Biomedical subjects
Publications and source records attributed to Feng Li.
Calcination of a layered double hydroxide precursor containing MgII, FeII and FeIII cations with an Mg2+:(FeII + FeIII) ratio of 0.5 affords a pure ferrite spinel, MgFe2O4, which has a higher saturation magnetization than samples of the same material produced by conventional ceramic routes.
In order to determine possible coordinate expression of major survival signals, immunofluorescent analyses for phosphorylated ERK (p-ERK) and phosphorylated Akt (p-Akt) were carried out after 90 min of transient middle cerebral artery occlusion (MCAO) in rats. p-Akt single positive cells (E-/A+) were found in the sham control brains with weak signal intensity. The levels of both survival signals concurrently increased from 1 to 3 h after the reperfusion with the peak at 1 h, and the signals were much stronger in the ischemic penumbra (IP) than ischemic core (IC). The number of E-/A+ cells was larger in both the IC and IP than that of p-ERK single positive cells (E+/A-). The E+/A- cells were primarily expressed at 1 h in the IP. The number of p-ERK plus p-Akt double positive cells (E+/A+) peaked at 1 h, and the intensity was much stronger in the IP than IC. These findings suggest that p-ERK and p-Akt play independent roles, respectively as emergency or maintenance signal for survival at an early stage after reperfusion, and that both signals were cooperatively expressed especially in the IP.
Molecular chaperones and their functions in protein folding have been implicated in several neurodegenerative diseases, including Parkinson's disease and Huntington's disease, which are characterized by accumulation of protein aggregates (e.g., alpha-synuclein and huntingtin, respectively). These aggregates have been shown in various experimental systems to respond to changes in levels of molecular chaperones suggesting the possibility of therapeutic intervention and a role for chaperones in disease pathogenesis. It remains unclear whether chaperones also play a role in Alzheimer's disease, a neurodegenerative disorder characterized by beta-amyloid and tau protein aggregates. Here, we report an inverse relationship between aggregated tau and the levels of heat shock protein (Hsp)7090 in tau transgenic mouse and Alzheimer's disease brains. In various cellular models, increased levels of Hsp70 and Hsp90 promote tau solubility and tau binding to microtubules, reduce insoluble tau and cause reduced tau phosphorylation. Conversely, lowered levels of Hsp70 and Hsp90 result in the opposite effects. We have also demonstrated a direct association of the chaperones with tau proteins. Our results suggest that up-regulation of molecular chaperones may suppress formation of neurofibrillary tangles by partitioning tau into a productive folding pathway and thereby preventing tau aggregation.
We report a new kind of compact and portable optical smoke sensor that uses an integrating cylinder as the light collector. Theoretical analysis shows that this smoke sensor can have high sensitivity and good linearity because a number of reflected lights participate in the measurement of smoke concentration. A smoke sensor has been constructed, and it has demonstrated improved sensitivity and linearity compared with the conventional direct-beam-based smoke sensor. Good agreement of theoretical and experimental results has been obtained.
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A peptide designated Luffin P1 was purified from the seeds of Luffa cylindrica. Its molecular mass was determined to be 5226.1 Da by MALDI-TOF MS analysis. The purified Luffin P1 shows a strong inhibitory activity on protein synthesis in the cell-free rabbit reticulocyte lysate with IC(50) of 0.88 nM. Its reaction mechanism is the same as that of the ribosome-inactivating protein trichosanthin, which is an rRNA N-glycosidase. Besides, the results of gel filtration chromatography suggested the existence of polymers of Luffin P1 and polymerization of Luffin P1 enhanced its rRNA N-glycosidase activity. Luffin P1 was the smallest peptide yet reported that has translational inhibitory activity. The cDNA and deduced amino acid sequence of Luffin P1 has also been determined.
