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71.
The present study evaluates freeze thaw as a simple approach for screening the most appropriate cryoprotectant. Freeze–thaw
study is based on the principle that an excipient, which protects nanoparticles during the first step of freezing, is likely
to be an effective cryoprotectant. Nanoparticles of rifampicin with high entrapment efficiency were prepared by the emulsion-solvent
diffusion method using dioctyl sodium sulfosuccinate (AOT) as complexing agent and Gantrez AN-119 as polymer. Freeze–thaw
study was carried out using trehalose and fructose as cryoprotectants. The concentration of cryoprotectant, concentration
of nanoparticles in the dispersion, and the freezing temperature were varied during the freeze–thaw study. Cryoprotection
increased with increase in cryoprotectant concentration. Further, trehalose was superior to fructose at equivalent concentrations
and moreover permitted use of more concentrated nanosuspensions for freeze drying. Freezing temperature did not influence
the freeze–thaw study. Freeze-dried nanoparticles revealed good redispersibility with a size increase that correlated well
with the freeze–thaw study at 20% w/v trehalose and fructose. Transmission electron microscopy revealed round particles with a size ∼400 nm, which correlated with
photon correlation spectroscopic measurements. Differential scanning calorimetry and X-ray diffraction suggested amorphization
of rifampicin. Fourier transfer infrared spectroscopy could not confirm interaction of drug with AOT. Nanoparticles exhibited
sustained release of rifampicin, which followed diffusion kinetics. Nanoparticles of rifampicin were found to be stable for
12 months. The good correlation between freeze thaw and freeze drying suggests freeze–thaw study as a simple and quick approach
for screening optimal cryoprotectant for freeze drying. 相似文献
72.
73.
Padma Murthi Sophie Brouillet Anita Pratt Anthony Borg Bill Kalionis Frederic Goffin Vassilis Tsatsaris Carine Munaut Jean-Jacques Feige Mohamed Benharouga Thierry Fournier Nadia Alfaidy 《Molecular medicine (Cambridge, Mass.)》2015,21(1):645-656
Idiopathic fetal growth restriction (FGR) is frequently associated with placental insufficiency. Previous reports have provided evidence that endocrine gland–derived vascular endothelial growth factor (EG-VEGF), a placental secreted protein, is expressed during the first trimester of pregnancy, controls both trophoblast proliferation and invasion, and its increased expression is associated with human FGR. In this study, we hypothesize that EG-VEGF-dependent changes in placental homeobox gene expressions contribute to trophoblast dysfunction in idiopathic FGR. The changes in EG-VEGF-dependent homeobox gene expressions were determined using a homeobox gene cDNA array on placental explants of 8–12 wks gestation after stimulation with EG-VEGF in vitro for 24 h. The homeobox gene array identified a greater-than-five-fold increase in HOXA9, HOXC8, HOXC10, HOXD1, HOXD8, HOXD9 and HOXD11, while NKX 3.1 showed a greater-than-two-fold decrease in mRNA expression compared with untreated controls. Homeobox gene NKX3.1 was selected as a candidate because it is a downstream target of EG-VEGF and its expression and functional roles are largely unknown in control and idiopathic FGR-affected placentae. Real-time PCR and immunoblotting showed a significant decrease in NKX3.1 mRNA and protein levels, respectively, in placentae from FGR compared with control pregnancies. Gene inactivation in vitro using short-interference RNA specific for NKX3.1 demonstrated an increase in BeWo cell differentiation and a decrease in HTR-8/SVneo proliferation. We conclude that the decreased expression of homeobox gene NKX3.1 downstream of EG-VEGF may contribute to the trophoblast dysfunction associated with idiopathic FGR pregnancies. 相似文献
74.
