Chinese pharmaceutical companies: an emerging industry.
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Journal Article↗
Biomedical subjects
X Yan
Publications and source records attributed to X Yan.
Is the linkage region of sphingolipids responsible for lipid raft formation?
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Molecular Structure↗
Reaction mechanism for mammalian pyruvate dehydrogenase using natural lipoyl domain substrates.
The pyruvate dehydrogenase (E1) component of the pyruvate dehydrogenase complex (PDC) catalyzes a two-step reaction. Recombinant production of substrate amounts of the lipoyl domains of the dihydrolipoyl transacetylase (E2) component of the mammalian PDC allowed kinetic characterization of the rapid physiological reaction catalyzed by E1. Using either the N-terminal (L1) or the internal (L2) lipoyl domain of E2 as a substrate, analyses of steady state kinetic data support a ping pong mechanism. Using standard E1 preparations, Michaelis constants (Km) were 52 +/- 14 microM for L1 and 24.8 +/- 3.8 microM for pyruvate and k(cat) was 26.3 s(-1). With less common, higher activity preparations of E1, the Km values were > or =160 microM for L1 and > or =35 microM for pyruvate and k(cat) was > or =70 s(-1). Similar results were found with the L2 domain. The best synthetic lipoylated-peptide (L2 residues 163-177) was a much poorer substrate (Km > or =15 mM, k(cat) approximately equals 5 s(-1); k(cat)/Km decreased >1,500-fold) than L1 or L2, but a far better substrate in the E1 reaction than free lipoamide (k(cat)/Km increased >500-fold). Each lipoate source was an effective substrate in the dihydrolipoyl dehydrogenase (E3) reaction, but E3 had a lower Km for the L2 domain than for lipoamide or the lipoylated peptides. In contrast to measurements with slow E1 model reactions that use artificial acceptors, we confirmed that the natural E1 reaction, using lipoyl domain acceptors, was completely inhibited (>99%) by phosphorylation of E1 and the phosphorylation strongly inhibited the reverse of the second step catalyzed by E1. The mechanisms by which phosphorylation interferes with E1 activity is interpreted based on accrued results and the location of phosphorylation sites mapped onto the 3-D structure of related alpha-keto acid dehydrogenases.
Acetylation↗
Distinct regulatory properties of pyruvate dehydrogenase kinase and phosphatase isoforms.
The mammalian pyruvate dehydrogenase complex (PDC) plays central and strategic roles in the control of the use of glucose-linked substrates as sources of oxidative energy or as precursors in the biosynthesis of fatty acids. The activity of this mitochondrial complex is regulated by the continuous operation of competing pyruvate dehydrogenase kinase (PDK) and pyruvate dehydrogenase phosphatase (PDP) reactions. The resulting interconversion cycle determines the fraction of active (nonphosphorylated) pyruvate dehydrogenase (E1) component. Tissue-specific and metabolic state-specific control is achieved by the selective expression and distinct regulatory properties of at least four PDK isozymes and two PDP isozymes. The PDK isoforms are members of a family of serine kinases that are not structurally related to cytoplasmic Ser/Thr/Tyr kinases. The catalytic subunits of the PDP isoforms are Mg2+-dependent members of the phosphatase 2C family that has binuclear metal-binding sites within the active site. The dihydrolipoyl acetyltransferase (E2) and the dihydrolipoyl dehydrogenase-binding protein (E3BP) are multidomain proteins that form the oligomeric core of the complex. One or more of their three lipoyl domains (two in E2) selectively bind each PDK and PDP1. These adaptive interactions predominantly influence the catalytic efficiencies and effector control of these regulatory enzymes. When fatty acids are the preferred source of acetyl-CoA and NADH, feedback inactivation of PDC is accomplished by the activity of certain kinase isoforms being stimulated upon preferentially binding a lipoyl domain containing a reductively acetylated lipoyl group. PDC activity is increased in Ca2+-sensitive tissues by elevating PDP1 activity via the Ca2+-dependent binding of PDP1 to a lipoyl domain of E2. During starvation, the irrecoverable loss of glucose carbons is restricted by minimizing PDC activity due to high kinase activity that results from the overexpression of specific kinase isoforms. Overexpression of the same PDK isoforms deleteriously hinders glucose consumption in unregulated diabetes.
