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排序方式: 共有336条查询结果,搜索用时 15 毫秒
301.
302.
Qureshi OS Kaur S Hou TZ Jeffery LE Poulter NS Briggs Z Kenefeck R Willox AK Royle SJ Rappoport JZ Sansom DM 《The Journal of biological chemistry》2012,287(12):9429-9440
CTLA-4 is one of the most important negative regulators of the T cell immune response. However, the subcellular distribution of CTLA-4 is unusual for a receptor that interacts with cell surface transmembrane ligands in that CTLA-4 is rapidly internalized from the plasma membrane. It has been proposed that T cell activation can lead to stabilization of CTLA-4 expression at the cell surface. Here we have analyzed in detail the internalization, recycling, and degradation of CTLA-4. We demonstrate that CTLA-4 is rapidly internalized from the plasma membrane in a clathrin- and dynamin-dependent manner driven by the well characterized YVKM trafficking motif. Furthermore, we show that once internalized, CTLA-4 co-localizes with markers of recycling endosomes and is recycled to the plasma membrane. Although we observed limited co-localization of CTLA-4 with lysosomal markers, CTLA-4 was nonetheless degraded in a manner inhibited by lysosomal blockade. T cell activation stimulated mobilization of CTLA-4, as judged by an increase in cell surface expression; however, this pool of CTLA-4 continued to endocytose and was not stably retained at the cell surface. These data support a model of trafficking whereby CTLA-4 is constitutively internalized in a ligand-independent manner undergoing both recycling and degradation. Stimulation of T cells increases CTLA-4 turnover at the plasma membrane; however, CTLA-4 endocytosis continues and is not stabilized during activation of human T cells. These findings emphasize the importance of clathrin-mediated endocytosis in regulating CTLA-4 trafficking throughout T cell activation. 相似文献
303.
304.
Louisa J. Wilson Will Lewis Richard Kucia-Tran Daniel G. Bracewell 《Biotechnology progress》2019,35(3):e2805
During early stage bioprocess development, characterizing interactions between unit operations is a key challenge. Such interactions include the release of host cell enzymes early in the process causing losses in product quality downstream. Using a CHO-expressed IgG1 system, the impact of cell culture duration was investigated using a 50 L bioreactor and performing scale-down protein A purification. While antibody titer doubled during the last week of culture, the post-protein A host cell protein (HCP) levels increased from 243 to 740 ppm. Effects of pH and temperature were then explored using fed-batch ambr250 bioreactors, and parameters enabling higher titers were linked to a decrease in post-protein A product purity. These trade-offs between titer and product quality were visualized using a window of operation. The downstream space was explored further by exposing shake flask material to shear representative of disc stack centrifugation, prior to purification, and by adding polishing chromatography. While product quality decreased with progressing cultivation, cells became more shear resistant. Polishing chromatography resulted in product fragmentation which increased fourfold from Day 10 to 24, adding constraint to achieving both efficient HCP clearance as well as high monomer purities. These examples highlight the importance of adopting integrated approaches to upstream and downstream development strategies to enable whole process optimization. 相似文献
305.
There is an increasing momentum within the marine conservation community to develop representative networks of marine protected
areas (MPAs) covering up to 30% of global marine habitats. However, marine conservation initiatives are perceived as uncoordinated
at most levels of planning and decision-making. These initiatives also face the challenge of being in conflict with ongoing
drives for sustained or increased resource extraction. Hence, there is an urgent need to develop large scale theoretical frameworks
that explicitly address conflicting objectives that are embedded in the design and development of a global MPA network. Further,
the frameworks must be able to guide the implementation of smaller scale initiatives within this global context. This research
examines the applicability of an integrated spatial decision support framework based on geographic information systems (GIS),
multicriteria evaluation (MCE) and fuzzy sets to objectively identify priority locations for future marine protection. MCE
is a well-established optimisation method used extensively in land use resource allocation and decision support, and which
has to date been underutilised in marine planning despite its potential to guide such efforts. The framework presented here
was implemented in the Pacific Canadian Exclusive Economic Zone (EEZ) using two conflicting objectives - biodiversity conservation
and fisheries profit-maximisation. The results indicate that the GIS-based MCE framework supports the objective identification
of priority locations for future marine protection. This is achieved by integrating multi-source spatial data, facilitating
the simultaneous combination of multiple objectives, explicitly including stakeholder preferences in the decisions, and providing
visualisation capabilities to better understand how global MPA networks might be developed under conditions of uncertainty
and complexity. 相似文献
306.
Yong Yi Zhen Robert S. Nicoll Leon S. Normore Ian G. Percival John R. Laurie Louisa M. Dent 《Palaeoworld》2021,30(2):249-277
The conodont fauna from the Willara Formation, a carbonate-dominated stratigraphic unit widely distributed in the subsurface Canning Basin of Western Australia, is represented by 41 species, including a new species, Erraticodon neopatu Zhen n. sp. The Jumudontus gananda and Histiodella altifrons biozones are recognized in the lower and upper parts, respectively, of the Willara Formation. Deposited primarily in shallow nearshore settings, the Willara Formation is characterized by the occurrence of predominantly long-range coniform species of Triangulodus, Scalpellodus, Drepanoistodus, Drepanodus, and Kirkupodus. Several widely distributed age-diagnostic species, including Histiodella altifrons, Histiodella holodentata, Histiodella serrata, and Jumudontus gananda, serve as keys for biostratigraphic analysis and correlation. Our study also shows that the basal and top boundaries of the Willara Formation are diachronous across the basin, extending from the middle Floian (Oepikodus communis Biozone) to middle Darriwilian (Histiodella holodentata-Eoplacognathus pseudoplanus Biozone). This contribution provides crucial new biostratigraphic data for precise correlation of the Willara Formation with its time equivalents regionally and internationally. 相似文献
307.
