric patients., Methods/design: The study will be performed as a prospective, controlled, multicenter trial. The study design is a comparison of remimazolam requirements to reach a bispectral index of 50 in patients with obstructive jaundice versus non-jaundiced patients with chronic cholecystitisor intrahepatic bile duct stones. Remimazolam was infused at 6 mg/kg/h until this endpoint was reached., Discussion: Remimazolam could be suitable for anesthesia of patients with obstructive jaundice, because remimazolam is not biotransformed in the liver. Hyperbilirubinemia has been well-described to have toxic effects on the brain, which causes the increasing of sensitivity to some anesthetics, such as desflurane, isoflurane, and etomidate. Furthermore, remimazolam and etomidate have the same mechanism of action when exerting an anesthetic effect. We aim to demonstrate that obstructive jaundice affects the pharmacodynamics of remimazolam, and the dose of remimazolam when administered to patients with obstructive jaundice should be modified., Trial Registration: Chinese Clinical Trial Registry ChiCTR2100043585 . Registered on 23 February 2021., (© 2022. The Author(s).)

This study aimed to determine whether self-report cognitive function is a predictor of symptomatic remission in amisulpride-treated schizophrenia. Patients with DSM-IV schizophrenia diagnoses who received amisulpride treatment, were recruited. Each patient received amisulpride with a flexible-dose strategy of 400-800 mg daily for eight weeks. Remission was defined by a shorter version of the Positive and Negative Symptom Scale(PANSS)criteria, which includes six items (PANSS-6) with scores of less than three in each item(criteria A) or total six scores of less than fourteen(criteria B). Three hundred and three patients completed the study in 15 hospitals in China. By criteria A, 244 (80.5%) achieved symptomatic remission at endpoint, and 258 (85.1%) by criteria B. Duration of illness (DOI) (criteria A: t = 2.31, P = 0.025,criteria B:t = 2.24,p = 0.026) and perceived deficits questionnaire at baseline (PDQ20 Day0) (criteria A: t = 3.32, P = 0.001,criteria B:t = 2.76,p = 0.006) in remission groups were less than that in non-remission groups. Logistic regression analysis took into account sex, age, age-onset, DOI, and PDQ20(Day0), and showed that PDQ20(Day0) was a predictor for symptomatic remission in criteria A (B = - 0.02, P = 0.014) and criteria B (B = - 0.03, P = 0.005). The odds ratio (OR) of achieving remission will be reduced by 2% in criteria A and 3% in criteria B. There were no significant differences in gender composition, age, BMI, education level, age-onset, a daily dose of amisulpride and the percentage of PDQ20 Improvement between remission and nonremission in criteria A or criteria B. Receiver operating characteristic(ROC) curves were found for PDQ20(Day0) to define the precise scores to predict remission of schizophrenia (criteria A:AUC = 0.614, S.E. = 0.041, 95% CI = 0.535-0.694, p = 0.007; criteria B:AUC = 0.633, S.E. = 0.045, 95% CI = 0.545-0.721, p = 0.005). Our data suggest that an early self-report cognitive function in amisulpride-treated schizophrenia is important in predicting for symptomatic remission, the fewer scores of PDQ20 at baseline mean the patients have less daily cognitive difficulty, the more likely the patient is to achieve symptomatic remission., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

Background: To retrospectively compare the effects of general anesthesia (GA) and thoracic paravertebral block (TPVB) combined with general anesthesia on the incidence of hypotension and postoperative pain in breast cancer (BC) surgery., Methods: We retrospectively collected the medical records of patients who underwent BC surgery under general anesthesia from January 2018 to December 2020, and divided them into 2 groups according to the patient's anesthesia management method: GA group (Group G) and TPVB combined with GA group (Group T). During the operation, the use of boosting drugs and ephedrine, amount of fluid infusion, amount of bleeding, and operation time of the 2 participant groups were recorded, as well as the pain score in the resting state., Results: During anesthesia, the bispectral index (BIS) value of Group G was significantly lower than that of Group T, the use of sufentanil and the use rate of ephedrine were significantly higher than that of Group T, and the difference was statistically significant (P<0.05). At the T4 time point, the blood pressure [systolic blood pressure/diastolic blood pressure (SBP/DBP)] of Group G was higher than that of Group T; at time point T3, the blood pressure (SBP/DBP) of Group G was lower than that of Group T. At the T4 time point, the heart rate of G group was higher than that of Group T, and the heart rate of G group was lower than that of Group T at the time points T2 and T3. The difference between the 2 groups was statistically significant. The change trend of the visual analogue scale (VAS) scores of the 2 participant groups was basically the same when they were resting peacefully, and there were statistical differences in the VAS scores at 1, 2, 4, and 8 h after surgery (P<0.05)., Conclusions: When TPVB is combined with GA, there is a lower incidence of hypotension, more stable circulatory state, and better postoperative analgesic effect.

