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41.
Morpurgo M Monfardini C Hofland LJ Sergi M Orsolini P Dumont JM Veronese FM 《Bioconjugate chemistry》2002,13(6):1238-1243
The effects of the type and location of polymer grafting on the biological activity of different mono-PEG derivatives of the somatostatin analogue RC160 were evaluated. A chemical strategy to obtain mono-PEG alkylation or acylation of the peptide's alpha-terminal or lysil-epsilon primary amines was devised. Selective BOC protection of the two available primary amines, followed by reaction with two different PEG reagents and removal of the protecting group, was carried out. Chemical characterization, structural studies, and the evaluation of the biological activity of the bioconjugates synthesized allowed the identification of the one having characteristics more suitable for therapeutic application. This corresponds to the mono-epsilon-lysil-pegylated form, obtained by reductive alkylation, where the amine's positive charge is preserved. The results obtained suggest the importance of preliminary studies in the development of new polymer-peptide conjugates with improved pharmacological properties. 相似文献
42.
Circo R Skerlavaj B Gennaro R Amoroso A Zanetti M 《Biochemical and biophysical research communications》2002,293(1):586-592
beta-Defensins are mammalian antimicrobial peptides that share a unique disulfide-bonding motif of six conserved cysteines. An intragenic polymorphism of the DEFB1 gene that changes a highly conserved Cys to Ser in the peptide coding region has recently been described. The deduced peptide cannot form three disulfide bonds, as one of the cysteines is unpaired. We have determined the cysteine connectivities of a corresponding synthetic hBD-1(Ser35) peptide, investigated the structure by circular dichroism spectroscopy, and assayed the in vitro antimicrobial activity. Despite a different arrangement of the disulfides, hBD-1(Ser35) proved as active as hBD-1 against the microorganisms tested. This activity likely depends on the ability of hBD-1(Ser35) to adopt an amphipathic conformation in hydrophobic environment, similar to the wild type peptide, as suggested by CD spectroscopy. 相似文献
43.
A crucial role for the vitamin D receptor in experimental inflammatory bowel diseases 总被引:16,自引:0,他引:16
Froicu M Weaver V Wynn TA McDowell MA Welsh JE Cantorna MT 《Molecular endocrinology (Baltimore, Md.)》2003,17(12):2386-2392
The active form of vitamin D (1,25D3) suppressed the development of animal models of human autoimmune diseases including experimental inflammatory bowel disease (IBD). The vitamin D receptor (VDR) is required for all known biologic effects of vitamin D. Here we show that VDR deficiency (knockout, KO) resulted in severe inflammation of the gastrointestinal tract in two different experimental models of IBD. In the CD45RB transfer model of IBD, CD4+/CD45RBhigh T cells from VDR KO mice induced more severe colitis than wild-type CD4+/CD45RBhigh T cells. The second model of IBD used was the spontaneous colitis that develops in IL-10 KO mice. VDR/IL-10 double KO mice developed accelerated IBD and 100% mortality by 8 wk of age. At 8 wk of age, all of the VDR and IL-10 single KO mice were healthy. Rectal bleeding was observed in every VDR/IL-10 KO mouse. Splenocytes from the VDR/IL-10 double KO mice cells transferred IBD symptoms. The severe IBD in VDR/IL-10 double KO mice is a result of the immune system and not a result of altered calcium homeostasis, or gastrointestinal tract function. The data establishes an essential role for VDR signaling in the regulation of inflammation in the gastrointestinal tract. 相似文献
44.
45.
Drug treatment in the development of mismatch repair defective acute leukemia and myelodysplastic syndrome 总被引:5,自引:0,他引:5
Casorelli I Offman J Mele L Pagano L Sica S D'Errico M Giannini G Leone G Bignami M Karran P 《DNA Repair》2003,2(5):547-559
DNA from therapy-related acute leukemia/myelodysplastic syndrome cases (tAL/MDS) from the GIMEMA [Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto] Archive was examined for the microsatellite instability (MSI(+)) phenotype that is diagnostic for defective DNA mismatch repair. More than 60% (16/25) of tAL/MDS cases were MSI(+) in contrast to <4% (0/28) of de novo cases. hMLH1 gene silencing was rare and evidence of promoter methylation was found in less than one-third of the MSI(+) cases. Among the GIMEMA patients who had been treated for breast cancer there was an apparent trend towards early onset primary breast disease. This suggests that there might be common predisposing factors for breast cancer and tAL/MDS. There were also three examples of mutations in the MRE11 gene among the 25 tAL/MDS cases suggesting that defective recombinational DNA repair may promote the development of secondary malignancy. MSI(+) tAL/MDS was significantly associated with previous chemotherapy and the frequency of MSI(+) among radiotherapy patients was considerably lower. In view of the established relationship between drug resistance and mismatch repair defects, we suggest that selection for therapeutic drug resistance may contribute to the incidence of MSI(+) tAL/MDS. 相似文献
46.
