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91.
Stellatin (4), isolated from Dysophylla stellata is a cyclooxygenase (COX) inhibitor. The present study reports the synthesis and biological evaluation of new stellatin derivatives for COX-1, COX-2 inhibitory and anti-inflammatory activities. Eight derivatives showed more pronounced COX-2 inhibition than stellatin and, 17 and 21 exhibited the highest COX-2 inhibition. They also exhibited the significant anti-inflammatory activity in TPA-induced mouse ear edema assay and their anti-inflammatory effects were more than that of stellatin and indomethacin at 0.5 mg/ear. The derivatives were further evaluated for antioxidant activity wherein 16 and 17 showed potent free radical scavenging activity against DPPH and ABTS radicals. Molecular docking study revealed the binding orientations of stellatin and its derivatives into the active sites of COX-1 and COX-2 and thereby helps to design the potent inhibitors. 相似文献
92.
Pandrea I Gaufin T Gautam R Kristoff J Mandell D Montefiori D Keele BF Ribeiro RM Veazey RS Apetrei C 《PLoS pathogens》2011,7(8):e1002170
Understanding the mechanism of infection control in elite controllers (EC) may shed light on the correlates of control of disease progression in HIV infection. However, limitations have prevented a clear understanding of the mechanisms of elite controlled infection, as these studies can only be performed at randomly selected late time points in infection, after control is achieved, and the access to tissues is limited. We report that SIVagm infection is elite-controlled in rhesus macaques (RMs) and therefore can be used as an animal model for EC HIV infection. A robust acute infection, with high levels of viral replication and dramatic mucosal CD4(+) T cell depletion, similar to pathogenic HIV-1/SIV infections of humans and RMs, was followed by complete and durable control of SIVagm replication, defined as: undetectable VLs in blood and tissues beginning 72 to 90 days postinoculation (pi) and continuing at least 4 years; seroreversion; progressive recovery of mucosal CD4(+) T cells, with complete recovery by 4 years pi; normal levels of T cell immune activation, proliferation, and apoptosis; and no disease progression. This "functional cure" of SIVagm infection in RMs could be reverted after 4 years of control of infection by depleting CD8 cells, which resulted in transient rebounds of VLs, thus suggesting that control may be at least in part immune mediated. Viral control was independent of MHC, partial APOBEC restriction was not involved in SIVagm control in RMs and Trim5 genotypes did not impact viral replication. This new animal model of EC lentiviral infection, in which complete control can be predicted in all cases, permits research on the early events of infection in blood and tissues, before the defining characteristics of EC are evident and when host factors are actively driving the infection towards the EC status. 相似文献
93.
Kirschnek S Vier J Gautam S Frankenberg T Rangelova S Eitz-Ferrer P Grespi F Ottina E Villunger A Häcker H Häcker G 《Cell death and differentiation》2011,18(11):1805-1814
Neutrophils enter the peripheral blood from the bone marrow and die after a short time. Molecular analysis of spontaneous neutrophil apoptosis is difficult as these cells die rapidly and cannot be easily manipulated. We use conditional Hoxb8 expression to generate mouse neutrophils and test the regulation of apoptosis by extensive manipulation of B-cell lymphoma protein 2 (Bcl-2)-family proteins. Spontaneous apoptosis was preceded by downregulation of anti-apoptotic Bcl-2 proteins. Loss of the pro-apoptotic Bcl-2 homology domain (BH3)-only protein Bcl-2-interacting mediator of cell death (Bim) gave some protection, but only neutrophils deficient in both BH3-only proteins, Bim and Noxa, were strongly protected against apoptosis. Function of Noxa was at least in part neutralization of induced myeloid leukemia cell differentiation protein (Mcl-1) in neutrophils and progenitors. Loss of Bim and Noxa preserved neutrophil function in culture, and apoptosis-resistant cells remained in circulation in mice. Apoptosis regulated by Bim- and Noxa-driven loss of Mcl-1 is thus the final step in neutrophil differentiation, required for the termination of neutrophil function and neutrophil-dependent inflammation. 相似文献
94.