A transportable fountain clock with high reliability is important for high-precision time-frequency measurements. Because of its relatively small cold atoms' collision frequency shift and ease of attaining high quantum state preparation efficiency, the rubidium atomic fountain clock has an indicated higher stability and reliability. This paper reports the design and operation of a transportable rubidium atomic fountain clock developed by the Shanghai Institute of Optical and Fine Mechanics, Chinese Academy of Science. After being transported more than 1000 km from Shanghai to the Changping Campus of the National Institute of Metrology, China, the optical platform and other hardware of the fountain clock did not need to be adjusted. The rubidium fountain clock maintained a stability of 4.0 × 10 -13 τ 1/2 , reaching 5.0 × 10 -16 at 300 000 s. After transportation, the rubidium fountain clock and a cesium fountain clock (NIM5) were operated together against the reference frequency of a hydrogen maser. In three separate operating periods, over a total of nearly three months, the average frequency repeatability of the rubidium fountain was less than 3.8 × 10 -15 .

Objective: To investigate the relationship between hematoma ventricle distance (HVD) and clinical outcome in patients with intracerebral hemorrhage (ICH)., Methods: We prospectively enrolled consecutive patients with ICH in a tertiary academic hospital between July 2011 and April 2018. We retrospectively reviewed images for all patients receiving a computed tomography (CT) within 6 h after onset of symptoms and at least one follow-up CT scan within 36 h. The minimum distance of hematoma border to nearest ventricle was measured as HVD. Youden index was used to evaluate the cutoff of HVD predicting functional outcome. Logistic regression model was used to assess the HVD data and clinical poor outcome (modified Rankin Scale 4-6) at 90 days., Results: A total of 325 patients were included in our final analysis. The median HVD was 2.4 mm (interquartile range, 0-5.7 mm), and 119 (36.6%) patients had poor functional outcome at 3 months. After adjusting for age, admission Glasgow coma scale, intraventricular hemorrhage, baseline ICH volume, admission systolic blood pressure, blood glucose, hematoma expansion, withdrawal of care, and hypertension, HVD ≤ 2.5 mm was associated with increased odds of clinical poor outcome [odd ratio, 3.59, (95%CI = 1.72-7.50); p = 0.001] in multivariable logistic regression analysis., Conclusion: Hematoma ventricle distance allows physicians to quickly select and stratify patients in clinical trials and thereby serve as a novel and useful addition to predict ICH prognosis., (Copyright © 2020 Deng, Zhang, Ji, Yang, Wei, Shen, Li, Zhang, Lv, Li, Tang, Wu, Zhao, Xie and Li.)

Objective: Methyltransferase-like 3 (Mettl3), one of "writers" for N6-methyladenosine RNA methylation is determined to participate in a variety of cell biological functions. However, the functions of Mettl3 on tumor growth of glioma remain unknown. Here, we conducted a research to explore the contribution of Mettl3 in the progression of glioma., Patients and Methods: To detect the expression level of RNAs, quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) was performed. To access the relative level of proteins, Western blot was conducted. The proliferative ability of glioma cells was detected by CCK-8 assay and colony formation assay. The migration and invasion of glioma cells were determined by wound healing assay and transwell invasion assay., Results: The expression of Mettl3 was significantly downregulated in tumor tissues compared to the adjacent normal tissues. The downregulation of Mettl3 led to the enhancement of glioma cell proliferation, migration, and invasion in vitro, and promoted the tumor growth of glioma cells in vivo. In addition, further investigation confirmed that Mettl3 plays critical roles in the development of glioma by targeting PI3K/Akt pathway., Conclusions: Our study proves that Mettl3 plays a critical role in the proliferation, migration, and invasion of glioma cells by inactivating PI3K/Akt signaling pathway, providing a novel mechanism of glioma tumorigenesis and raising a new target for the treatment of glioma.

Background: Forkhead box C1 (FOXC1) is an important cancer-associated gene in tumor. PPAR-γ and C/EBPα are both transcriptional regulators involved in tumor development., Objective: We aimed to clarify the function of PPAR-γ, C/EBPα in hepatocellular carcinoma (HCC) and the relationship of PPAR-γ, C/EBPα and FOXC1 in HCC., Methods: Western blotting, immunofluorescent staining, and immunohistochemistry were used to evaluate protein expression. qRT-PCR was used to assess mRNA expression. Co-IP was performed to detect the protein interaction. And ChIP and fluorescent reporter detection were used to determine the binding between protein and FOXC1 promoter., Results: C/EBPα could bind to FOXC1 promoter and PPAR-γ could strengthen C/EBPα's function. Expressions of C/EBPα and PPAR-γ were both negatively related to FOXC1 in human HCC tissue. Confocal displayed that C/EBPα was co-located with FOXC1 in HepG2 cells. C/EBPα could bind to FOXC1 promoter by ChIP. Luciferase activity detection exhibited that C/EBPα could inhibit FOXC1 promoter activity, especially FOXC1 promoter from -600 to -300 was the critical binding site. Only PPAR-γ could not influence luciferase activity but strengthen inhibited effect of C/EBPα. Further, the Co-IP displayed that PPAR-γ could bind to C/EBPα. When C/EBPα and PPAR-γ were both high expressed, cell proliferation, migration, invasion, and colony information were inhibited enormously. C/EBPα plasmid combined with or without PPAR-γ agonist MDG548 treatment exhibited a strong tumor inhibition and FOXC1 suppression in mice., Conclusion: Our data establish C/EBPα targeting FOXC1 as a potential determinant in the HCC, which supplies a new pathway to treat HCC. However, PPAR-γ has no effect on FOXC1 expression., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The space cold atom clock (CAC) suffers more degradation of frequency stability from the local oscillator noise compared with fountain clocks operating on the ground because of the larger dead time of the clock cycle. Therefore, low phase noise is required for the microwave source of the space CAC in addition to robustness, compactness, and adaptability to the space environment. This paper presents the design and measurements of a low-phase-noise space qualified microwave source for the cold atom clock experiment in space CAC operating in the Tiangong-2 Chinese space laboratory. At frequencies near the carrier, a phase noise level of 10 -6.7 × f -1.5 rad 2 /Hz ( f is the Fourier frequency) is achieved. This guarantees a frequency stability of 1.4 × 10 -13 τ -1/2 ( τ is the average time in seconds) for the typical space CAC operation cycle.