Amino Acid Sequence↗
SOM integrated with CCA for the feature map and classification of complex chemical patterns.
Considering that the two-dimensional (2D) feature map of the high-dimensional chemical patterns can more concisely and efficiently represent the pattern characteristic, a new procedure integrating self-organizing map (SOM) networks with correlative component analysis (CCA) is proposed. Firstly, CCA was used to identify the most important classification characteristics (CCs) from the original high-dimensional chemical pattern information. Then, the SOM maps the first several CCs, which include the most useful information for pattern classification, onto a 2D plane, on which the pattern classification feature is concisely represented. To improve the learning efficiency of SOM networks, two new algorithms for dynamically adjusting the learning rate and the range of neighborhood around the winning unit were further worked out. Besides, a convenient method for detecting the topologic nature of SOM results was proposed. Finally, a typical example of mapping two classes natural spearmint essence was employed to verify the effectiveness of the new approach. The feature-topology-preserving (FTP) map obtained can well represent the classification of original patterns and is much better than what obtained by SOM alone.
Journal Article↗
An accurate analytical approach to electron crystallography.
A much more accurate analytical expression of dynamical electron diffraction than the phase object approximation (POA) formula has been derived in this paper which decreases the restriction of sample thickness up to almost one order of magnitude compared to POA theory. The importance of the new expression is twofold. First, a sample with such a thickness that new expression remains valid can be prepared experimentally. Second, the new expression reveals a clear and straightforward relationship between the wave function and crystal potential. In the expression, the effect of dynamical diffraction on wave function can be simply attributed to two factors TP(D) = (sin(lambda pi zg2))/(4pi2g2) and TA(D) = [1 - cos(lambda pi zg2)]/4pi2g2. Compared to the effect of transfer functions of an electron microscope on wave function, we found that TP(d) and TA(d) play the same role as transfer function but are independent of the instrument. For this reason, we here call the former as "extrinsic transfer functions" and the latter as "intrinsic" ones. In principle, one should correct not only extrinsic transfer functions but also intrinsic ones if one desires to achieve higher resolution.
Journal Article↗
Ultrasound-Induced hyperthermia increases cellular uptake and cytotoxicity of P-glycoprotein substrates in multi-drug resistant cells.
PURPOSE: Localized hyperthermia has been shown previously to augment the cytotoxicity of some lipophilic anticancer drugs. Because many of the substrates for the multi-drug resistance (MDR) transporter P-glycoprotein (P-gp) are lipophilic in nature, studies were conducted to test the hypothesis that hyperthermia induced by ultrasound could also increase cellular uptake and cytotoxicity of P-gp substrates by P-gp-expressing cells. METHODS: To test this hypothesis, we studied the effects of hyperthermia and ultrasound on cellular accumulation of putative P-gp substrates, rhodamine 123 (R123) and doxorubicin (DOX), and cytotoxicity of DOX in the parent and MDR variants of two human cancer cell lines. RESULTS: Treatment of cells with hyperthermia or ultrasound (20 min at 41 degrees C) both caused a significant increase over controls (no ultrasound treatment) in R123 and DOX accumulation in the parent and MDR lines of MV522 and KB cells. Ultrasound also substantially increased the antiproliferative effects of DOX in both the parent and MDR variants of MV522 and KB cell lines when compared with controls. Our results also indicated that ultrasound exerted a much greater effect on cellular accumulation of R123 and DOX and cytotoxicity enhancement of DOX in the MDR variants than putative P-gp antagonist such as verapamil. CONCLUSION: The present results point to the potential use of ultrasound-induced hyperthermia as a much safer alternative to P-gp antagonist for reversal of MDR.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Estimation of wet, dry and bulk deposition of atmospheric nitrogen in Connecticut.
