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Alterations of plasma lipids in mice via adenoviral-mediated hepatic overexpression of human ABCA1 总被引:3,自引:0,他引:3
Wellington CL Brunham LR Zhou S Singaraja RR Visscher H Gelfer A Ross C James E Liu G Huber MT Yang YZ Parks RJ Groen A Fruchart-Najib J Hayden MR 《Journal of lipid research》2003,44(8):1470-1480
ATP binding cassette transporter A1 (ABCA1) is a widely expressed lipid transporter essential for the generation of HDL. ABCA1 is particularly abundant in the liver, suggesting that the liver may play a major role in HDL homeostasis. To determine how hepatic ABCA1 affects plasma HDL cholesterol levels, we treated mice with an adenovirus (Ad)-expressing human ABCA1 under the control of the cytomegalovirus promoter. Treated mice showed a dose-dependent increase in hepatic ABCA1 protein, ranging from 1.2-fold to 8.3-fold using doses from 5 x 108 to 1.5 x 109 pfu, with maximal expression observed on Day 3 posttreatment. A selective increase in HDL cholesterol occurred at Day 3 in mice treated with 5 x 108 pfu Ad-ABCA1, but higher doses did not further elevate HDL cholesterol levels. In contrast, total cholesterol, triglycerides, phospholipids, non-HDL cholesterol, and apolipoprotein B levels all increased in a dose-dependent manner, suggesting that excessive overexpression of hepatic ABCA1 in the absence of its normal regulatory sequences altered total lipid homeostasis. At comparable expression levels, bacterial artificial chromosome transgenic mice, which express ABCA1 under the control of its endogenous regulatory sequences, showed a greater and more specific increase in HDL cholesterol than Ad-ABCA1-treated mice. Our results suggest that appropriate regulation of ABCA1 is critical for a selective increase in HDL cholesterol levels. 相似文献
4.
A Chinese Hamster Ovary cell line, CHO1-15500, producing recombinant human tissue type plasminogen activator (tPA) via the dihydrofolate reductase (DHFR) amplification
system, was studied in batch culture. In this system both DHFR and tPA are under the control of the strong constitutive viral
SV40 early promoter. Employing the cumulative viable cell-hour approach, the specific productivity of tPA had maxima in the
lag (0.065 pg cell−1 h−1) and early decline (0.040 pg cell−1 h−1) population growth phases. The viable population was assigned into four subpopulations (G1, S, G2/M phase, and Apoptotic
cells) using flow cytometric analysis. As expected, intracellular DHFR was maximally expressed during the S cell cycle phase.
The production of tPA, however, was found to be a direct linear function of the G1 phase, with a subpopulation specific productivity
of 0.080 pg c-h−1. Productivity maxima in the lag and early decline corroborate the flow cytometric data, indicative that this recombinant
tPA production occurs primarily in the G1 cell cycle phase, not the S phase. This suggests that endogenous regulatory mechanisms
are important controlling influences on the production of recombinant tPA in this ovarian cell line. Productivity from recombinant
cell lines cannot be inferred from either the plasmid construct or the host cell alone. Elucidation of the relationship between
expression of recombinant protein and the cell cycle phases of the host cell is a major component of the characterization
of the animal cell production system. This information facilitates rational process design, including operating mode, modelling
and control, and medium formulation. 相似文献
5.
Kuttanelloor Roshni Chelapurath Radhakrishnan Renjithkumar 《Zeitschrift fur angewandte Ichthyologie》2021,37(1):135-136
The length–weight relationships (LWRs) of four fish species were determined from Vembanad-Kole Wetland, Kerala, India between June 2015 and May 2016. Fish samples were collected monthly from various fishing gears such as gill nets (50 m long and 1.5 m height, mesh sizes 30–100 mm, soaking time 8 hr) and seine nets (mesh sizes 8–16 mm). Values of the parameter b ranged from 2.896 to 3.165 and such values are within the expected range. This study reports the new maximum total length for Channa pseudomarulius and Hyporhamphus xanthopterus. 相似文献
6.