Atomic clocks based on laser-cooled atoms are widely used as primary frequency standards. Deploying such cold atom clocks (CACs) in space is foreseen to have many applications. Here we present tests of a CAC operating in space. In orbital microgravity, the atoms are cooled, trapped, launched, and finally detected after being interrogated by a microwave field using the Ramsey method. Perturbing influences from the orbital environment on the atoms such as varying magnetic fields and the passage of the spacecraft through Earth's radiation belt are also controlled and mitigated. With appropriate parameters settings, closed-loop locking of the CAC is realized in orbit and an estimated short-term frequency stability close to 3.0 × 10 -13 τ -1/2 has been attained. The demonstration of the long-term operation of cold atom clock in orbit opens possibility on the applications of space-based cold atom sensors.

Aim: Liguzinediol is a novel derivative of ligustrazine isolated from the traditional Chinese medicine Chuanxiong (Ligusticum wallichii Franch), and produces significant positive inotropic effect in isolated rat hearts. In this study we investigated the effects of liguzinediol on a rat model of heart failure., Methods: To induce heart failure, male SD rats were injected with doxorubicin (DOX, 2 mg/kg, ip) once a week for 4 weeks. Then the rats were administered with liguzinediol (5, 10, 20 mg·kg(-1)·d(-1), po) for 2 weeks. Hemodynamic examination was conducted to evaluate heart function. Myocardial cell apoptosis was examined morphologically. The expression of related genes and proteins were analyzed using immunohistochemical staining and Western blot assays, respectively., Results: Oral administration of liguzinediol dose-dependently improved the heart function in DOX-treated rats. Electron microscopy revealed that liguzinediol (10 mg·kg(-1)·d(-1)) markedly attenuated DOX-induced injury of cardiomyocytes, and decreased the number of apoptotic bodies in cardiomyocytes. Furthermore, liguzinediol significantly decreased Bax protein level, and increased Bcl-2 protein level in cardiomyocytes of DOX-treated rats, led to an increase in the ratio of Bcl-2/Bax. Moreover, liguzinediol significantly decreased the expression of both cleaved caspase-3 and NF-κB in cardiomyocytes of DOX-treated rats. Administration of digitalis (0.0225 mg·kg(-1)·d(-1)) also markedly improved the heart function and the morphology of cardiomyocytes in DOX-treated rats., Conclusion: Liguzinediol improves the heart function and inhibits myocardial cell apoptosis in the rat model of heart failure, which is associated with regulating Bcl-2, Bax, caspase-3 and NF-κB expression.

Aim: Our previous works have demonstrated that Chinese herb medicine yanhusuo (Corydalis yanhusuo W. T. Wang) has strong anti-cancer proliferation effect in MDA-MB-231 cells. The goal of this study was to find out the synergic cytotoxicity effect of three natural compounds, tetrahydropalmatine (THP), berberine (Ber), and dehydrocorydaline (DHC), isolated from C. yanhusuo W. T. Wang., Materials and Methods: The IC50 of THP Ber and DHC in single use, as well as in combination use at fixed ratios and doses was measured by MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay. Isobologram, combination index and modified coefficient of drug interaction (CDI) methods were used for evaluation the combination effects of THF! Ber, and DHC in different ratio and concentration., Results: The results indicated that the combination of THP and Ber shown the strongest anti-cancer cell proliferation effect at the ratio of 2:3 (Ber: THF the average CDI value was 0.5795). DHC and THP have additive cytotoxicity in MDA-MB-231 cells. However, there wasn't any synergistic effect between Ber and DHC, and it even exhibited antagonistic effect when the percentage of DHC was >50%., Conclusion: Our findings suggested that the combination of THP and Ber might be beneficial for anti-proliferation of MDA-MB-231 breast cancer cells through a significant synergy effect.