Atmospheric nitrogen species including NO3-, NH4+ and total nitrogen in air and precipitation samples were collected with low-volume filter packs and wet deposition collectors from March 1999 through the end of December 2000 in seven sampling locations in Connecticut. Three sampling locations were chosen along the shores of Long Island Sound and four were chosen in interior sections of Connecticut. Sampling sites were chosen to represent both rural and urban sectors. Wet deposition flux of nitrogen species was calculated using wet concentrations, the volume of collected precipitation and the opening surface area of the Aerochemetrics wet deposition collector. The dry deposition flux of nitrogen species was estimated with the application of the dry deposition inferential model (DDIM). Bulk deposition of nitrogen was collected with the aid of a device based on the Swedish IVL Sampler. The dry deposition fluxes of NO3-, NH4+ and total nitrogen were found to be significantly higher in urban areas than the rural sampling locations. There was, however, no significant difference between the wet deposition fluxes of different nitrogen species in rural and urban sampling locations. When inland and coastal sites were compared, the dry deposition fluxes of NH4+ and total nitrogen were significantly higher in inland locations and there was no significant difference between coastal and inland sampling locations for wet deposition fluxes of nitrogen species. No significant difference was observed between the bulk deposition and the sum of the wet and dry deposition fluxes of total nitrogen at rural sampling locations. In urban sampling locations, the bulk deposition flux of total nitrogen was significantly lower than the sum of dry and wet deposition fluxes. There appears to be a similar seasonal trend in wet and dry deposition fluxes of total nitrogen in Connecticut with high and low deposition fluxes occurring in summer and winter periods, respectively.
Air Pollutants↗
Silver-haired bat rabies virus variant does not induce apoptosis in the brain of experimentally infected mice.
To examine whether induction of apoptosis plays a role in the pathogenesis of street rabies, we compared the distribution of viral antigens, histopathology, and the induction of apoptosis in the brain of mice infected with a street rabies virus (silver-haired bat rabies virus, SHBRV) and with a mouse-adapted laboratory rabies virus strain (challenge virus standard, CVS-24). Inflammation was identified in the meninges, but not in the parenchyma of the brain of mice infected with either CVS-24 or SHBRV. Necrosis was present in numerous cortical, hippocampal, and Purkinje neurons in CVS-24-infected mice, but only minimal necrosis was identified in mice infected with SHBRV. Likewise, extensive terminal deoxynucleotidyl transferase-mediated dUTP-digoxigenin nick end-labeling (TUNEL) staining was observed in the brain of mice infected with CVS-24 but little or none in the brain of mice infected with SHBRV. Rabies virus antigens were distributed similarly in the CNS infected with either virus. However, the expression of the glycoprotein (G) is more widespread and the staining of G is generally stronger in CVS- than SHBRV-infected mice, whereas the expression of rabies virus nucleoprotein (N) is similar in mice infected with either CVS or SHBRV. The positive TUNEL staining thus correlates with the high level of G expression in CVS-infected mouse brain. Northern blot hybridization revealed that the ratio between the N and G transcripts is similar in brains infected with either virus, indicating that the reduced expression of G protein is not caused by reduced transcription in SHBRV-infected animals. Taken together, these observations suggest that apoptosis is not an essential pathogenic mechanism for the outcome of a street rabies virus infection and that other pathologic processes may contribute to the profound neuronal dysfunction characteristic of street rabies.
Animals↗
Human monoclonal autoantibodies to B-cell epitopes outside the thyroid peroxidase autoantibody immunodominant region.