RATIONALE AND OBJECTIVES: To report the detection rate for lung cancers in computed tomography (CT) screening in Japanese adults, and to analyze differences in the appearance of the cancers in non-smokers versus smokers. MATERIALS AND METHODS: Subjects consisted of 7,847 Japanese adults who received low-dose CT screening at least once in a 3-year period. The detection rate of lung cancers and the correlation of imaging, clinical, and pathologic findings of cancers in non-smokers versus smokers were examined. RESULTS: The detection rate for lung cancer was 1.1% for both non-smokers (45 of 4,251) and smokers (39 of 3,596). The prevalence of well-differentiated adenocarcinomas was greater in non-smokers (88%; 22 of 25) than in smokers (29%; 4 of 14) (P < .001). The prevalence and incidence of pathologic stage IA disease were greater in non-smokers than in smokers (92%; [22 of 24] vs 58% [7 of 12], and 100% [19 of 19] vs 70% [14 of 20]) (both P < .05). The mean size of the tumors in the non-smokers (12.4 mm) was smaller than that in smokers (18.2 mm) (P < .001). The percentage of cancers categorized as pure or mixed ground-glass opacity (86%; 38 of 44) on CT was greater in non-smokers than in smokers (46%; 16 of 35) (P < .001). CONCLUSION: Most of the lung cancers in non-smokers were slow-growing adenocarcinomas appearing as faint ground-glass opacities on CT, whereas rapidly growing cancers appearing as solid nodules were more commonly seen in smokers.
Differential proteome profiles of human lung squamous carcinoma tissue compared to paired tumor-adjacent normal bronchial epithelial tissue were established and analyzed by means of immobilized pH gradient-based two-dimensional polyacrylamide gel electrophoresis (2-D PAGE) and matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF-MS). The results showed that well-resolved, reproducible 2-DE patterns of human lung squamous carcinoma and adjacent normal bronchial epithelial tissues were obtained under the condition of 0.75-mg protein-load. The average deviation of spot position was 0.733+/-0.101 mm in IEF direction, and 0.925+/-0.207 mm in SDS-PAGE direction. For tumor tissue, a total of 1241+/-88 spots were detected, 987+/-65 spots were matched with an average matching rate of 79.5%. For control, a total of 1190+/-72 spots were detected, and 875+/-48 spots were matched with an average matching rate of 73.5%. A total of 864+/-34 spots were matched between tumors and controls. Forty-three differential proteins were characterized: some proteins were related to oncogenes, and others involved in the regulation of cell cycle and signal transduction. It is suggested that the differential proteomic approach is valuable for mass identification of differentially expressed proteins involved in lung carcinogenesis. These data will be used to establish human lung cancer proteome database to further study human lung squamous carcinoma.
The C-terminal binding protein 1 (CtBP) is a ubiquitous corepressor linking the recruitment of DNA- and histone-modifying proteins to sequence-specific DNA-binding proteins and facilitating gene regulation during development and oncogenesis. We describe here the binding, phosphorylation and functional regulation of CtBP by the p21-activated kinase 1 (Pak1). Pak1 phosphorylates CtBP selectively on Ser158 within a putative regulatory loop, triggering CtBP cellular redistribution and blocking CtBP corepressor functions. A S158A substitution in CtBP or Pak1 knockdown by short interference RNA blocked CtBP phosphorylation, redistribution and attenuation of CtBP corepressor functions in reporter and chromatin assays. In the presence of NADH, Pak1 superphosphorylates CtBP and inhibits CtBP dehydrogenase activity, suggesting that preferential phosphorylation of active CtBP may alter secondary structures and influence both enzymatic and corepressor functions. Pak1 regulation of CtBP represents a new model of corepressor regulation whereby cellular signaling cascades may influence gene expression in mammalian cells.
A novel ribosome-inactivating protein designated Moschatin from the mature seeds of pumpkin (Cucurbita moschata) has been successively purified to homogeneity, using ammonium sulfate precipitation, CM-cellulose 52 column chromatography, Blue Sepharose CL-6B Affinity column chromatography and FPLC size-exclusion column chromatography. Moschatin is a type 1 RIP with a pI of 9.4 and molecular weight of approximately 29 kD. It is a rRNA N-glycosidase and potently blocked the protein synthesis in the rabbit reticulocyte lysate with a IC50 of 0.26 nM. Using the anti-human melanoma McAb Ng76, a novel immunotoxin Moschatin-Ng76 was prepared successfully and it efficiently inhibited the growth of targeted melanoma cells M21 with a IC50 of 0.04 nM, 1500 times lower than that of free Moschatin. The results implied that Moschatin could be used as a new potential anticancer agent.