MUC1 is a large transmembrane glycoprotein and oncogene expressed by epithelial cells and overexpressed and underglycosylated in cancer cells. The MUC1 cytoplasmic subunit (MUC1-C) can translocate to the nucleus and regulate gene expression. It is frequently assumed that the MUC1 extracellular subunit (MUC1-N) does not enter the nucleus. Based on an unexpected observation that MUC1 extracellular domain antibody produced an apparently nucleus-associated staining pattern in trophoblasts, we have tested the hypothesis that MUC1-N is expressed inside the nucleus. Three different antibodies were used to identify MUC1-N in normal epithelial cells and tissues as well as in several cancer cell lines. The results of immunofluorescence and confocal microscopy analyses as well as subcellular fractionation, Western blotting, and siRNA/shRNA studies, confirm that MUC1-N is found within nuclei of all cell types examined. More detailed examination of its intranuclear distribution using a proximity ligation assay, subcellular fractionation, and immunoprecipitation suggests that MUC1-N is located in nuclear speckles (interchromatin granule clusters) and closely associates with the spliceosome protein U2AF65. Nuclear localization of MUC1-N was abolished when cells were treated with RNase A and nuclear localization was altered when cells were incubated with the transcription inhibitor 5,6-dichloro-1-b-d-ribofuranosylbenzimidazole (DRB). While MUC1-N predominantly associated with speckles, MUC1-C was present in the nuclear matrix, nucleoli, and the nuclear periphery. In some nuclei, confocal microscopic analysis suggest that MUC1-C staining is located close to, but only partially overlaps, MUC1-N in speckles. However, only MUC1-N was found in isolated speckles by Western blotting. Also, MUC1-C and MUC1-N distributed differently during mitosis. These results suggest that MUC1-N translocates to the nucleus where it is expressed in nuclear speckles and that MUC1-N and MUC1-C have dissimilar intranuclear distribution patterns.

There is still no animal model available that can mimic all the cognitive, behavioral, biochemical, and histopathological abnormalities observed in patients with Alzheimer&apos;s disease (AD). We undertook to consider the interaction between genetic factors, including amyloid precursor protein (APP) and presenilin-1 (PS1), and environmental factors, such as Aluminum (Al) in determining susceptibility outcomes when studying the pathogenesis of AD. In this article, we provide an AD model in APP/PS1 transgenic mice triggered by Al. The animal model was established via intracerebral ventricular microinjection of aluminum chloride once a day for 5 days in APP/PS1 transgenic mice. Twenty wild type (WT) mice and 20 APP/PS1 transgenic (TG) mice were separately divided into 2 groups (control and Al group), and a stainless steel injector with stopper was used for microinjection into the left-lateral cerebral ventricle of each mouse. The Morris water maze task was used to evaluate behavioral function of learning and memory ability on the 20th day after the last injection. This AD model&apos;s brain was analyzed by: (1) amyloid beta immunohistochemical staining; (2) Tunnel staining; (3) apoptotic rates; (4) caspase-3 gene expression. Here, decrease of cognitive ability and neural cells loss were shown in APP/PS1 transgenic mice exposed to Al, which were more extensive than those in APP/PS1 TG alone and WT mice exposed to Al alone. These findings indicate that there is a close relationship between over-expression of APP and PS1 genes and Al overload. It is also suggested that APP/PS1 TG mice exposed to Al have potential value for improving AD models.

The solvothermal reaction of In(III) and 1,2,4,5-benzeneteracarboxylic acid with the presence of piperazine leads to the generation of a novel 3D chiral porous coordination polymer with PtS topological net. Interestingly, the resulting crystals were not a racemic mixture but enantiomeric excess, which was confirmed by the measurement of optical rotation of bulk samples using solid vibrational circular dichroism (VCD) spectra and the solid circular dichroism (CD) spectra based on large crystals from one crystallization. High-pressure CO(2) and CH(4) adsorption measurement at 298 K reveals that activated 1 can absorb 45.8 cm(3) (STP)/g CO(2) at 22 atm and 22.5 cm(3) (STP)/g CH(4) at 25 atm., (This journal is © The Royal Society of Chemistry 2011)

Objective: To establish reference values for fat-free mass index (FFMI), fat mass index (FMI), and percent body fat (%BF) in a large Korean adult group of apparently healthy subjects, and to analyze the characteristics of body composition indices among the subtypes of obesity in Korean adults., Subjects and Methods: A multicenter, cross-sectional study was conducted on a sample of 1275 community-dwelling healthy Koreans, 504 men and 771 women, aged 18-89 years. Body composition parameters were measured by dual-energy X-ray absorptiometry. FFMI (FFM/height squared) and FMI (FM/height squared) were calculated, and then three subtypes of obesity were divided by FFMI; underlean (or sarcopenic), proportional, and heavy (or muscular) obesity., Results: The reference values (5th-95th percentile) of the reference group (18-59 yr) for the FFMI was 16.3-22.3 kg/m(2) in men and 13.3-17.8 kg/m(2) in women. The %BF increased with age because of the reduction of FFM. Due to lower FFMI in the oldest men, they had the lowest BMI while FMI and BMI of Korean women increased with age like Caucasian women. The %BF among three subtypes of obesity was similar while FMI and BMI were increased as FFMI increased. The prevalence of underlean obesity in men was more than double in women., Conclusion: It is essential to analyze FFMI as well as %BF because %BF alone cannot explain the effects of ageing on FFM and the characteristics of subtypes of obesity. This is the first study to present DXA-determined age- and sex-specific percentiles for body composition indices in Korean adults. These reference values may be useful for clinical evaluation of body composition and nutritional status for Korean adults., (© 2011 Asian Oceanian Association for the Study of Obesity . Published by Elsevier Ltd. All rights reserved.)