Carter BZ Mak DH Morris SJ Borthakur G Estey E Byrd AL Konopleva M Kantarjian H Andreeff M 《Apoptosis : an international journal on programmed cell death》2011,16(1):67-74
XIAP, a potent caspase inhibitor, is highly expressed in acute myeloid leukemia (AML) cells and contributes to chemoresistance.
A multi-center phase 1/2 trial of XIAP antisense oligonucleotide AEG35156 in combination with idarubicin/cytarabine was conducted
in 56 patients with relapsed/refractory AML. Herein we report the pharmacodynamic studies of the patients enrolled at M. D.
Anderson Cancer Center. A total of 13 patients were enrolled in our institution: five in phase 1 (12–350 mg/m2 AEG35156) and eight in phase 2 (350 mg/m2 AEG35156) of the protocol. AEG35156 was administered on 3 consecutive days and then weekly up to a maximum of 35 days. Blood
samples were collected from patients on days 1 through 5 and on day 28–35 post-chemotherapy for detection of XIAP levels and
apoptosis. AEG35156 treatment led to dose-dependent decreases of XIAP mRNA levels (42–100% reduction in phase 2 patients).
XIAP protein levels were reduced in all five samples measured. Apoptosis induction was detected in 1/4 phase 1 and 4/5 phase
2 patients. Importantly, apoptosis was most pronounced in CD34
+
38
−
AML stem cells and all phase 2 patients showing apoptosis induction in CD34
+
38
−
cells achieved response. We conclude that at 350 mg/m2, AEG35156 is effective in knocking down XIAP in circulating blasts accompanied by the preferential induction of apoptosis
in CD34
+
38
−
AML stem cells. 相似文献
95.
Since the discovery and clinical application of antibiotics, pathogens and the human microbiota have faced a near continuous exposure to these selective agents. A well-established consequence of this exposure is the evolution of multidrug-resistant pathogens, which can become virtually untreatable. Less appreciated are the concomitant changes in the human microbiome in response to these assaults and their contribution to clinical resistance problems. Studies have shown that pervasive changes to the human microbiota result from antibiotic treatment and that resistant strains can persist for years. Additionally, culture-independent functional characterization of the resistance genes from the microbiome has demonstrated a close evolutionary relationship between resistance genes in the microbiome and in pathogens. Application of these techniques and novel cultivation methods are expected to significantly expand our understanding of the interplay between antibiotics and the microbiome. 相似文献
96.
97.
Spatial Independent Component Analysis (ICA) decomposes the time by space functional MRI (fMRI) matrix into a set of 1-D basis time courses and their associated 3-D spatial maps that are optimized for mutual independence. When applied to resting state fMRI (rsfMRI), ICA produces several spatial independent components (ICs) that seem to have biological relevance - the so-called resting state networks (RSNs). The ICA problem is well posed when the true data generating process follows a linear mixture of ICs model in terms of the identifiability of the mixing matrix. However, the contrast function used for promoting mutual independence in ICA is dependent on the finite amount of observed data and is potentially non-convex with multiple local minima. Hence, each run of ICA could produce potentially different IC estimates even for the same data. One technique to deal with this run-to-run variability of ICA was proposed by [1] in their algorithm RAICAR which allows for the selection of only those ICs that have a high run-to-run reproducibility. We propose an enhancement to the original RAICAR algorithm that enables us to assign reproducibility p-values to each IC and allows for an objective assessment of both within subject and across subjects reproducibility. We call the resulting algorithm RAICAR-N (N stands for null hypothesis test), and we have applied it to publicly available human rsfMRI data (http://www.nitrc.org). Our reproducibility analyses indicated that many of the published RSNs in rsfMRI literature are highly reproducible. However, we found several other RSNs that are highly reproducible but not frequently listed in the literature. 相似文献
98.