An automated computerized scheme has been developed for determination of the likelihood measure of malignancy of pulmonary nodules on low-dose helical CT (LDCT) images. Our database consisted of 76 primary lung cancers (147 slices) and 413 benign nodules (576 slices). With this automated computerized scheme, the location of a nodule was first indicated by a radiologist. The outline of the nodule was segmented automatically by use of a dynamic programming technique. Various objective features on the nodules were determined by use of outline analysis and image analysis, and the likelihood measure of malignancy was determined by use of linear discriminant analysis (LDA). The effect of many different combinations of features and the performance of LDA in distinguishing benign nodules from malignant ones were evaluated by means of receiver operating characteristic (ROC) analysis. The Az value (area under the ROC curve) obtained by the computerized scheme in distinguishing benign nodules from malignant ones was 0.828 when a single slice was employed for each of the nodules. However, the Az value was improved to 0.846 when multiple slices were used for determination of the likelihood measure of malignancy. The Az values obtained by the computerized scheme on LDCT images were significantly greater than the Az value of 0.70, which was obtained from our previous observer studies by radiologists in distinguishing benign nodules from malignant ones on LDCT images. The automated computerized scheme for determination of the likelihood measure of malignancy would be useful in assisting radiologists to distinguish between benign and malignant pulmonary nodules on LDCT images.
We have evaluated the performance of an automated classifier applied to the task of differentiating malignant and benign lung nodules in low-dose helical computed tomography (CT) scans acquired as part of a lung cancer screening program. The nodules classified in this manner were initially identified by our automated lung nodule detection method, so that the output of automated lung nodule detection was used as input to automated lung nodule classification. This study begins to narrow the distinction between the "detection task" and the "classification task." Automated lung nodule detection is based on two- and three-dimensional analyses of the CT image data. Gray-level-thresholding techniques are used to identify initial lung nodule candidates, for which morphological and gray-level features are computed. A rule-based approach is applied to reduce the number of nodule candidates that correspond to non-nodules, and the features of remaining candidates are merged through linear discriminant analysis to obtain final detection results. Automated lung nodule classification merges the features of the lung nodule candidates identified by the detection algorithm that correspond to actual nodules through another linear discriminant classifier to distinguish between malignant and benign nodules. The automated classification method was applied to the computerized detection results obtained from a database of 393 low-dose thoracic CT scans containing 470 confirmed lung nodules (69 malignant and 401 benign nodules). Receiver operating characteristic (ROC) analysis was used to evaluate the ability of the classifier to differentiate between nodule candidates that correspond to malignant nodules and nodule candidates that correspond to benign lesions. The area under the ROC curve for this classification task attained a value of 0.79 during a leave-one-out evaluation.