Objective: To investigate the brain oxidative stress injury induced by nano-alumina particles in ICR mice., Methods: Sixty male ICR mice were randomly divided into 6 groups: control group, solvent control group, 100 mg/kg micro-alumina particles group, 3 groups exposed to nano-alumina particles at the doses of 50, 100 and 200 mg/kg. The mice were exposed by nasal drip for 30 days. Then levels of malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-PX) in brain tissues of mice were detected., Results: There was no difference of SOD activity in mouse brain between control group [(17.32 +/- 6.23)U/gHb] and 50 mg/kg nano-alumina particles group [(17.89 +/- 1.82) U/gHb]. The SOD activity [(4.93 +/- 2.30)U/gHb] in 200 mg/kg nano-alumina particles group was significantly lower than that in control group (P < 0.05). The MDA levels in 3 nano-alumina particles groups were (0.76 +/- 0.13), (1.00 +/- 0.30) and (1.16 +/- 0.39)nmol/ml, respectively, which were significantly higher than that [( 0.24 +/- 0.09)nmol/ml] in control group (P < 0.05). The GSH levels in 3 nano-alumina particles groups were (0.72 +/- 0.08), (0.55 +/- 0.19) and (0.61 +/- 0.20)mg/gpro, respectively, which were significantly lower than that [(1.55 +/- 0.34)mg/gpro]] in control group (P < 0.05). The CAT activity in 50 and 100 mg/kg nano-alumina particles groups were (10.40 +/- 3.84) and (10.40 +/- 2.00)U/mgpro, respectively, which were significantly higher than that [(5.79 +/- 0.96) U/mgpro] in control group (P < 0.05). The CAT activity [(3.25 +/- 1.04)U/mgpro] in 200 mg/kg nano-alumina particles group was significantly lower than that in control group (P < 0.05 )., Conclusion: Nano-alumina particles can induce the oxidative stress damage in brain tissues of mice.

The rapid development and expanding applications of nanotechnology have led to enhanced exposure of human body to nanoparticles. It is, therefore, necessary to address the safety issue via rigorous toxicological evaluation and to understand the underlying interaction mechanism. However, only a few studies to date have evaluated the safety of nano-sized materials and their potential adverse effects on biological systems. In this study, we sought to investigate the potential toxicity of aluminum oxide (alumina) nanoparticles in ICR strained mice, focusing on potential neurobehavioral defects and the possible mechanisms. The results demonstrated that nano-alumina impaired neurobehavioral functions, including lengthened escape latency, shorter time spent in the target quadrant and reductions in the number of platform crossing. In addition, it induced cell necrosis and apoptosis, which were likely mediated by the reduction of MMP and ROS, and the induction of the caspase-3 gene. Our results implicated that mitochondrial impairment plays a key role in neurotoxicity of nano-alumina, sequent oxidative damage and neural cell loss, especially necrosis, may be direct causes for the neurobehavioral defects. Collectively, nano-alumina presents a strong pro-cell death effect on ICR mice in vivo, suggesting that nano-alumina may serve as an inducer for neural toxicology. Findings in the present study indicating that surface chemical characteristics and nanoscale sizes of nano-alumina could co-contribute significantly to neurotoxicity. The impaired neurobehavioral patterns indicate that nano-alumina particles are more toxic to the cerebrum than those of nano-carbon with the same nanoparticle size and micro-alumina with the same surface chemical characteristics.

The hydrothermal reaction of Co(II)/Cu(II), 5-hydroxyisophthalic acid and dipyridophenazine leads to the generation of two 3D chiral coordination polymers, [M(hip)(DPPZ)](n) (M = Co(), Cu(), H(2)hip = 5-hydroxyisophthalic acid, DPPZ = dipyridophenazine), which contain M-hip-M helical chains (M = Co, Cu) and possess a new four-connected 6(6) topological net. The resulting crystals were not a racemic mixture but an enantiomeric excess, which was confirmed by the measurement of optical rotation of the bulk samples using solid state vibrational circular dichroism (VCD) and solid circular dichroism (CD) based on the large crystals from one crystallization. The magnetic properties of 1 and 2 have been investigated by variable-temperature magnetic susceptibility and magnetization measurements, and the results reveal that antiferromagnetic interactions exist in 1 and 2.

Background: Our previous studies demonstrated that mutant IkappaBalpha (IkappaBalphaM) inhibited the occurrence, growth and angiogenesis of human glioblastoma multiform (GBM). However, the specific mechanism by which IkappaBalphaM regulates protein-degrading enzymes secreted from GBM to inhibit invasion and metastasis has remained unclear. The aim of the present study was to investigate the regulatory role and significance of IkappaBalphaM genes in the expression of tissue inhibitor of metalloproteinase (TIMP)-2 and matrix metalloproteinase (MMP)-9 in human GBM., Methods: We established the following four GBM cell lines stably expressing IkappaBalphaM by plasmid construction, gene transfection and screening for IkappaBalphaM protein expression: mutant IkappaBalpha-transfected cells (G36Delta-M), wild-type IkappaBalpha-transfected cells (G36Delta-W), empty plasmid transfected cells (G36Delta-P) and untransfected cells (G36Delta). The TIMP-2 and MMP-9 expression was detected by RT-PCR and Western blotting. Tumor cells were then implanted subcutaneously into nude mice to establish an animal model of ectopic tumor growth, and TIMP-2 and MMP-9 expression was determined by immunohistochemical methods., Results: The results showed that there was a significant increase in TIMP-2 expression and a significant decrease in MMP-9 expression in the G36Delta-M group at both the RNA and protein levels compared with the G36Delta-W group, G36Delta-P group and G36Delta group. Similar results were observed in the immunohistochemical staining analysis of tumor tissues. In the G36Delta-M group, TIMP-2 expression was significantly higher while MMP-9 expression was significantly lower than in the other three groups., Conclusions: Our findings indicate that IkappaBalphaM inhibits the activation of NF-kappaB. It significantly up-regulates TIMP-2 expression in human malignant glioma cells and down-regulates the expression of MMP-9. Thus, IkappaBalphaM maintains the integrity of the extracellular matrix and further inhibits the growth and metastasis of tumor tissues.

