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151.
Takuya Osada Peter Berglund Michael A. Morse Bolyn Hubby Whitney Lewis Donna Niedzwiecki Xiao Yi Yang Amy Hobeika Bruce Burnett Gayathri R. Devi Timothy M. Clay Jonathan Smith H. Kim Lyerly 《Cancer immunology, immunotherapy : CII》2012,61(11):1941-1951
We recently demonstrated that Venezuelan equine encephalitis virus-based replicon particle (VRPs) encoding tumor antigens could break tolerance in the immunomodulatory environment of advanced cancer. We hypothesized that local injection of VRP-expressing interleukin-12 (IL-12) at the site of injections of VRP-based cancer vaccines would enhance the tumor-antigen-specific T cell and antibody responses and antitumor efficacy. Mice were immunized with VRP encoding the human tumor-associated antigen, carcinoembryonic antigen (CEA) (VRP-CEA(6D)), and VRP-IL-12 was also administered at the same site or at a distant location. CEA-specific T cell and antibody responses were measured. To determine antitumor activity, mice were implanted with MC38-CEA-2 cells and immunized with VRP-CEA with and without VRP-IL-12, and tumor growth and mouse survival were measured. VRP-IL-12 greatly enhanced CEA-specific T cell and antibody responses when combined with VRP-CEA(6D) vaccination. VRP-IL-12 was superior to IL-12 protein at enhancing immune responses. Vaccination with VRP-CEA(6D) plus VRP-IL-12 was superior to VRP-CEA(6D) or VRP-IL-12 alone in inducing antitumor activity and prolonging survival in tumor-bearing mice. Importantly, local injection of VRP-IL-12 at the VRP-CEA(6D) injection site provided more potent activation of CEA-specific immune responses than that of VRP-IL-12 injected at a distant site from the VRP-CEA injections. Together, this study shows that VRP-IL-12 enhances vaccination with VRP-CEA(6D) and was more effective at activating CEA-specific T cell responses when locally expressed at the vaccine site. Clinical trials evaluating the adjuvant effect of VRP-IL-12 at enhancing the immunogenicity of cancer vaccines are warranted. 相似文献
152.
Shahabi V Whitney G Hamid O Schmidt H Chasalow SD Alaparthy S Jackson JR 《Cancer immunology, immunotherapy : CII》2012,61(5):733-737
Ipilimumab, a fully human monoclonal antibody against cytotoxic T lymphocyte antigen-4, has demonstrated significant improvement
in overall survival in previously treated advanced melanoma patients. The BRAF inhibitor, vemurafenib, has shown up to 78%
objective response rates in melanoma patients harboring the BRAF-V600E mutation but not in patients lacking the mutation.
As an immune potentiator, the mechanism of action of ipilimumab may not be dependent of the activity of the BRAF pathway.
To test this, we investigated whether the clinical activity of ipilimumab would be affected by the BRAF-V600E mutation status
of the tumors. Thus, this retrospective analysis was carried using a set of tumor biopsies from a completed phase II clinical
trial. CA184004 was a randomized, double-blind, multicenter trial of 82 previously treated or untreated patients with unresectable
stage III/IV melanoma. Patients received ipilimumab 3 or 10 mg/kg every 3 weeks for four doses followed by maintenance dosing
in eligible patients. The BRAF-V600E mutation status for 80 patients was determined in tumor biopsies by PCR-based assays.
Data on disease control were available for 69 patients with evaluated BRAF-V600E mutation status. Rates of objective responses
and stable disease in patients with BRAF-V600E mutation positive tumors (30%) were comparable to those in patients with the
wild-type gene (~33%). Eleven patients displayed Durable Disease Control (DDC) of which 55% had BRAF-V600E mutation positive
tumors and 45% did not. In the 48 patients showing no DDC, the mutation frequency was 50%. In this study, no association between
BRAF-V600E mutation status of melanoma tumors and DDC after treatment with ipilimumab was detected. 相似文献
153.