Human autoantibodies to thyroid peroxidase (TPO) interact with a restricted or immunodominant region (IDR) on intact TPO. However, a smaller proportion of polyclonal serum TPO autoantibodies bind outside this region. To isolate monoclonal nonimmunodominant region (non-IDR) TPO autoantibodies, we screened a thyroid-derived immunoglobulin gene phage display library while "epitope masking" the TPO IDR with four human TPO monoclonal autoantibodies that define the IDR. Among 31 non-IDR autoantibodies obtained (expressed as Fab), 8 representatives were analyzed further based on their restriction digestion profiles. All are encoded by almost identical H chains (VH3 family), with extremely long D regions, paired with three different types of light chains. In contrast, IDR TPO Fab from the same patient utilize seven different heavy chains (VH1 and VH5 families) paired nonpromiscuously with different light chains. Use of VH5 genes has not been reported previously for TPO autoantibodies. Both non-IDR and IDR Fab bind specifically to TPO and not to other proteins. The non-IDR Fab affinities for TPO are moderately high (Kd 1-2 x 10(-9) M), somewhat lower than those for most IDR Fab (Kd 1-4 x 10(-10) M). The epitopes of the three types of non-IDR Fab overlap with each other, indicating a major role for their heavy chain in TPO binding. Most importantly, the epitopes of non-IDR Fab are recognized by patients' serum autoantibodies. In summary, we provide the first insight into the immunoglobulin genes, affinities and epitopes of human monoclonal autoantibodies that bind outside the TPO-immunodominant region.
Amino Acid Sequence↗
Induction of a major leaf acid phosphatase does not confer adaptation to low phosphorus availability in common bean.
Acid phosphatase is believed to be important for phosphorus scavenging and remobilization in plants, but its role in plant adaptation to low phosphorus availability has not been critically evaluated. To address this issue, we compared acid phosphatase activity (APA) in leaves of common bean (Phaseolus vulgaris) in a phosphorus-inefficient genotype (DOR364), a phosphorus-efficient genotype (G19833), and their F(5.10) recombinant inbred lines (RILs). Phosphorus deficiency substantially increased leaf APA, but APA was much higher and more responsive to phosphorus availability in DOR364 than in G19833. Leaf APA segregated in the RILs, with two discrete groups having either high (mean = 1.71 micromol/mg protein/min) or low (0.36 micromol/mg protein/min) activity. A chi-square test indicated that the observed difference might be controlled by a single gene. Non-denaturing protein electrophoresis revealed that there are four visible isoforms responsible for total APA in common bean, and that the difference in APA between contrasting genotypes could be attributed to the existence of a single major isoform. Qualitative mapping of the APA trait and quantitative trait loci analysis with molecular markers indicated that a major gene contributing to APA is located on linkage group B03 of the unified common bean map. This locus was not associated with loci conferring phosphorus acquisition efficiency or phosphorus use efficiency. RILs contrasting for APA had similar phosphorus pools in old and young leaves under phosphorus stress, arguing against a role for APA in phosphorus remobilization. Our results do not support a major role for leaf APA induction in regulating plant adaptation to phosphorus deficiency.
Acid Phosphatase↗
Structural comparison of recombinant human macrophage colony stimulating factor beta and a partially reduced derivative using hydrogen deuterium exchange and electrospray ionization mass spectrometry.
Hydrogen deuterium exchange, monitored by electrospray ionization mass spectrometry, has been employed to characterize structural features of a derivative of recombinant human macrophage colony stimulating factor beta (rhm-CSFbeta) in which two of the nine disulfide bridges (Cys157/Cys159-Cys'157/Cys'159) were selectively reduced and alkylated. Removal of these two disulfide bridges did not affect the biological activity of the protein. Similarities between CD and fluorescence spectra for rhm-CSFbeta and its derivative indicate that removing the disulfide bonds did not strongly alter the overall three-dimensional structure of rhm-CSFbeta. However, differences between deuterium exchange data of the intact proteins indicate that more NHs underwent fast deuterium exchange in the derivative than in rhm-CSFbeta. Regions located near the disulfide bond removal site were shown to exhibit faster deuterium exchange behavior in the derivative than in rhm-CSFbeta.
Amino Acid Sequence↗
Metabolic responses to leptin in obese db/db mice are strain dependent.