Oxidative damage of the gastric mucosa in Helicobacter pylori positive chronic atrophic and nonatrophic gastritis, before and after eradication 总被引:3,自引:0,他引:3
Iacopini F Consolazio A Bosco D Marcheggiano A Bella A Pica R Paoluzi OA Crispino P Rivera M Mottolese M Nardi F Paoluzi P 《Helicobacter》2003,8(5):503-512
Background. Helicobacter pylori is the main cause of gastritis and a primary carcinogen. The aim of this study was to assess oxidative damage in mucosal compartments of gastric mucosa in H. pylori positive and negative atrophic and nonatrophic gastritis. Materials and methods. Five groups of 10 patients each were identified according to H. pylori positive or negative chronic atrophic (Hp‐CAG and CAG, respectively) and nonatrophic gastritis (Hp‐CG and CG, respectively), and H. pylori negative normal mucosa (controls). Oxidative damage was evaluated by nitrotyrosine immunohistochemistry in the whole mucosa and in each compartment at baseline and at 2 and 12 months after eradication. Types of intestinal metaplasia were classified by histochemistry. Results. Total nitrotyrosine levels appeared significantly higher in H. pylori positive than in negative patients, and in Hp‐CAG than in Hp‐CG (p < .001); no differences were found between H. pylori negative gastritis and normal mucosa. Nitrotyrosine were found in foveolae and intestinal metaplasia only in Hp‐CAG. At 12 months after H. pylori eradication, total nitrotyrosine levels showed a trend toward a decrease in Hp‐CG and decreased significantly in Hp‐CAG (p = .002), disappearing from the foveolae (p = .002), but remaining unchanged in intestinal metaplasia. Type I and II of intestinal metaplasia were present with the same prevalence in Hp‐CAG and CAG, and did not change after H. pylori eradication. Conclusions. Oxidative damage of the gastric mucosa increases from Hp‐CG to Hp‐CAG, involving the foveolae and intestinal metaplasia. H. pylori eradication induces a complete healing of foveolae but not of intestinal metaplasia, reducing the overall oxidative damage in the mucosa. 相似文献
47.
The objective of this research was to determine if confinement of 8-day-old calves for varying lengths of time is associated with an increase in motivation to perform locomotor behaviors. Holstein heifer and bull calves (N=48) were used in a factorial arrangement with two crossed factors. Factor A was housing with two levels (individual confinement versus group pens) and factor B was hours in confinement with four levels (6, 12, 24, and 48h). Individual confinement was in 1.06mx1.06m pens, while group pens had a 3.68mx6.09m outside run and a 3.68mx6.09m covered area that also contained a 3.68mx2.44m area bedded with wood shavings. The calves were placed on treatment when they were 8+/-2 days of age.At the end of the treatments, a blood sample was taken for plasma cortisol determination and lymphocyte counts and the calves were open-field tested for 5min.Walk, trot, distance traveled and behaviors performed while standing during the open-field test were higher in the calves kept in group pens (P=0.0003, 0.01, 0.04 and 0.04), but were not influenced by hours in treatment. Calves confined for 48h had greater incidences of kicking and falling (P=0.014 and 0.025). Lymphocyte count (P=0.029) was lower in the calves confined for 12h, but there was not a trend across hours in confinement that indicated a consistent effect. Housing or hours in treatment did not affect canter, buck, buck-kick, rear, stumble, vocalization and cortisol concentrations. The interaction between hours in treatment and housing was not significant for any of the variables tested.This study suggests that 2 days may not have been enough time for the effects of close confinement to influence motivation in young calves, or that calves averaging 8 days of age may be too young to display increased motivation for locomotor activity. Confinement of such young calves actually inhibits locomotor activity in open-field tests. 相似文献
48.
Hematopoietic growth factors in autologous transplantation 总被引:1,自引:0,他引:1
Hematopoietic growth factors (HGFs) sustain the survival, proliferation and differentiation of hematopoietic stem cells and
some functions of mature blood cells. In man several HGFs have been characterised and cloned so far, and this has allowed
investigators to confer the rationale for the clinical application of these molecules in hematology and oncology. In particular
G-CSF and GM-CSF are currently utilised to abrogate the hematological toxicity of chemotherapy for standard and dose-intensified
therapy, neutropenia following bone marrow and peripheral blood stem cell transplantation. Moreover there has recently been
great interest in the ex vivo expansion of hematopoietic stem and progenitor cells for a variety of applications, such as
in vitro tumor cell purging or for reducing the volume of blood processed by the leukapheresis. Several combinations of HGFs
have been described to sustain the ex vivo survival and proliferation of these cells disclosing new opportunities in the field
of stem cells transplants. 相似文献
49.
Monica Averna Roberta De Tullio Marco Pedrazzi Margherita Bavestrello Matteo Pellegrini Franca Salamino Sandro Pontremoli Edon Melloni 《PloS one》2015,10(1)
Here we demonstrate that heat shock protein 90 (HSP90) interacts with calpain-1, but not with calpain-2, and forms a discrete complex in which the protease maintains its catalytic activity, although with a lower affinity for Ca2+. Equilibrium gel distribution experiments show that this complex is composed by an equal number of molecules of each protein partner. Moreover, in resting cells, cytosolic calpain-1 is completely associated with HSP90. Since calpain-1, in association with HSP90, retains its proteolytic activity, and the chaperone is displaced by calpastatin also in the absence of Ca2+, the catalytic cleft of the protease is not involved in this association. Thus, calpain-1 can form two distinct complexes depending on the availability of calpastatin in the cytosol. The occurrence of a complex between HSP90 and calpain-1, in which the protease is still activable, can prevent the complete inhibition of the protease even in the presence of high calpastatin levels. We also demonstrate that in basal cell conditions HSP90 and calpain-1, but not calpain-2, are inserted in the multi-protein N-Methyl-D-Aspartate receptor (NMDAR) complex. The amount of calpain-1 at the NMDAR cluster is not modified in conditions of increased [Ca2+]i, and this resident protease is involved in the processing of NMDAR components. Finally, the amount of calpain-1 associated with NMDAR cluster is independent from Ca2+-mediated translocation. Our findings show that HSP90 plays an important role in maintaining a given and proper amount of calpain-1 at the functional sites. 相似文献
50.
Ylenia Ingrasciotta Janet Sultana Francesco Giorgianni Andrea Fontana Antonio Santangelo Daniele Ugo Tari Domenico Santoro Vincenzo Arcoraci Margherita Perrotta Luisa Ibanez Gianluca Trifirò 《PloS one》2015,10(4)