Roshni Baby Thomas Shilpa Joy M. S. Ajayan C. S. Paulose 《Cellular and molecular neurobiology》2013,33(8):1065-1074
Neonatal hypoglycaemia initiates a series of events leading to neuronal death, even if glucose and glycogen stores return to normal. Disturbances in the cortical dopaminergic function affect memory and cognition. We recommend Bacopa monnieri extract or Bacoside A to treat neonatal hypoglycaemia. We investigated the alterations in dopaminergic functions by studying the Dopamine D1 and D2 receptor subtypes. Receptor-binding studies revealed a significant decrease (p < 0.001) in dopamine D1 receptor number in the hypoglycaemic condition, suggesting cognitive dysfunction. cAMP content was significantly (p < 0.001) downregulated in hypoglycaemic neonatal rats indicating the reduction in cell signalling of the dopamine D1 receptors. It is attributed to the deficits in spatial learning and memory. Hypoglycaemic neonatal rats treated with Bacopa extract alone and Bacoside A ameliorated the dopaminergic and cAMP imbalance as effectively as the glucose therapy. The upregulated Bax expression in the present study indicates the high cell death in hypoglycaemic neonatal rats. Enzyme assay of SOD confirmed cortical cell death due to free radical accumulation. The gene expression of SOD in the cortex was significantly downregulated (p < 0.001). Bacopa treatment showed a significant reversal in the altered gene expression parameters (p < 0.001) of Bax and SOD. Our results suggest that in the rat experimental model of neonatal hypoglycaemia, Bacopa extract improved alterations in D1, D2 receptor expression, cAMP signalling and cell death resulting from oxidative stress. This is an important area of study given the significant motor and cognitive impairment that may arise from neonatal hypoglycaemia if proper treatment is not implemented. 相似文献
7.
Xuan Li Eduardo Ximenes Mary Anne Roshni Amalaradjou Hunter B. Vibbert Kirk Foster Jim Jones Xingya Liu Arun K. Bhunia Michael R. Ladisch 《Applied and environmental microbiology》2013,79(22):7048-7054
This paper reports an approach to enable rapid concentration and recovery of bacterial cells from aqueous chicken homogenates as a preanalytical step of detection. This approach includes biochemical pretreatment and prefiltration of food samples and development of an automated cell concentration instrument based on cross-flow microfiltration. A polysulfone hollow-fiber membrane module having a nominal pore size of 0.2 μm constitutes the core of the cell concentration instrument. The aqueous chicken homogenate samples were circulated within the cross-flow system achieving 500- to 1,000-fold concentration of inoculated Salmonella enterica serovar Enteritidis and naturally occurring microbiota with 70% recovery of viable cells as determined by plate counting and quantitative PCR (qPCR) within 35 to 45 min. These steps enabled 10 CFU/ml microorganisms in chicken homogenates or 102 CFU/g chicken to be quantified. Cleaning and sterilizing the instrument and membrane module by stepwise hydraulic and chemical cleaning (sodium hydroxide and ethanol) enabled reuse of the membrane 15 times before replacement. This approach begins to address the critical need for the food industry for detecting food pathogens within 6 h or less. 相似文献
8.
Rajesh Ramakrishnan Roshni Mehta Vasudha Sundaravaradan Tiffany Davis Nafees Ahmad 《Retrovirology》2006,3(1):1-18
Background
HIV-1 envelope gp41 is a transmembrane protein that promotes fusion of the virus with the plasma membrane of the host cells required for virus entry. In addition, gp41 is an important target for the immune response and development of antiviral and vaccine strategies, especially when targeting the highly variable envelope gp120 has not met with resounding success. Mutations in gp41 may affect HIV-1 entry, replication, pathogenesis, and transmission. We, therefore, characterized the molecular properties of gp41, including genetic diversity, functional motifs, and evolutionary dynamics from five mother-infant pairs following perinatal transmission.Results
The gp41 open reading frame (ORF) was maintained with a frequency of 84.17% in five mother-infant pairs' sequences following perinatal transmission. There was a low degree of viral heterogeneity and estimates of genetic diversity in gp41 sequences. Both mother and infant gp41 sequences were under positive selection pressure, as determined by ratios of non-synonymous to synonymous substitutions. Phylogenetic analysis of 157 mother-infant gp41 sequences revealed distinct clusters for each mother-infant pair, suggesting that the epidemiologically linked mother-infant pairs were evolutionarily closer to each other as compared with epidemiologically unlinked sequences. The functional domains of gp41, including fusion peptide, heptad repeats, glycosylation sites and lentiviral lytic peptides were mostly conserved in gp41 sequences analyzed in this study. The CTL recognition epitopes and motifs recognized by fusion inhibitors were also conserved in the five mother-infant pairs.Conclusion
The maintenance of an intact envelope gp41 ORF with conserved functional domains and a low degree of genetic variability as well as positive selection pressure for adaptive evolution following perinatal transmission is consistent with an indispensable role of envelope gp41 in HIV-1 replication and pathogenesis. 相似文献9.