Benito J Shi Y Szymanska B Carol H Boehm I Lu H Konoplev S Fang W Zweidler-McKay PA Campana D Borthakur G Bueso-Ramos C Shpall E Thomas DA Jordan CT Kantarjian H Wilson WR Lock R Andreeff M Konopleva M 《PloS one》2011,6(8):e23108
Recent studies indicate that interactions between leukemia cells and the bone marrow (BM) microenvironment promote leukemia cell survival and confer resistance to anti-leukemic drugs. There is evidence that BM microenvironment contains hypoxic areas that confer survival advantage to hematopoietic cells. In the present study we investigated whether hypoxia in leukemic BM contributes to the protective role of the BM microenvironment. We observed a marked expansion of hypoxic BM areas in immunodeficient mice engrafted with acute lymphoblastic leukemia (ALL) cells. Consistent with this finding, we found that hypoxia promotes chemoresistance in various ALL derived cell lines. These findings suggest to employ hypoxia-activated prodrugs to eliminate leukemia cells within hypoxic niches. Using several xenograft models, we demonstrated that administration of the hypoxia-activated dinitrobenzamide mustard, PR-104 prolonged survival and decreased leukemia burden of immune-deficient mice injected with primary acute lymphoblastic leukemia cells. Together, these findings strongly suggest that targeting hypoxia in leukemic BM is feasible and may significantly improve leukemia therapy. 相似文献
99.
Sandra Jose Sreevidya
S. Devi Anjana Sajeev Sosmitha Girisa Mohammed
S. Alqahtani Mohamed Abbas Abdulrahman Alshammari Gautam Sethi Ajaikumar
B. Kunnumakkara 《Bioscience reports》2023,43(3)
Farnesoid X receptor (FXR) modulates the expression of genes involved in lipid and carbohydrate homeostasis and inflammatory processes. This nuclear receptor is likely a tumor suppressor in several cancers, but its molecular mechanism of suppression is still under study. Several studies reported that FXR agonism increases the survival of colorectal, biliary tract, and liver cancer patients. In addition, FXR expression was shown to be down-regulated in many diseases such as obesity, irritable bowel syndrome, glomerular inflammation, diabetes, proteinuria, and ulcerative colitis. Therefore, development of novel FXR agonists may have significant potential in the prevention and treatment of these diseases. In this scenario, computer-aided drug design procedures can be resourcefully applied for the rapid identification of promising drug candidates. In the present study, we applied the molecular docking method in conjunction with molecular dynamics (MD) simulations to find out potential agonists for FXR based on structural similarity with the drug that is currently used as FXR agonist, obeticholic acid. Our results showed that alvimopan and montelukast could be used as potent FXR activators and outperform the binding affinity of obeticholic acid by forming stable conformation with the protein in silico. However, further investigational studies and validations of the selected drugs are essential to figure out their suitability for preclinical and clinical trials. 相似文献
100.
Hou Y Chang V Capper AB Taussig R Gautam N 《The Journal of biological chemistry》2001,276(23):19982-19988
In comparison with the alpha subunit of G proteins, the role of the beta subunit in signaling is less well understood. During the regulation of effectors by the betagamma complex, it is known that the beta subunit contacts effectors directly, whereas the role of the beta subunit is undefined in receptor-G protein interaction. Among the five G protein beta subunits known, the beta(4) subunit type is the least studied. We compared the ability of betagamma complexes containing beta(4) and the well characterized beta(1) to stimulate three different effectors: phospholipase C-beta2, phospholipase C-beta3, and adenylyl cyclase type II. beta(4)gamma(2) and beta(1)gamma(2) activated all three of these effectors with equal efficacy. However, nucleotide exchange in a G protein constituting alpha(o)beta(4)gamma(2) was stimulated significantly more by the M2 muscarinic receptor compared with alpha(o)beta(1)gamma(2). Because alpha(o) forms heterotrimers with beta(4)gamma(2) and beta(1)gamma(2) equally well, these results show that the beta subunit type plays a direct role in the receptor activation of a G protein. 相似文献