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61.
Tudor Groza Sebastian K?hler Dawid Moldenhauer Nicole Vasilevsky Gareth Baynam Tomasz Zemojtel Lynn?Marie Schriml Warren?Alden Kibbe Paul?N. Schofield Tim Beck Drashtti Vasant Anthony?J. Brookes Andreas Zankl Nicole?L. Washington Christopher?J. Mungall Suzanna?E. Lewis Melissa A. Haendel Helen Parkinson Peter?N. Robinson 《American journal of human genetics》2015,97(1):111-124
The Human Phenotype Ontology (HPO) is widely used in the rare disease community for differential diagnostics, phenotype-driven analysis of next-generation sequence-variation data, and translational research, but a comparable resource has not been available for common disease. Here, we have developed a concept-recognition procedure that analyzes the frequencies of HPO disease annotations as identified in over five million PubMed abstracts by employing an iterative procedure to optimize precision and recall of the identified terms. We derived disease models for 3,145 common human diseases comprising a total of 132,006 HPO annotations. The HPO now comprises over 250,000 phenotypic annotations for over 10,000 rare and common diseases and can be used for examining the phenotypic overlap among common diseases that share risk alleles, as well as between Mendelian diseases and common diseases linked by genomic location. The annotations, as well as the HPO itself, are freely available. 相似文献
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Wilkerson MD Yin X Walter V Zhao N Cabanski CR Hayward MC Miller CR Socinski MA Parsons AM Thorne LB Haithcock BE Veeramachaneni NK Funkhouser WK Randell SH Bernard PS Perou CM Hayes DN 《PloS one》2012,7(5):e36530
BACKGROUND: Lung adenocarcinoma (LAD) has extreme genetic variation among patients, which is currently not well understood, limiting progress in therapy development and research. LAD intrinsic molecular subtypes are a validated stratification of naturally-occurring gene expression patterns and encompass different functional pathways and patient outcomes. Patients may have incurred different mutations and alterations that led to the different subtypes. We hypothesized that the LAD molecular subtypes co-occur with distinct mutations and alterations in patient tumors. METHODOLOGY/PRINCIPAL FINDINGS: The LAD molecular subtypes (Bronchioid, Magnoid, and Squamoid) were tested for association with gene mutations and DNA copy number alterations using statistical methods and published cohorts (n = 504). A novel validation (n = 116) cohort was assayed and interrogated to confirm subtype-alteration associations. Gene mutation rates (EGFR, KRAS, STK11, TP53), chromosomal instability, regional copy number, and genomewide DNA methylation were significantly different among tumors of the molecular subtypes. Secondary analyses compared subtypes by integrated alterations and patient outcomes. Tumors having integrated alterations in the same gene associated with the subtypes, e.g. mutation, deletion and underexpression of STK11 with Magnoid, and mutation, amplification, and overexpression of EGFR with Bronchioid. The subtypes also associated with tumors having concurrent mutant genes, such as KRAS-STK11 with Magnoid. Patient overall survival, cisplatin plus vinorelbine therapy response and predicted gefitinib sensitivity were significantly different among the subtypes. CONCLUSIONS/ SIGNIFICANCE: The lung adenocarcinoma intrinsic molecular subtypes co-occur with grossly distinct genomic alterations and with patient therapy response. These results advance the understanding of lung adenocarcinoma etiology and nominate patient subgroups for future evaluation of treatment response. 相似文献
64.