Jagadeesan B Fleishman Littlejohn AE Amalaradjou MA Singh AK Mishra KK La D Kihara D Bhunia AK 《PloS one》2011,6(6):e20694
Background
Listeria adhesion protein (LAP) is a housekeeping bifunctional enzyme consisting of N-terminal acetaldehyde dehydrogenase (ALDH) and C-terminal alcohol dehydrogenase (ADH). It aids Listeria monocytogenes in crossing the epithelial barrier through a paracellular route by interacting with its host receptor, heat shock protein 60 (Hsp60). To gain insight into the binding interaction between LAP and Hsp60, LAP subdomain(s) participating in the Hsp60 interaction were investigated.Methods
Using a ModBase structural model, LAP was divided into 4 putative subdomains: the ALDH region contains N1 (Met1–Pro223) and N2 (Gly224–Gly411), and the ADH region contains C1 (Gly412–Val648) and C2 (Pro649–Val866). Each subdomain was cloned and overexpressed in Escherichia coli and purified. Purified subdomains were used in ligand overlay, immunofluorescence, and bead-based epithelial cell adhesion assays to analyze each domain''s affinity toward Hsp60 protein or human ileocecal epithelial HCT-8 cells.Results
The N2 subdomain exhibited the greatest affinity for Hsp60 with a K D of 9.50±2.6 nM. The K D of full-length LAP (7.2±0.5 nM) to Hsp60 was comparable to the N2 value. Microspheres (1 µm diameter) coated with N2 subdomain showed significantly (P<0.05) higher binding to HCT-8 cells than beads coated with other subdomains and this binding was inhibited when HCT-8 cells were pretreated with anti-Hsp60 antibody to specifically block epithelial Hsp60. Furthermore, HCT-8 cells pretreated with purified N2 subdomain also reduced L. monocytogenes adhesion by about 4 log confirming its involvement in interaction with epithelial cells.Conclusion
These data indicate that the N2 subdomain in the LAP ALDH domain is critical in initiating interaction with mammalian cell receptor Hsp60 providing insight into the molecular mechanism of pathogenesis for the development of potential anti-listerial control strategies. 相似文献10.
Identification and functional analysis of a naturally occurring E89K mutation in the ABCA1 gene of the WHAM chicken 总被引:1,自引:0,他引:1
Attie AD Hamon Y Brooks-Wilson AR Gray-Keller MP MacDonald ML Rigot V Tebon A Zhang LH Mulligan JD Singaraja RR Bitgood JJ Cook ME Kastelein JJ Chimini G Hayden MR 《Journal of lipid research》2002,43(10):1610-1617
The Wisconsin hypoalpha mutant (WHAM) chicken has a >90% reduction in plasma HDL due to hypercatabolism by the kidney of lipid-poor apoA-I. The WHAM chickens have a recessive white skin phenotype caused by a single-gene mutation that maps to the chicken Z-chromosome. This corresponds to human 9q31.1, a chromosomal segment that contains the ATP-binding cassette protein-1 (ABCA1) gene, which is mutated in Tangier Disease and familial hypoalphalipoproteinemia. Complete sequencing of the WHAM ABCA1 cDNA identified a missense mutation near the N-terminus of the protein (E89K). The substitution of this evolutionary conserved glutamate residue for lysine in the mouse ABCA1 transporter leads to complete loss of function, resulting principally from defective intracellular trafficking and very little ABCA1 reaching the plasma membrane. The WHAM chicken is a naturally occurring animal model for Tangier Disease. 相似文献