Obese, diabetic C57BL/Ks db/db mice that lack the long-form leptin receptor exhibit no decrease in body weight or food intake when treated with leptin. Here we compared responses to leptin in two strains of db/db mice: C57BL/6J mice that are hyperglycemic and hyperinsulinemic and C57BL/Ks that are hyperglycemic and normo- or hypoinsulinemic. Chronic intraperitoneal infusion of 10 microgram leptin/day partially reversed hyperglycemia in C57BL/6J male mice but exaggerated the diabetic state of female mice. Bolus intraperitoneal injections of 40 microgram leptin/day did not effect glucose in either strain of male db/db mice, whereas chronic intraperitoneal infusion of 20 microgram leptin/day significantly reduced fasting blood glucose in male mice from both strains, especially C57BL/6J mice. Food intake, body weight, rectal temperature, and body fat did not change. Chronic intraperitoneal infusion of 10 microgram leptin/day significantly reduced body fat in lean db/+ C57BL/6J but not in C57BL/Ks mice. Thus peripherally administered leptin is active in mice that have only short-form leptin receptors, and the response is dependent on the method of leptin administration and the background strain.
Adipose Tissue↗
The DEAD box protein DP103 is a regulator of steroidogenic factor-1.
The nuclear receptor steroidogenic factor-1 (SF-1) is essential for development of the gonads, adrenal gland, and the ventromedial hypothalamic nucleus. It also regulates the expression of pivotal steroidogenic enzymes and other important proteins in the reproductive system. We sought to elucidate the mechanisms that govern the transcriptional activity of SF-1. We demonstrate here that a previously uncharacterized domain, located C-terminal to the DNA binding domain of SF-1, exhibits transcriptional repression function. Point mutations in this domain markedly potentiate the transcriptional activity of native SF-1. Using an SF-1 region that spans this proximal repression domain as bait in a yeast two-hybrid system, we cloned an SF-1 interacting protein that is homologous to human DP103, a member of the DEAD box family of putative RNA helicases. DP103 directly interacts with the proximal repression domain of SF-1, and mutations in this domain abrogate its interaction with DP103. DP103 is expressed predominantly in the testis and is also expressed at a lower level in other steroidogenic and nonsteroidogenic tissues. Functionally, DP103 exhibits a native transcriptional repression function that localizes to the C-terminal region of the protein and represses the activity of wild-type, but not mutant, SF-1. Together, the physical and functional interaction of DP103 with a previously unrecognized repression domain within SF-1 represents a novel mechanism for regulation of SF-1 activity.
Amino Acid Sequence↗
Effect of phosphorus availability on basal root shallowness in common bean.
Root gravitropism may be an important element of plant response to phosphorus availability because it determines root foraging in fertile topsoil horizons, and thereby phosphorus acquisition. In this study we seek to test this hypothesis in both two dimensional paper growth pouch and three-dimensional solid media of sand and soil cultures. Five common bean ( Phaseolus vulgaris L.) genotypes with contrasting adaptation to low phosphorus availability were evaluated in growth pouches over 6 days of growth, and in sand culture and soil culture over 4 weeks of growth. In all three media, phosphorus availability regulated the gravitropic response of basal roots in a genotype-dependent manner. In pouches, sand, and soil, the phosphorus-inefficient genotype DOR 364 had deeper roots with phosphorus stress, whereas the phosphorus-efficient genotype G19833 responded to phosphorus stress by producing shallower roots. Genotypes were most responsive to phosphorus stress in sand culture, where relative root allocation to the 0-3- and 3-6-cm horizons increased 50% with phosphorus stress, and varied 300% (3-6 cm) to 500% (0-3 cm) among genotypes. Our results indicate that (1) phosphorus availability regulates root gravitropic growth in both paper and solid media, (2) responses observed in young seedlings continue throughout vegetative growth, (3) the response of root gravitropism to phosphorus availability varies among genotypes, and (4) genotypic adaptation to low phosphorus availability is correlated with the ability to allocate roots to shallow soil horizons under phosphorus stress.