Hristov KL Chen M Soder RP Parajuli SP Cheng Q Kellett WF Petkov GV 《American journal of physiology. Cell physiology》2012,302(2):C360-C372
Voltage-gated K(+) (K(V)) channels are implicated in detrusor smooth muscle (DSM) function. However, little is known about the functional role of the heterotetrameric K(V) channels in DSM. In this report, we provide molecular, electrophysiological, and functional evidence for the presence of K(V)2.1 and electrically silent K(V) channel subunits in guinea pig DSM. Stromatoxin-1 (ScTx1), a selective inhibitor of the homotetrameric K(V)2.1, K(V)2.2, and K(V)4.2 as well as the heterotetrameric K(V)2.1/6.3 and K(V)2.1/9.3 channels, was used to examine the role of these K(V) channels in DSM function. RT-PCR indicated mRNA expression of K(V)2.1, K(V)6.2-6.3, K(V)8.2, and K(V)9.1-9.3 subunits in isolated DSM cells. K(V)2.1 protein expression was confirmed by Western blot and immunocytochemistry. Perforated whole cell patch-clamp experiments revealed that ScTx1 (100 nM) inhibited the amplitude of the K(V) current in freshly isolated DSM cells. ScTx1 (100 nM) did not significantly change the steady-state activation and inactivation curves for K(V) current. However, ScTx1 (100 nM) decreased the activation time-constant of the K(V) current at positive voltages. Although our patch-clamp data could not exclude the presence of the homotetrameric K(V)2.1 channels, the biophysical characteristics of the ScTx1-sensitive current were consistent with the presence of heterotetrameric K(V)2.1/silent K(V) channels. Current-clamp recordings showed that ScTx1 (100 nM) did not change the DSM cell resting membrane potential. ScTx1 (100 nM) increased the spontaneous phasic contraction amplitude, muscle force, and muscle tone as well as the amplitude of the electrical field stimulation-induced contractions of isolated DSM strips. Collectively, our data revealed that K(V)2.1-containing channels are important physiological regulators of guinea pig DSM excitability and contractility. 相似文献
154.
Olson SD Pollock K Kambal A Cary W Mitchell GM Tempkin J Stewart H McGee J Bauer G Kim HS Tempkin T Wheelock V Annett G Dunbar G Nolta JA 《Molecular neurobiology》2012,45(1):87-98
There is much interest in the use of mesenchymal stem cells/marrow stromal cells (MSC) to treat neurodegenerative disorders, in particular those that are fatal and difficult to treat, such as Huntington's disease. MSC present a promising tool for cell therapy and are currently being tested in FDA-approved phase I-III clinical trials for many disorders. In preclinical studies of neurodegenerative disorders, MSC have demonstrated efficacy, when used as delivery vehicles for neural growth factors. A number of investigators have examined the potential benefits of innate MSC-secreted trophic support and augmented growth factors to support injured neurons. These include overexpression of brain-derived neurotrophic factor and glial-derived neurotrophic factor, using genetically engineered MSC as a vehicle to deliver the cytokines directly into the microenvironment. Proposed regenerative approaches to neurological diseases using MSC include cell therapies in which cells are delivered via intracerebral or intrathecal injection. Upon transplantation, MSC in the brain promote endogenous neuronal growth, encourage synaptic connection from damaged neurons, decrease apoptosis, reduce levels of free radicals, and regulate inflammation. These abilities are primarily modulated through paracrine actions. Clinical trials for MSC injection into the central nervous system to treat amyotrophic lateral sclerosis, traumatic brain injury, and stroke are currently ongoing. The current data in support of applying MSC-based cellular therapies to the treatment of Huntington's disease is discussed. 相似文献
155.
156.
Nicholas M. Whitney Richard L. Pyle Kim N. Holland Jessica T. Barcz 《Environmental Biology of Fishes》2012,93(1):121-136
Despite being a common apex-level predator on coral reefs throughout the tropical Indo-Pacific, surprisingly little is known
about whitetip reef shark (Triaenodon obesus) movements and biology. This study used photo-identification from community-contributed photographs to reveal patterns in
movements, reproductive biology, and fisheries interactions in this species that have not been previously revealed through
more traditional methods. At least 178 individual sharks were identified, and 26 movements were observed. These included movement
distances of up to 26.4 km, movement rates of up to 3.27 km/day (9.8 km in 3 days), and movements that required the transit
of a 140 m deep channel. Other animals showed high philopatry, being re-sighted at the same locality on multiple occasions
(up to 13 sightings for one individual) over periods of up to 7 years. Females showed higher philopatry than males and were
more likely than males to be found at shallow (<10 m depth) localities throughout the year. The proportion of male sightings
at shallow localities was significantly higher in April and May than other months of the year, possibly due to males coming
into the shallows to mate with females. A peak in sightings of late-term females followed by an abrupt decline suggests that
pupping season is May into early June, and two females were observed pregnant in consecutive years despite evidence that the
gestation period is approximately 1 year for this species. Nine percent of animals carried fishing tackle or exhibited jaw
injuries associated with fishery interactions, with multiple individuals found dead after being hooked by fishers. 相似文献
157.