VEGF is a key promoter of angiogenesis and a major target of proangiogenic therapy for peripheral arterial disease (PAD). Greater understanding of VEGF angiogenic signaling and guidance by gradients for new capillaries will aid in developing new proangiogenic therapies and improving existing treatments. However, in vivo measurements of VEGF concentration gradients at the cell scale are currently impossible. We have developed a computational model to quantify VEGF distribution in extensor digitorum longus skeletal muscle using measurements of VEGF, VEGF receptor (VEGFR), and neuropilin-1 (NRP1) expression in an experimental model of rat PAD. VEGF is secreted by myocytes, diffuses through and interacts with extracellular matrix and basement membranes, and binds VEGFRs and NRP1 on endothelial cell surfaces of blood vessels. We simulate the effects of increased NRP1 expression and of therapeutic exercise training on VEGF gradients, receptor signaling, and angiogenesis. Our study predicts that angiogenic therapy for PAD may be achieved not only through VEGF upregulation but also through modulation of VEGFRs and NRP1. We predict that expression of 10(4) NRP1/cell can increase VEGF binding to receptors by 1.7-fold (vs. no NRP1); in nonexercise-trained muscle with PAD, angiogenesis is hindered due to limited VEGF upregulation, signaling, and gradients; in exercise-trained muscle, VEGF signaling is enhanced by upregulation of VEGFRs and NRP1, and VEGF signaling is strongest within the first week of exercise therapy; and hypoxia-induced VEGF release is important to direct angiogenesis towards unperfused tissue.

The induction of angiogenesis is a promising therapeutic strategy for the amelioration of peripheral arterial disease (PAD). This occlusive disease results in muscle ischemia, and neovascularization is a route to increasing the perfusion in the tissue. The vascular endothelial growth factor (VEGF) family of potent pro-angiogenic cytokines is a potential therapeutic agent, increasing VEGF-receptor signaling on tissue vasculature. To investigate the effects of possible therapies on the VEGF concentrations and gradients within the tissue, we consider three such strategies: VEGF gene therapy (e.g. by adeno-associated virus); VEGF cell-based therapy (injected myoblasts that overexpress VEGF); and chronic exercise (which upregulates VEGF receptor expression). The multi-scale computational model used to investigate these strategies is an integration of several components: an anatomical description of the muscle geometry and cell types; microvascular blood flow; tissue oxygen distribution; VEGF secretion from muscle fibers; VEGF transport through interstitial space; and VEGF-receptor binding on microvascular endothelial cells. Exercise training, which results in increased VEGF secretion in hypoxic tissue and increased VEGF receptor expression, exhibits increases in both VEGF concentration and VEGF gradients, and is predicted to be more effective than the other, VEGF-only treatments.

Although spermatogenesis is a complex process under hormonal control, which includes mainly follicle stimulating hormone (FSH) and androgens, little is known about the intra-testicular mediators of these hormones. In the present study, galectin-3 (Gal-3) expression has been identified in human, rat and porcine testes where it is under hormonal control. Gal-3 is present in Sertoli cells and appears to be absent in human and (probably) in rat germ cells. Gal-3 expression was evidenced in the testes, in terms of both mRNA and protein (31 kDa). Gal-3 expression in cultured porcine Sertoli cells was shown to be under the positive control of FSH as well as of two cytokines epidermal growth factor (EGF) and tumour necrosis factor-alpha (TNF-alpha). Gal-3 expression in Sertoli cells is also potentially under the control of mature germ cells as an increased expression was observed in adult rat testes depleted in spermatocytes or spermatids. Although the function of testicular Gal-3 remains to be investigated, a potential role of Gal-3 in germ cell survival/regeneration is suggested based on its increased expression 1 month after a transient germ cell death process triggered by 10 days of treatment with the antiandrogen flutamide. Finally, although in the normal human testes, Gal-3 is exclusively located in the Sertoli cell cytoplasm, a nuclear localization is observed in the infertile testes. Together, the present findings have shown that (i) Gal-3 is expressed in the porcine, rat and human Sertoli cells; (ii) Gal-3 is under the positive control of FSH as well as of EGF and TNF-alpha and possibly of adult germ cells. These observations are compatible with a potential pro-survival role of Gal-3 in the testes.