Biomass↗
Clinicopathologic study of mucosa-associated lymphoid tissue lymphoma of the salivary gland.
OBJECTIVE: To study the histopathologic features and pathogenesis of mucosa-associated lymphoid tissue lymphoma (MALT-oma) of salivary glands. METHODS: Clinical data, paraffin-embedded sections, immunohistochemical slides (SP method) and electron microscopic features of surgical specimens of 32 cases of salivary gland MALT-oma were studied. RESULTS: The patients were 27 males and 5 females, with a mean age of 54.76 years. The lesions were located in the parotid area in 17 cases, and in the submandibular gland in the remaining 15 cases. Much of the MALT-oma was replaced by infiltration of a great amount of centrocyte-like cells (CCL) as background and occasional large cells (centroblast- or immunoblast-like). In MALT-omas "lymphoepithelial lesions" were present. Immunohistochemically, CD20 expression was found to be positive and CD45RO expression was negative in all MALT-omas. CONCLUSION: Most of the MALT-omas are low grade malignant tumors and have a "homing back" phenomenon. The cases were managed by surgery and chemotherapy. In a few MALT-omas which turned into high grade malignant tumors, the prognosis was poor. Acquired MALT may develop as a reaction to autoimmune disease and infection. Hyper-immune reaction and MALT hyperplasia under stimulation may result in myoepithelial sialadenitis and lead to MALT-oma of the salivary gland.
Adolescent↗
Primary studies on heroin abuse and injury induced by oxidation and lipoperoxidation.
OBJECTIVE: To further reveal serious risks of heroin abuse to human body and clarify grave injuries of oxidation, peroxidation and lipoperoxidation induced by nitric oxide and other free radicals to heroin abusers. METHODS: Determined and compared plasma levels of nitric oxide (P-NO), vitamin C (P-VC), vitamin E (P-VE), beta-carotene (P-beta-CAR), lipoperoxides (P-LPO) and erythrocyte activities of superoxide dismutase (E-SOD), catalase (E-CAT), glutathione peroxidase (E-GSH-Px) and erythrocyte level of lipoperoxides (E-LPO) in 137 cases of heroin abusers (HAs) and 100 cases of healthy volunteers (HVs), used linear regression and correlation, stepwise regression and correlation to analyze correlation among heroin-abusing-duration (HAD), daily-heroin-abusing-quantity (DHAQ) with above determination values in the HAs. RESULTS: Compared with the above average values in the HVs group, the average values of P-NO, P-LPO, E-LPO in the HAs group were significantly increased (P < 0.0001), the average values of P-VC, P-VE, P-beta-CAR, E-SOD, E-CAT and E-GSH-Px were significantly decreased (P < 0.0001); the analysis of linear regression and correlation showed that with ascending of the HAD and DHAQ in the HAs, the values of P-NO, P-LPO, E-LPO were gradually increased (P < 0.0001), the values of P-VC, P-VE, P-beta-CAR, E-SOD, E-CAT, E-GSH-Px were gradually decreased (P < 0.0001); the analysis of stepwise regression and correlation suggested that the correlation among the HAD, DHAQ with the values of P-NO, P-VC, P-VE was the closest. CONCLUSION: The balance between oxidation and antioxidation in the HAs was seriously destroyed, and the injuries induced by nitric oxide and other free radicals, oxidation, peroxidation and lipoperoxidation reactions to the body of HAs gravely exacerbated. In the abstaining from heroin dependence, therefore, it should consider that sufficient quantum antioxidants such as VC, VE and beta-CAR are dosed to the HAs so as to abate the injuries to their bodies.
Adult↗
[Several basic issues of forest gap model. I. Effect of simulated plot area].
A case study on the effect of different plot area on forest gap model simulation was conducted with forest gap model NEWCOP in broad-leaved Korean pine forests at Changbai Mt. of Northeastern China. The results showed that change of plot area affected the tree species composition and the gap appearance periodicity of simulated forest stand, which was applied to determine 400-800 m2 as the area of forest gap.
China↗