Olal D Kuehne AI Bale S Halfmann P Hashiguchi T Fusco ML Lee JE King LB Kawaoka Y Dye JM Saphire EO 《Journal of virology》2012,86(5):2809-2816
Antibody 14G7 is protective against lethal Ebola virus challenge and recognizes a distinct linear epitope in the prominent mucin-like domain of the Ebola virus glycoprotein GP. The structure of 14G7 in complex with its linear peptide epitope has now been determined to 2.8 Å. The structure shows that this GP sequence forms a tandem β-hairpin structure that binds deeply into a cleft in the antibody-combining site. A key threonine at the apex of one turn is critical for antibody interaction and is conserved among all Ebola viruses. This work provides further insight into the mechanism of protection by antibodies that target the protruding, highly accessible mucin-like domain of Ebola virus and the structural framework for understanding and characterizing candidate immunotherapeutics. 相似文献
75.
Inamdar SR Savanur MA Eligar SM Chachadi VB Nagre NN Chen C Barclays M Ingle A Mahajan P Borges A Shastry P Kalraiya RD Swamy BM Rhodes JM Yu LG 《Glycobiology》2012,22(9):1227-1235
Glycan array analysis of Sclerotium rolfsii lectin (SRL) revealed its exquisite binding specificity to the oncofetal Thomsen-Friedenreich (Galβ1-3GalNAcα-O-Ser/Thr, T or TF) antigen and its derivatives. This study shows that SRL strongly inhibits the growth of human colon cancer HT29 and DLD-1 cells by binding to cell surface glycans and induction of apoptosis through both the caspase-8 and -9 mediated signaling. SRL showed no or very weak binding to normal human colon tissues but strong binding to cancerous and metastatic tissues. Intratumor injection of SRL at subtoxic concentrations in NOD-SCID mice bearing HT29 xenografts resulted in total tumor regression in 9 days and no subsequent tumor recurrence. As the increased expression of TF-associated glycans is commonly seen in human cancers, SRL has the potential to be developed as a therapeutic agent for cancer. 相似文献
76.
Bhat S Olaleye O Meyer KJ Shi W Zhang Y Liu JO 《Bioorganic & medicinal chemistry》2012,20(14):4507-4513
Our previous target validation studies established that inhibition of methionine aminopeptidases (MtMetAP, type 1a and 1c) from Mycobacterium tuberculosis (Mtb) is an effective approach to suppress Mtb growth in culture. A novel class of MtMetAP1c inhibitors comprising of N'-hydroxy-N-(4H,5H-naphtho[1,2-d]thiazol-2-yl)methanimidamide (4c) was uncovered through a high-throughput screen (HTS). A systematic structure-activity relationship study (SAR) yielded variants of the hit, 4b, 4h, and 4k, bearing modified A- and B-rings as potent inhibitors of both MtMetAPs. Except methanimidamide 4h that showed a moderate Mtb inhibition, a desirable minimum inhibitory concentration (MIC) was not obtained with the current set of MtMetAP inhibitors. However, the SAR data generated thus far may prove valuable for further tuning of this class of inhibitors as effective anti-tuberculosis agents. 相似文献
77.
Brockhausen I Benn M Bhat S Marone S Riley JG Montoya-Peleaz P Vlahakis JZ Paulsen H Schutzbach JS Szarek WA 《Glycoconjugate journal》2006,23(7-8):525-541
Galactosyltransferases are important enzymes for the extension of the glycan chains of glycoproteins and glycolipids, and
play critical roles in cell surface functions and in the immune system. In this work, the acceptor specificity and several
inhibitors of bovine β1,4-Gal-transferase T1 (β4GalT, EC 2.4.1.90) were studied. Series of analogs of N-acetylglucosamine (GlcNAc) and GlcNAc-carrying glycopeptides were synthesized as acceptor substrates. Modifications were
made at the 3-, 4- and 6-positions of the sugar ring of the acceptor, in the nature of the glycosidic linkage, in the aglycone
moiety and in the 2-acetamido group. The acceptor specificity studies showed that the 4-hydroxyl group of the sugar ring was
essential for β4GalT activity, but that the 3-hydroxyl could be replaced by an electronegative group. Compounds having the
anomeric β-configuration were more active than those having the α-configuration, and O-, S- and C-glycosyl compounds were all active as substrates. The aglycone was a major determinant for the rate of Gal-transfer. Derivatives
containing a 2-naphthyl aglycone were inactive as substrates although quinolinyl groups supported activity. Several compounds
having a bicyclic structure as the aglycone were found to bind to the enzyme and inhibited the transfer of Gal to control
substrates. The best small hydrophobic GlcNAc-analog inhibitor was found to be 1-thio-N-butyrylGlcNβ-(2-naphthyl) with a Ki of 0.01 mM. These studies help to delineate β4GalT–substrate interactions and will aid in the development of biologically
applicable inhibitors of the enzyme. 相似文献
78.