In this study, we investigated a pattern-recognition technique based on an artificial neural network (ANN), which is called a massive training artificial neural network (MTANN), for reduction of false positives in computerized detection of lung nodules in low-dose computed tomography (CT) images. The MTANN consists of a modified multilayer ANN, which is capable of operating on image data directly. The MTANN is trained by use of a large number of subregions extracted from input images together with the teacher images containing the distribution for the "likelihood of being a nodule." The output image is obtained by scanning an input image with the MTANN. The distinction between a nodule and a non-nodule is made by use of a score which is defined from the output image of the trained MTANN. In order to eliminate various types of non-nodules, we extended the capability of a single MTANN, and developed a multiple MTANN (Multi-MTANN). The Multi-MTANN consists of plural MTANNs that are arranged in parallel. Each MTANN is trained by using the same nodules, but with a different type of non-nodule. Each MTANN acts as an expert for a specific type of non-nodule, e.g., five different MTANNs were trained to distinguish nodules from various-sized vessels; four other MTANNs were applied to eliminate some other opacities. The outputs of the MTANNs were combined by using the logical AND operation such that each of the trained MTANNs eliminated none of the nodules, but removed the specific type of non-nodule with which the MTANN was trained, and thus removed various types of non-nodules. The Multi-MTANN consisting of nine MTANNs was trained with 10 typical nodules and 10 non-nodules representing each of nine different non-nodule types (90 training non-nodules overall) in a training set. The trained Multi-MTANN was applied to the reduction of false positives reported by our current computerized scheme for lung nodule detection based on a database of 63 low-dose CT scans (1765 sections), which contained 71 confirmed nodules including 66 biopsy-confirmed primary cancers, from a lung cancer screening program. The Multi-MTANN was applied to 58 true positives (nodules from 54 patients) and 1726 false positives (non-nodules) reported by our current scheme in a validation test; these were different from the training set. The results indicated that 83% (1424/1726) of non-nodules were removed with a reduction of one true positive (nodule), i.e., a classification sensitivity of 98.3% (57 of 58 nodules). By using the Multi-MTANN, the false-positive rate of our current scheme was improved from 0.98 to 0.18 false positives per section (from 27.4 to 4.8 per patient) at an overall sensitivity of 80.3% (57/71).
An automated computerized scheme has been developed for the detection and characterization of diffuse lung diseases on high-resolution computed tomography (HRCT) images. Our database consisted of 315 HRCT images selected from 105 patients, which included normal and abnormal slices related to six different patterns, i.e., ground-glass opacities, reticular and linear opacities, nodular opacities, honeycombing, emphysematous change, and consolidation. The areas that included specific diffuse patterns in 315 HRCT images were marked by three radiologists independently on the CRT monitor in the same manner as they commonly describe in their radiologic reports. The areas with a specific pattern, which three radiologists marked independently and consistently as the same patterns, were used as "gold standard" for specific abnormal opacities in this study. The lungs were first segmented from the background in each slice by use of a morphological filter and a thresholding technique, and then divided into many contiguous regions of interest (ROIs) with a 32x32 matrix. Six physical measures which were determined in each ROI included the mean and the standard deviation of the CT value, air density components, nodular components, line components, and multilocular components. Artificial neural networks (ANNs) were employed for distinguishing between seven different patterns which included normals and six patterns associated with diffuse lung disease. The sensitivity of this computerized method for a detection of the six abnormal patterns in each ROI was 99.2% (122/123) for ground-glass opacities, 100% (15/15) for reticular and linear opacities, 88.0% (132/150) for nodular opacities, 100% (98/98) for honeycombing, 95.8% (369/385) for emphysematous change, and 100% (43/43) for consolidation. The specificity in detecting a normal ROI was 88.1% (940/1067). This computerized method may be useful in assisting radiologists in their assessment of diffuse lung disease in HRCT images.
We have been developing a computerized scheme to assist radiologists in improving the diagnostic accuracy for lung cancers on low-dose computed tomography (LDCT) scans by use of similar images for malignant nodules and benign nodules. A database of 415 LDCT scans including 73 cases with 76 confirmed cancers and 342 cases with 413 confirmed benign nodules was first collected in an LDCT screening program for early detection of lung cancers in Nagano, Japan. An observer study by use of receiver operating characteristics analysis was first conducted with five radiologists to demonstrate that presenting similar images for malignant nodules and benign nodules can significantly improve radiologists' performance in the diagnosis of unknown nodules. Another observer study was then conducted for obtaining reliable data on subjective similarity ratings by 10 radiologists. Based on the subjective similarity ratings, three important features were selected from a number of nodule features, and four different techniques for the determination of similarity measures, namely, a feature-based technique, a pixel-value-difference based technique, a cross-correlation-based technique, and a neural-network-based technique, were investigated and evaluated in terms of the correlation coefficient with the subjective similarity ratings. The experimental results in this study indicated that the neural-network-based technique can provide a reliable psychophysical similarity measure which is comparable to the subjective similarity ratings for a single radiologist when evaluated by use of correlation with the average similarity ratings for the other nine radiologists.