Thomas Walker Shannon Quek Claire L. Jeffries Janvier Bandibabone Vishaal Dhokiya Roland Bamou Mojca Kristan Louisa A. Messenger Alexandra Gidley Emily A. Hornett Enyia R. Anderson Cintia Cansado-Utrilla Shivanand Hegde Chimanuka Bantuzeko Jennifer C. Stevenson Neil F. Lobo Simon C. Wagstaff Christophe Antonio Nkondjio Grant L. Hughes 《Current biology : CB》2021,31(11):2310-2320.e5
308.
Nabila El-Bassel Louisa Gilbert Dawn Goddard-Eckrich Mingway Chang Elwin Wu Tim Hunt Matt Epperson Stacey A. Shaw Jessica Rowe Maria Almonte Susan Witte 《PloS one》2014,9(11)
Importance
This study is designed to address the need for evidence-based HIV/STI prevention approaches for drug-involved women under criminal justice community supervision.Objective
We tested the efficacy of a group-based traditional and multimedia HIV/STI prevention intervention (Project WORTH: Women on the Road to Health) among drug-involved women under community supervision.Design, Setting, Participants, and Intervention
We randomized 306 women recruited from community supervision settings to receive either: (1) a four-session traditional group-based HIV/STI prevention intervention (traditional WORTH); (2) a four-session multimedia group-based HIV/STI prevention intervention that covered the same content as traditional WORTH but was delivered in a computerized format; or (3) a four-session group-based Wellness Promotion intervention that served as an attention control condition. The study examined whether the traditional or multimedia WORTH intervention was more efficacious in reducing risks when compared to Wellness Promotion; and whether multimedia WORTH was more efficacious in reducing risks when compared to traditional WORTH.Main Outcomes and Measures
Primary outcomes were assessed over the 12-month post-intervention period and included the number of unprotected sex acts, the proportion of protected sex acts, and consistent condom use. At baseline, 77% of participants reported unprotected vaginal or anal sex (n = 237) and 63% (n = 194) had multiple sex partners.Results
Women assigned to traditional or multimedia WORTH were significantly more likely than women assigned to the control condition to report an increase in the proportion of protected sex acts (β = 0.10; 95% CI = 0.02–0.18) and a decrease in the number of unprotected sex acts (IRR = 0.72; 95% CI = 0.57–0.90).Conclusion and Relevance
The promising effects of traditional and multimedia WORTH on increasing condom use and high participation rates suggest that WORTH may be scaled up to redress the concentrated epidemics of HIV/STIs among drug-involved women in the criminal justice system.Trial Registration
ClinicalTrials.gov NCT01784809相似文献309.
Richard J. P. Brown George Koutsoudakis Richard A. Urbanowicz Deeman Mirza Corinne Ginkel Nina Riebesehl Noémie Calland Anna Albecka Louisa Price Natalia Hudson Véronique Descamps Matthijs Backx C. Patrick McClure Gilles Duverlie Eve-Isabelle Pecheur Jean Dubuisson Sofia Perez-del-Pulgar Xavier Forns Eike Steinmann Alexander W. Tarr Thomas Pietschmann Jonathan K. Ball 《Journal of virology》2014,88(1):667-678
Serine is encoded by two divergent codon types, UCN and AGY, which are not interchangeable by a single nucleotide substitution. Switching between codon types therefore occurs via intermediates (threonine or cysteine) or via simultaneous tandem substitutions. Hepatitis C virus (HCV) chronically infects 2 to 3% of the global population. The highly variable glycoproteins E1 and E2 decorate the surface of the viral envelope, facilitate cellular entry, and are targets for host immunity. Comparative sequence analysis of globally sampled E1E2 genes, coupled with phylogenetic analysis, reveals the signatures of multiple archaic codon-switching events at seven highly conserved serine residues. Limited detection of intermediate phenotypes indicates that associated fitness costs restrict their fixation in divergent HCV lineages. Mutational pathways underlying codon switching were probed via reverse genetics, assessing glycoprotein functionality using multiple in vitro systems. These data demonstrate selection against intermediate phenotypes can act at the structural/functional level, with some intermediates displaying impaired virion assembly and/or decreased capacity for target cell entry. These effects act in residue/isolate-specific manner. Selection against intermediates is also provided by humoral targeting, with some intermediates exhibiting increased epitope exposure and enhanced neutralization sensitivity, despite maintaining a capacity for target cell entry. Thus, purifying selection against intermediates limits their frequencies in globally sampled strains, with divergent functional constraints at the protein level restricting the fixation of deleterious mutations. Overall our study provides an experimental framework for identification of barriers limiting viral substitutional evolution and indicates that serine codon-switching represents a genomic “fossil record” of historical purifying selection against E1E2 intermediate phenotypes. 相似文献
310.