Extensive experimental studies have identified vascular endothelial growth factor (VEGF) concentrations and concentration gradients as major factors in angiogenesis; however, localized in vivo measurements of these parameters have not been possible. We developed a three-dimensional computational model of skeletal muscle fibers, blood vessels, and interstitial space. Here it is applied to rat extensor digitorum longus. VEGF isoforms are secreted by myocytes, diffuse through extracellular matrix and basement membranes, and bind endothelial cell surface receptors on blood vessels. In addition, one isoform, VEGF164, binds to proteoglycans in the interstitial space. VEGF secretion rate is determined from the predicted tissue oxygen level through its effect on the hypoxia inducible factor-1alpha transcription factor. We estimate VEGF secretion and its concentrations and gradients in resting muscle and for different levels of exercise. The effects of low levels of inspired oxygen are also studied. We predict that the high spatial heterogeneity of muscle fiber VEGF secretion in hypoxic tissue leads to significant gradients of VEGF concentration and VEGF receptor activation. VEGF concentration gradients are predicted to be significant in both resting and exercising muscle (4% and 6-8% change in VEGF over 10 microm, respectively), sufficient for chemotactic guidance of 50-microm-long sprout tip cells. VEGF gradients also result in heterogeneity in VEGF receptor activation--a possible explanation for the stochasticity of sprout location. In the absence of interstitial flow, gradients are 10-fold steeper in the transverse direction (i.e., perpendicular to the muscle fibers) than in the longitudinal direction. This may explain observed perpendicular anastomoses in skeletal muscle.

Members of the vascular endothelial growth factor (VEGF) family of proteins are critical regulators of angiogenesis. VEGF concentration gradients are important for activation and chemotactic guidance of capillary sprouting, but measurement of these gradients in vivo is not currently possible. We have constructed a biophysically and molecularly detailed computational model to study microenvironmental transport of two isoforms of VEGF in rat extensor digitorum longus skeletal muscle under in vivo conditions. Using parameters based on experimental measurements, the model includes: VEGF secretion from muscle fibers; binding to the extracellular matrix; binding to and activation of endothelial cell surface VEGF receptors; and internalization. For 2-D cross sections of tissue, we analyzed predicted VEGF distributions, gradients, and receptor binding. Significant VEGF gradients (up to 12% change in VEGF concentration over 10 mum) were predicted in resting skeletal muscle with uniform VEGF secretion, due to non-uniform capillary distribution. These relative VEGF gradients were not sensitive to extracellular matrix composition, or to the overall VEGF expression level, but were dependent on VEGF receptor density and affinity, and internalization rate parameters. VEGF upregulation in a subset of fibers increased VEGF gradients, simulating transplantation of pro-angiogenic myoblasts, a possible therapy for ischemic diseases. The number and relative position of overexpressing fibers determined the VEGF gradients and distribution of VEGF receptor activation. With total VEGF expression level in the tissue unchanged, concentrating overexpression into a small number of adjacent fibers can increase the number of capillaries activated. The VEGF concentration gradients predicted for resting muscle (average 3% VEGF/10 mum) is sufficient for cellular sensing; the tip cell of a vessel sprout is approximately 50 mum long. The VEGF gradients also result in heterogeneity in the activation of blood vessel VEGF receptors. This first model of VEGF tissue transport and heterogeneity provides a platform for the design and evaluation of therapeutic approaches.

We identified 13 transcript isoforms of a trinucleotide-repeat-containing gene, cag-8, that is expressed almost exclusively in the mouse brain. The polypeptide deduced from the cDNA consists of 137 AAs, of which 74 are glutamines. The 130-kb gene is composed of 16 exons, from which at least 13 isoforms with variable UTRs are formed by alternative splicing. A strong positive cis-acting element was found in the neuroblastomaxglioma hybrid NG108-15 and human embryonic kidney HEK293 cell lines. The cag-8 protein was localized in the cytosol and in granular bodies within the nucleus. These findings indicate that cag-8 is a novel poly(Q)-encoding gene, the expression of which is confined primarily to the brain.

Oxygen transport from capillary networks in muscle at a high oxygen consumption rate was simulated using a computational model to assess the relative efficacies of sprouting and splitting modes of angiogenesis. Efficacy was characterized by the volumetric fraction of hypoxic tissue and overall heterogeneity of oxygen distribution at steady state. Oxygen transport was simulated for a three-dimensional vascular network using parameters for rat extensor digitorum longus (EDL) muscle when oxygen consumption by tissue reached 6, 12, and 18 times basal consumption. First, a control network was generated by using straight non-anastomosed capillaries to establish baseline capillarity. Two networks were then constructed simulating either abluminal lateral sprouting or intraluminal splitting angiogenesis such that capillary surface area was equal in both networks. The sprouting network was constructed by placing anastomosed capillaries between straight capillaries of the control network with a higher probability of placement near hypoxic tissue. The splitting network was constructed by splitting capillaries from the control network into two branches at randomly chosen branching points. Under conditions of moderate oxygen consumption (6 times basal), only minor differences in oxygen delivery resulted between the sprouting and splitting networks. At higher consumption levels (12 and 18 times basal), the splitting network had the lowest volume of hypoxic tissue of the three networks. However, when total blood flow in all three networks was made equal, the sprouting network had the lowest volume of hypoxic tissue. This study also shows that under the steady-state conditions the effect of myoglobin (Mb) on oxygen transport was small.

