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21.
Jennifer S Michaelson Stephen J Demarest Brian Miller Aldo Amatucci William B Snyder Xiufeng Wu Flora Huang Samantha Phan Sharon Gao Adam Doern Graham K Farrington Alexey Lugovskoy Ingrid Joseph Veronique Bailly Xin Wang Ellen Garber Jeff Browning Scott M Glaser 《MABS-AUSTIN》2009,1(2):128-141
Bispecific antibodies (BsAbs) represent an emerging class of biologics that achieve dual targeting with a single agent. Recombinant DNA technologies have facilitated a variety of creative bispecific designs with many promising therapeutic applications; however, practical methods for producing high quality BsAbs that have good product stability, long serum half-life, straightforward purification, and scalable production have largely been limiting. Here we describe a protein-engineering approach for producing stable, scalable tetravalent IgG-like BsAbs. The stability-engineered IgG-like BsAb was envisioned to target and crosslink two TNF family member receptors, TRAIL-R2 (TNF-Related Apoptosis Inducing Ligand Receptor-2) and LTβR (Lymphotoxin-beta Receptor), expressed on the surface of epithelial tumor cells with the goal of triggering an enhanced anti-tumor effect. Our IgG-like BsAbs consists of a stability-engineered anti-LTβR single chain Fv (scFv) genetically fused to either the N- or C-terminus of the heavy chain of a full-length anti-TRAIL-R2 IgG1 monoclonal antibody. Both N- or C-terminal BsAbs were active in inhibiting tumor cell growth in vitro, and with some cell lines demonstrated enhanced activity relative to the combination of parental Abs. Pharmacokinetic studies in mice revealed long serum half-lives for the BsAbs. In murine tumor xenograft models, therapeutic treatment with the BsAbs resulted in reduction in tumor volume either comparable to or greater than the combination of parental antibodies, indicating that simultaneously targeting and cross-linking receptor pairs is an effective strategy for treating tumor cells. These studies support that stability-engineering is an enabling step for producing scalable IgG-like BsAbs with properties desirable for biopharmaceutical development.Key words: bispecific antibodies, single-chain Fv, immunoglobulins, antibody therapeutics, protein stability, pharmacokinetics, protein engineering, tumor inhibition, cancer treatment 相似文献
22.
Van Onckelen Henri A.; Horemans Stefaan; De Greef Jan A. 《Plant & cell physiology》1981,22(3):507-515
During the early stages of germination and vegetative development,cotyledons of intact bean (Phaseolus vulgaris L.) seedlingsshowed active ABA catabolism causing a low endogenous ABA content.At the end of the substrate mobilizing phase, when the cotyledonsbecame senescent, a drastic increase of the endogenous ABA contentlinked with a decrease of the ABA catabolic activity was observed.This indicates that a close connection exists between senescenceand endogenous ABA content and metabolism in bean cotyledons. Removal of the apical growth region induced in the cotyledonsactivation of the ABA catabolism and the endogenous ABA concentrationdecreased below the detection limit (0.1 ng/g fr wt) at theonset of the outgrowth of the axillary buds. From then, apicaldominance was restored and the cotyledons returned to the senescentstate, which was correlated with a drastic increase of theirendogenous ABA content.
1 Bevoegd verklaard navorser N. F. W. O.
2 Wetenschappelijk medewerker F. K. F. O. (Received November 25, 1980; Accepted February 13, 1981) 相似文献
23.
24.
Shyh-Ming Yang Yuting Tang Rui Zhang Huajun Lu Gee-Hong Kuo Michael D. Gaul Yaxin Li George Ho James G. Conway Yin Liang James M. Lenhard Keith T. Demarest William V. Murray 《Bioorganic & medicinal chemistry letters》2013,23(24):6773-6776
A new series of urea-based, 4-bicyclic heteroaryl-piperidine derivatives as potent SCD1 inhibitors is described. The structure–activity relationships focused on bicyclic heteroarenes and aminothiazole–urea portions are discussed. A trend of dose-dependent decrease in body weight gain in diet-induced obese (DIO) mice is also demonstrated. 相似文献
25.
Cultural attraction theory (CAT) describes a general evolutionary process, cultural attraction, by which the spread and stability of cultural items (beliefs, practices, artifacts, etc.) result not just from differential reproduction, but also from transformations that systematically favor the reconstruction of cultural items of specific types. In this way, CAT aims to provide a general framework for the study of cultural evolution. In a thoughtful critical analysis, Buskell questions the ability of CAT to provide methodological guidance for research in cultural evolution. Can CAT be used to develop the sort of mid‐range theories and models that often drive empirical work? Here we argue that CAT can indeed be used in this way, and we outline the methodological practices that students of cultural attraction have used and are currently developing. 相似文献
26.