Previous evaluations of inactivated whole-virus and envelope subunit vaccines to equine infectious anemia virus (EIAV) have revealed a broad spectrum of efficacy ranging from highly type-specific protection to severe enhancement of viral replication and disease in experimentally immunized equids. Among experimental animal lentivirus vaccines, immunizations with live attenuated viral strains have proven most effective, but the vaccine efficacy has been shown to be highly dependent on the nature and severity of the vaccine virus attenuation. We describe here for the first time the characterization of an experimental attenuated proviral vaccine, EIAV(UK)deltaS2, based on inactivation of the S2 accessory gene to down regulate in vivo replication without affecting in vitro growth properties. The results of these studies demonstrated that immunization with EIAV(UK)deltaS2 elicited mature virus-specific immune responses by 6 months and that this vaccine immunity provided protection from disease and detectable infection by intravenous challenge with a reference virulent biological clone, EIAV(PV). This level of protection was observed in each of the six experimental horses challenged with the reference virulent EIAV(PV) by using a low-dose multiple-exposure protocol (three administrations of 10 median horse infectious doses [HID(50)], intravenous) designed to mimic field exposures and in all three experimentally immunized ponies challenged intravenously with a single inoculation of 3,000 HID(50). In contrast, naïve equids subjected to the low- or high-dose challenge develop a detectable infection of challenge virus and acute disease within several weeks. Thus, these data demonstrate that the EIAV S2 gene provides an optimal site for modification to achieve the necessary balance between attenuation to suppress virulence and replication potential to sufficiently drive host immune responses to produce vaccine immunity to viral exposure.
Little is known about cell cycle regulation in hypoxic cells, despite its significance. We utilized an experimentally tractable model to study the proliferative responses of rat fibroblasts when rendered hypoxic (0.5% oxygen) or anoxic (<0.01% oxygen). Hypoxic cells underwent G1 arrest, whereas anoxic cells also demonstrated S-phase arrest due to suppression of DNA initiation. Upon reoxygenation, only those cells arrested in G1 were able to resume proliferation. The oncoprotein E1a induced p53-independent apoptosis in anoxic cells, which when suppressed by Bcl-2 permitted proliferation despite anoxia. E1a expression led to marked increases in the transcription factor E2F, and overexpression of E2F-1 allowed proliferation in hypoxic cells, although it had minimal effect on the anoxic suppression of DNA initiation. We thus demonstrate two distinct cell cycle responses to low oxygen and suggest that alterations that lead to increased E2F can overcome hypoxic G1 arrest but that additional alterations, promoted by E1a expression, are necessary for neoplastic cells to proliferate despite anoxia.
PURPOSE: To further test the hypothesis that light-adaptation-mediated photoreceptor protection works through inhibition of apoptosis by activation and/or upregulation of neuroprotective molecules. METHODS: Albino rats were born and raised in 5-lux cyclic light (12 hours OFF and ON). At 8 weeks of age, animals were adapted to 400-lux cyclic light for different periods. Light damage was induced by exposure to constant light for 1 day at an illumination of 1700 lux. Animals were killed, and their eyes were removed for morphometric and biochemical analysis. TUNEL assay was used to evaluate photoreceptor cell apoptosis and Western blot analyses were used to determine the levels of basic fibroblast growth factor (bFGF), neuronal nitric oxide synthase (nNOS), and caspase-3. RESULTS: Exposure of dim-reared rats to constant light for 1 day dramatically increased TUNEL-positive cells in the outer nuclear layer. Adaptation to 400-lux bright cyclic light for 4 days significantly reduced TUNEL-positive cells induced by exposure to constant light, which correlated with a significant increase in bFGF expression. Compared with control retinas, caspase-3 levels were not changed by exposure to constant light or after adaptation to 400 lux. There was a significant increase in nNOS level in the constant-light-exposed group, but not in the group adapted to 400-lux bright light before exposure to constant light. CONCLUSIONS: The retina of the adult rat can rapidly upregulate neuroprotective mechanisms when switched from dim to bright cyclic light. Identification of the molecules involved in this process may allow rational development of therapeutic approaches to treat retinal degenerative diseases.