Using in silico approaches and RACE we cloned a full length trinucleotide (CAG) repeat-containing cDNA (cag-3). The cDNA is 2478 bp long and the deduced polypeptide consists of 140 amino acids of which 73 are glutamines. The genomic sequence spans approximately 79 kb on mouse chromosome 7 and the gene is composed of four exons. Standard and real-time PCR analyses of several mouse tissues showed that the gene is exclusively expressed in the brain and is not detected in embryonic stages. Within the brain, it is expressed throughout the forebrain region with predominant expression in the hypothalamus and olfactory bulb and very low levels in the mid- and hindbrain.

Both erythropoietin (EPO) and the short-form thrombopoietin (TPO) were expressed at low levels whereas the long-form TPO was expressed at high levels in transgenic animals. To elucidate the role of carboxy-terminal half of the long-form TPO which is absent in the short-form, we generated recombinant TPO or EPO expression vectors which contain or lack the carboxy-terminal half of TPO and examined their expression in the HC11 and 293 cells. The long-form TPO was expressed higher than the short-form regardless of the cell types, transfection modes, and promoters. When 3'-half of the long-form TPO cDNA was placed downstream of the EPO cDNA to act as a 3'-untranslated region, expression of EPO was moderately increased at the RNA level, however, no remarkable increase was observed at the protein level. These results suggest that the low expression of EPO, as like as the short-form TPO, is due to absence of the 3'-half in the full-length TPO that confers stability both at the RNA and protein levels.

We have isolated the human homologue if the TGF beta-stimulated clone 22 gene from a human embryo cDNA library. This gene maps to the q14 region of chromosome 13. Its deduced amino acid sequence is almost 99% identical to that of mouse or rat proteins and includes a putative leucine zipper motif. An abundant major transcript of 1.8 kb and in some instances an additional 5 kb transcript were detected by Northern blotting of several human tissues. The TSC-22 protein has been shown to be well conserved across evolution as evidenced by the existence of a Drosophila homologue. These observations prompt discussion on the strong conservation of TSC-22 during evolution but also on its general function as a primary response gene expressed either when stimulated by several different factors during early human development, or in the adult in response to inducing differentiation signals.

The human progesterone receptor (hPR) is a ligand-dependent transcription factor which contains two distinct transcription activation functions (TAFs). The full-length hPR and its individual TAFs were overexpressed in the baculovirus system and tested in a HeLa cell-derived in vitro transcription system. hPR stimulated transcription in a ligand-independent manner. When the two TAFs fused to the DNA-binding domain of GAL4 were tested, only the constitutive TAF-1 was functional in vitro, strongly suggesting that the transcriptional activity of baculovirus-expressed hPR comes solely from TAF-1. The GAL-TAF-1 activator was found to self-squelch without affecting basal transcription. A partially purified fraction relieved this self-squelching and, moreover, stimulated transcriptional activation by GAL-TAF-1, while having no influence on basal transcription. These results strongly suggest that the transcriptional activity of GAL-TAF-1 requires a factor(s) distinct from the general transcription factors.

RU486 induced the binding to a palindromic progestin responsive element (PRE) in vitro of homo- and heterodimers of the human progesterone receptor (hPR) isoforms A and B, present in T47D breast cancer cells or in HeLa cells transiently expressing the recombinant proteins. The resulting complexes were indistinguishable from those induced with the agonist R5020 with respect to specificity, affinity and stability. Ligand exposure was a necessary prerequisite to observe PR/PRE complexes. Antagonist-induced complexes migrated more rapidly during electrophoresis than agonist-induced ones, and no 'mixed' PR/RU486-PR/R5020 complexes were observed, suggesting that the dimerization interfaces of agonist- and antagonist-bound molecules are non-compatible. The analysis of a series of deletion mutants and chimeric receptors revealed the presence of two transcription activation functions (TAFs), located in the N-terminal region A/B (TAF-1) and the hormone binding domain (TAF-2). In the presence of agonists, both TAFs were active in HeLa cells. In the presence of RU486 TAF-2 was inactive, while TAF-1 within the hPR form B/RU486 complex activated transcription from a reporter gene containing a single palindromic PRE. We consider this to be the most convincing evidence that the receptor/RU486-complex does in fact bind to PREs in vivo. No transcriptional activation was observed in the presence of RU486 from a reporter gene containing the complex MMTV-LTR PRE. In contrast to hPR form B, form A was not able to activate transcription from PRE/GRE-tk-CAT in the presence of RU486. In vivo competition between hPR/RU486 and either cPR/R5020 or the human glucocorticoid receptor/dexamethasone (hGR/Dex) complex further supported that hPR/RU486 bound in vivo to its cognate responsive element. Indeed, the observed inhibition of transcription was shown to be due to competition for the MMTV PRE, since no transcriptional interference by the hPR/RU486 was observed, and since no heterodimers were formed between hPR/RU486 and cPR/R5020 or hGR/Dex. That the ligand-free hPR, however, was unable to compete, demonstrated that ligand binding is the prerequisite for DNA binding of hPR in vivo.