Curtin JF Candolfi M Fakhouri TM Liu C Alden A Edwards M Lowenstein PR Castro MG 《PloS one》2008,3(4):e1983
Background
Regulatory T lymphocytes (Treg) infiltrate human glioblastoma (GBM); are involved in tumor progression and correlate with tumor grade. Transient elimination of Tregs using CD25 depleting antibodies (PC61) has been found to mediate GBM regression in preclinical models of brain tumors. Clinical trials that combine Treg depletion with tumor vaccination are underway to determine whether transient Treg depletion can enhance anti-tumor immune responses and improve long term survival in cancer patients.Findings
Using a syngeneic intracrabial glioblastoma (GBM) mouse model we show that systemic depletion of Tregs 15 days after tumor implantation using PC61 resulted in a decrease in Tregs present in tumors, draining lymph nodes and spleen and improved long-term survival (50% of mice survived >150 days). No improvement in survival was observed when Tregs were depleted 24 days after tumor implantation, suggesting that tumor burden is an important factor for determining efficacy of Treg depletion in clinical trials. In a T cell dependent model of brain tumor regression elicited by intratumoral delivery of adenoviral vectors (Ad) expressing Fms-like Tyrosine Kinase 3 ligand (Flt3L) and Herpes Simplex Type 1-Thymidine Kinase (TK) with ganciclovir (GCV), we demonstrate that administration of PC61 24 days after tumor implantation (7 days after treatment) inhibited T cell dependent tumor regression and long term survival. Further, depletion with PC61 completely inhibited clonal expansion of tumor antigen-specific T lymphocytes in response to the treatment.Conclusions
Our data demonstrate for the first time, that although Treg depletion inhibits the progression/eliminates GBM tumors, its efficacy is dependent on tumor burden. We conclude that this approach will be useful in a setting of minimal residual disease. Further, we also demonstrate that Treg depletion, using PC61 in combination with immunotherapy, inhibits clonal expansion of tumor antigen-specific T cells, suggesting that new, more specific targets to block Tregs will be necessary when used in combination with therapies that activate anti-tumor immunity. 相似文献65.
66.
Background
Partitioning of a protein into structural components, known as domains, is an important initial step in protein classification and for functional and evolutionary studies. While the systematic assignments of domains by human experts exist (CATH and SCOP), the introduction of high throughput technologies for structure determination threatens to overwhelm expert approaches. A variety of algorithmic methods have been developed to expedite this process, allowing almost instant structural decomposition into domains. The performance of algorithmic methods can approach 85% agreement on the number of domains with the consensus reached by experts. However, each algorithm takes a somewhat different conceptual approach, each with unique strengths and weaknesses. Currently there is no simple way to automatically compare assignments from different structure-based domain assignment methods, thereby providing a comprehensive understanding of possible structure partitioning as well as providing some insight into the tendencies of particular algorithms. Most importantly, a consensus assignment drawn from multiple assignment methods can provide a singular and presumably more accurate view. 相似文献67.
Rebecca Bliege Bird Brooke ScelzaDouglas W. Bird Eric Alden Smith 《Evolution and human behavior》2012,33(1):64-78
Cooperative hunting is often assumed to be mutualistic, maintained through returns to scale, where, by working together, foragers can gain higher per capita return rates or harvest sizes than they can by hunting alone. We test this hypothesis among Martu hunters and find that cooperation only provides increased returns to poorer hunters while disadvantaging better hunters. Even so, better hunters still cooperate as frequently as poorer hunters. We ask whether better hunters are advantaged in secondary sharing distributions or whether they bias their partner choice to kin or household members. We find that better hunters are not more likely to pair up with kin and they do not gain consumption benefits from acquiring more. They share a greater proportion of their harvest than poorer hunters: no matter how much one produces — better hunter, worse hunter, cooperator, solitary hunter — all eat the same amount in the end. Such a result suggests the hypothesis that cooperation might be a costly signal of commitment to the public interest on the part of better hunters, which generates trust among camp members and facilitates strong social networks, particularly among women, who cooperate more than men. While some foragers may benefit through cooperation from returns to scale or risk reduction, others may benefit more through signaling commitment and generating trust. 相似文献
68.
Book reviewed in this article:
CENTRAL AND SOUTH AMERICA: Preliminary Report on the Smithsonian Institution-Harvard University Archaeological Expedition to Northwestern Honduras, 1936 . W illiam D uncan S trong , A lfred K idder II and A. J. D rexel P aul , J r .
CENTRAL AND SOUTH AMERICA: An Archaeological Reconnaissance of Northwestern Honduras: A Report of the Work of the Tulane University-Danish National Museum Expedition to Central America 1935 . J ens Y de . 相似文献
CENTRAL AND SOUTH AMERICA: Preliminary Report on the Smithsonian Institution-Harvard University Archaeological Expedition to Northwestern Honduras, 1936 . W illiam D uncan S trong , A lfred K idder II and A. J. D rexel P aul , J r .
CENTRAL AND SOUTH AMERICA: An Archaeological Reconnaissance of Northwestern Honduras: A Report of the Work of the Tulane University-Danish National Museum Expedition to Central America 1935 . J ens Y de . 相似文献
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70.
F R Salemme S T Freer R A Alden J Kraut 《Biochemical and biophysical research communications》1973,54(1):47-52
Atomic coordinates and backbone torsion angles are tabulated for ferricytochrome of . 相似文献