Song J Jie C Polk P Shridhar R Clair T Zhang J Yin L Keppler D 《Biochemical and biophysical research communications》2006,340(1):175-182
79.
Chen G Liu P Pattar GR Tackett L Bhonagiri P Strawbridge AB Elmendorf JS 《Molecular endocrinology (Baltimore, Md.)》2006,20(4):857-870
Evidence suggests that chromium supplementation may alleviate symptoms associated with diabetes, such as high blood glucose and lipid abnormalities, yet a molecular mechanism remains unclear. Here, we report that trivalent chromium in the chloride (CrCl3) or picolinate (CrPic) salt forms mobilize the glucose transporter, GLUT4, to the plasma membrane in 3T3-L1 adipocytes. Concomitant with an increase in GLUT4 at the plasma membrane, insulin-stimulated glucose transport was enhanced by chromium treatment. In contrast, the chromium-mobilized pool of transporters was not active in the absence of insulin. Microscopic analysis of an exofacially Myc-tagged enhanced green fluorescent protein-GLUT4 construct revealed that the chromium-induced accumulation of GLUT4-containing vesicles occurred adjacent to the inner cell surface membrane. With insulin these transporters physically incorporated into the plasma membrane. Regulation of GLUT4 translocation by chromium did not involve known insulin signaling proteins such as the insulin receptor, insulin receptor substrate-1, phosphatidylinositol 3-kinase, and Akt. Consistent with a reported effect of chromium on increasing membrane fluidity, we found that chromium treatment decreased plasma membrane cholesterol. Interestingly, cholesterol add-back to the plasma membrane prevented the beneficial effect of chromium on both GLUT4 mobilization and insulin-stimulated glucose transport. Furthermore, chromium action was absent in methyl-beta-cyclodextrin-pretreated cells already displaying reduced plasma membrane cholesterol and increased GLUT4 translocation. Together, these data reveal a novel mechanism by which chromium may enhance GLUT4 trafficking and insulin-stimulated glucose transport. Moreover, these findings at the level of the cell are consistent with in vivo observations of improved glucose tolerance and decreased circulating cholesterol levels after chromium supplementation. 相似文献
80.
Yokota Y Bargagna-Mohan P Ravindranath PP Kim KB Mohan R 《Bioorganic & medicinal chemistry letters》2006,16(10):2603-2607
The natural product withaferin A (WFA) is a potent angiogenesis inhibitor and it targets the ubiquitin-proteasome pathway in vascular endothelial cells. We generated a biotinylated affinity analog WFA-LC(2)B for use as a probe to study angiogenesis. WFA-LC(2)B inhibits angiogenic sprouting in vitro and it causes levels of ubiquitinated proteins to increase in tumor necrosis factor-alpha-treated human umbilical vein endothelial cells, confirming the retention of WFA's biological activity. We show that WFA-LC(2)B forms protein adducts in endothelial cells which are competed by free WFA in vivo. This WFA-LC(2)B analog will be useful to isolate the biological target of WFA. 相似文献