Hybridization is hypothesized to promote invasiveness, but empirical tests comparing the performance of hybrid taxa versus parental taxa in novel regions are lacking. We experimentally compared colonization ability of populations of wild radish (Raphanus raphanistrum) with populations of advanced-generation hybrids between wild radish and cultivated radish (Raphanus sativus) in a southeast Texas pasture, well beyond the known invasive range of hybrid radish. We also manipulated the strength of interspecific competition to better generalize across variable environments. In both competitive environments, hybrid populations produced at least three times more seeds than did wild radish populations, a distinction that was driven by greater hybrid seedling emergence, earlier hybrid emergence, and more hybrid seedlings surviving to flower, rather than by greater individual fecundity. Flowering duration in hybrids was less negatively affected by competition than it was in wild radish, while early emergence was associated with subsequent high seed output in both biotypes. Our data show that hybridization can enhance colonization success in a novel region and, by comparison with previous studies, that the life-history traits enhancing hybrid success can differ across regions, even for lineages originating from the same hybridization event. These results imply a much larger arena for hybrid success than previously appreciated. 相似文献
158.
Apirat Chaikuad Ivan Alfano Georgina Kerr Caroline E. Sanvitale Jan H. Boergermann James T. Triffitt Frank von Delft Stefan Knapp Petra Knaus Alex N. Bullock 《The Journal of biological chemistry》2012,287(44):36990-36998
Bone morphogenetic protein (BMP) receptor kinases are tightly regulated to control development and tissue homeostasis. Mutant receptor kinase domains escape regulation leading to severely degenerative diseases and represent an important therapeutic target. Fibrodysplasia ossificans progressiva (FOP) is a rare but devastating disorder of extraskeletal bone formation. FOP-associated mutations in the BMP receptor ALK2 reduce binding of the inhibitor FKBP12 and promote leaky signaling in the absence of ligand. To establish structural mechanisms of receptor regulation and to address the effects of FOP mutation, we determined the crystal structure of the cytoplasmic domain of ALK2 in complex with the inhibitors FKBP12 and dorsomorphin. FOP mutations break critical interactions that stabilize the inactive state of the kinase, thereby facilitating structural rearrangements that diminish FKBP12 binding and promote the correct positioning of the glycine-serine-rich loop and αC helix for kinase activation. The balance of these effects accounts for the comparable activity of R206H and L196P. Kinase activation in the clinically benign mutant L196P is far weaker than R206H but yields equivalent signals due to the stronger interaction of FKBP12 with R206H. The presented ALK2 structure offers a valuable template for the further design of specific inhibitors of BMP signaling. 相似文献
159.
160.
Viswanathan K Frey KM Scocchera EW Martin BD Swain Iii PW Alverson JB Priestley ND Anderson AC Wright DL 《PloS one》2012,7(2):e29434
Hospital- and community-acquired, complicated skin and soft tissue infections, often attributed to Staphylococcus aureus and Streptococcus pyogenes, present a significant health burden that is associated with increased health care costs and mortality. As these two species are difficult to discern on diagnosis and are associated with differential profiles of drug resistance, the development of an efficacious antibacterial agent that targets both organisms is a high priority. Herein we describe a structure-based drug development effort that has produced highly potent inhibitors of dihydrofolate reductase from both species. Optimized propargyl-linked antifolates containing a key pyridyl substituent display antibacterial activity against both methicillin-resistant S. aureus and S. pyogenes at MIC values below 0.1 μg/mL and minimal cytotoxicity against mammalian cells. Further evaluation against a panel of clinical isolates shows good efficacy against a range of important phenotypes such as hospital- and community-acquired strains as well as strains resistant to vancomycin. 相似文献