Sahouli Salima Abdeddaim Katia K. Werbrouck Stefaan P. O. 《In vitro cellular & developmental biology. Plant》2022,58(4):664-670
In Vitro Cellular & Developmental Biology - Plant - Oleasters are olive genotypes that range from wild to feral. They are tolerant to biotic and abiotic stresses and are easily propagated. This... 相似文献
27.
Stefaan De Wildeman Gabriele Diekert Herman Van Langenhove Willy Verstraete 《Applied microbiology》2003,69(9):5643-5647
The suspected carcinogen 1,2-dichloroethane (1,2-DCA) is the most abundant chlorinated C2 groundwater pollutant on earth. However, a reductive in situ detoxification technology for this compound does not exist. Although anaerobic dehalorespiring bacteria are known to catalyze several dechlorination steps in the reductive-degradation pathway of chlorinated ethenes and ethanes, no appropriate isolates that selectively and metabolically convert them into completely dechlorinated end products in defined growth media have been reported. Here we report on the isolation of Desulfitobacterium dichloroeliminans strain DCA1, a nutritionally defined anaerobic dehalorespiring bacterium that selectively converts 1,2-dichloroethane and all possible vicinal dichloropropanes and -butanes into completely dechlorinated end products. Menaquinone was identified as an essential cofactor for growth of strain DCA1 in pure culture. Strain DCA1 converts chiral chlorosubstrates, revealing the presence of a stereoselective dehalogenase that exclusively catalyzes an energy-conserving anti mechanistic dichloroelimination. Unlike any known dehalorespiring isolate, strain DCA1 does not carry out reductive hydrogenolysis reactions but rather exclusively dichloroeliminates its substrates. This unique dehalorespiratory biochemistry has shown promising application possibilities for bioremediation purposes and fine-chemical synthesis. 相似文献
28.
Elizabeth A. Proctor Pradeep Kota Stephen J. Demarest Justin A. Caravella Nikolay V. Dokholyan 《Proteins》2013,81(5):884-895
The ability to generate and design antibodies recognizing specific targets has revolutionized the pharmaceutical industry and medical imaging. Engineering antibody therapeutics in some cases requires modifying their constant domains to enable new and altered interactions. Engineering novel specificities into antibody constant domains has proved challenging due to the complexity of inter‐domain interactions. Covarying networks of residues that tend to cluster on the protein surface and near binding sites have been identified in some proteins. However, the underlying role these networks play in the protein resulting in their conservation remains unclear in most cases. Resolving their role is crucial, because residues in these networks are not viable design targets if their role is to maintain the fold of the protein. Conversely, these networks of residues are ideal candidates for manipulating specificity if they are primarily involved in binding, such as the myriad interdomain interactions maintained within antibodies. Here, we identify networks of evolutionarily‐related residues in C‐class antibody domains by evaluating covariation, a measure of propensity with which residue pairs vary dependently during evolution. We computationally test whether mutation of residues in these networks affects stability of the folded antibody domain, determining their viability as design candidates. We find that members of covarying networks cluster at domain‐domain interfaces, and that mutations to these residues are diverse and frequent during evolution, precluding their importance to domain stability. These results indicate that networks of covarying residues exist in antibody domains for functional reasons unrelated to thermodynamic stability, making them ideal targets for antibody design. Proteins 2013. © 2012 Wiley Periodicals, Inc. 相似文献
29.
Kang FA Allan G Guan J Jain N Linton O Tannenbaum P Xu J Zhu P Gunnet J Chen X Demarest K Lundeen S Sui Z 《Bioorganic & medicinal chemistry letters》2007,17(4):907-910
A novel series of oxa-steroids 6 derived from (8S, 13S, 14R)-7-oxa-estra-4,9-diene-3,17-dione 1 have been synthesized and identified as potent and selective progesterone receptor antagonists. These novel oxa-steroids showed similar potency to mifepristone. Preliminary SAR study resulted in the most potent 17-phenylethynyl oxa-steroid 6i wih an IC(50) of 1.4nM. In contrast to the equipotent mifepristone toward the progesterone receptor (PR) and glucocorticoid receptor (GR), compound 6i had over 200-fold selectivity for PR over GR. 相似文献
30.
Genome sequencing and analysis of the versatile cell factory Aspergillus niger CBS 513.88 总被引:1,自引:0,他引:1
Pel HJ de Winde JH Archer DB Dyer PS Hofmann G Schaap PJ Turner G de Vries RP Albang R Albermann K Andersen MR Bendtsen JD Benen JA van den Berg M Breestraat S Caddick MX Contreras R Cornell M Coutinho PM Danchin EG Debets AJ Dekker P van Dijck PW van Dijk A Dijkhuizen L Driessen AJ d'Enfert C Geysens S Goosen C Groot GS de Groot PW Guillemette T Henrissat B Herweijer M van den Hombergh JP van den Hondel CA van der Heijden RT van der Kaaij RM Klis FM Kools HJ Kubicek CP van Kuyk PA Lauber J 《Nature biotechnology》2007,25(2):221-231