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Properties and inhibition of the first two enzymes of the non-mevalonate pathway of isoprenoid biosynthesis 总被引:3,自引:0,他引:3
Mueller C Schwender J Zeidler J Lichtenthaler HK 《Biochemical Society transactions》2000,28(6):792-793
Enzymes of the 1-deoxy-D-xylulose 5-phosphate/2-C-methylerythritol 4-phosphate (DOXP/MEP) pathway are targets for new herbicides and antibacterial drugs. Until now, no inhibitors for the DOXP synthase have been known of. We show that one of the breakdown products of the herbicide clomazone affects the DOXP synthase. One inhibitor of the non-mevalonate pathway, fosmidomycin, blocks the DOXP reductoisomerase (DXR) of plants and bacteria. The I(50) values of plants are, however, higher than those found for the DXR of Escherichia coli. The DXR of plants, isolated from barley seedlings, shows a pH optimum of 8.1, which is typical for enzymes active in the chloroplast stroma. 相似文献
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Summary Panels of 3 M KCl extracts of squamous-cell carcinomas, adenocarcinomas and oat-cell carcinomas of the lung were used for a comprehensive analysis of cross-reactivity in the leucocyte migration test. Lung cancer patients' leucocytes showed positive reactivity in 69%–100% of cases (n=353). No significant differences were observed when data were grouped with respect to the histological type of the tumours used for extraction or of the tumours of the leukocyte donors. Leukocytes of patients bearing tumours of nonpulmonary origin exposed to lung cancer extract panels and leukocytes of lung cancer patients exposed to gastrointestinal cancer extract panels were definitely less reactive (35%–47% and 6%–38%, respectively). However, a high reaction frequency was found in patients with lung metastases from different nonpulmonary tumours. This group of patients also frequently showed reactivity (52%) with normal lung tissue extracts. Patients with benign lung diseases reacted positively with lung tumour extracts in 25%–39% of cases, but donors with other benign disease and healthy controls were virtually nonreactive (0–14%).Hence, a high degree of cross-reactivity occurs in the lung cancer system and restricted cross-reactivity occurs with tumours of other organs. Possible explanations for the lung-oriented reactivity of patients with lung metastases are discussed.Abbreviations LMI
leucocyte migration inhibition
- MI
migration index
- LMT
leucocyte migration test
- SCC
squamous-cell carcinoma
- OCC
oat-cell carcinoma
- AC
adenocarcinoma 相似文献
106.
JAK/STAT signalling in vertebrates is activated by multiple cytokines and growth factors. By contrast, the Drosophila genome encodes for only three related JAK/STAT ligands, Upd, Upd2 and Upd3. Identifying the differences between these three ligands will ultimately lead to a greater understanding of this disease-related signalling pathway and its roles in development. Here, we describe the analysis of the least well characterised of the Upd-like ligands, Upd3. We show that in tissue culture-based assays Upd3-GFP is secreted from cells and appears to interact with the extracellular matrix (ECM) in a similar manner to Upd, while still non-autonomously activating JAK/STAT signalling. Quantification of each of the Upd-like ligands in conditioned media has allowed us to determine the activity of equal amounts of each ligand on JAK/STAT ex vivo and reveals that Upd is the most potent ligand in this system. Finally, investigations into the effects of ectopic expression of Upd3 in vivo have confirmed its ability to activate pathway signalling at long-distance. 相似文献
107.
gp350, the major envelope protein of Epstein-Barr-Virus, confers B-cell tropism to the virus by interacting with the B lineage marker CD21. Here we utilize gp350 to generate tailored exosomes with an identical tropism. These exosomes can be used for the targeted co-transfer of functional proteins to normal and malignant human B cells. We demonstrate here the co-transfer of functional CD154 protein on tailored gp350+ exosomes to malignant B blasts from patients with B chronic lymphocytic leukemia (B-CLL), rendering B blasts immunogenic to tumor-reactive autologous T cells. Intriguingly, engulfment of gp350+ exosomes by B-CLL cells and presentation of gp350-derived peptides also re-stimulated EBV-specific T cells and redirected the strong antiviral cellular immune response in patients to leukemic B cells. In essence, we show that gp350 alone confers B-cell tropism to exosomes and that these exosomes can be further engineered to simultaneously trigger virus- and tumor-specific immune responses. The simultaneous exploitation of gp350 as a tropism molecule for tailored exosomes and as a neo-antigen in malignant B cells provides a novel attractive strategy for immunotherapy of B-CLL and other B-cell malignancies. 相似文献
108.
Chiara Testa Anna Maria Papini Reinhard Zeidler Daniela Vullo Fabrizio Carta Claudiu T. Supuran Paolo Rovero 《Journal of enzyme inhibition and medicinal chemistry》2022,37(1):592
We report for the first time Antibody-Drug-Conjugates (ADCs) containing human (h) Carbonic Anhydrase (CA; EC 4.2.1.1) directed Monoclonal Antibodies (MAbs) linked to low molecular weight inhibitors of the same enzymes by means of hydrophilic peptide spacers. In agreement with the incorporated CA directed MAb fragments, in vitro inhibition data of the obtained ADCs showed sub-nanomolar KI values for the tumour associated CAs IX and XII which were up to 10-fold more potent when compared to the corresponding unconjugated MAbs. In addition, the introduction of the CA inhibitor (CAI) benzenesulfonamide allowed the ADCs to potently inhibit the housekeeping tumoral off-target human CA II isoform. Such results are supporting the definition of an unprecedented reported class of ADCs able to hit simultaneously multiple hCAs physiologically cooperative in maintaining altered cellular metabolic pathways, and therefore ideal for the treatment of chronic diseases such as cancers and inflammation diseases. 相似文献
109.
MicroRNAs are minor constituents of extracellular vesicles that are rarely delivered to target cells
110.
Battke C Kremmer E Mysliwietz J Gondi G Dumitru C Brandau S Lang S Vullo D Supuran C Zeidler R 《Cancer immunology, immunotherapy : CII》2011,60(5):649-658
The carbonic anhydrases (CAs) constitute a family of almost ubiquitous enzymes of significant importance for many physiological
and pathological processes. CAs reversely catalyse the conversion of CO2 + H2O to HCO3
− and H+, thereby contributing to the regulation of intracellular pH. Above all, CAs are of key importance for cells that perform
glycolysis that inevitably leads to the intracellular accumulation of lactate. CA XII is a plasma membrane-associated isoform
of the enzyme, which is induced by hypoxia and oestrogen and, consequently, expressed at high levels on various types of cancer
and, intriguingly, on cancer stem cells. The enzyme is directly involved in tumour progression, and its inhibition has an
anti-tumour effect. Apart from its role in carcinogenesis, the enzyme contributes to various other diseases like glaucoma
and arteriosclerotic plaques, among others. CA XII is therefore regarded as promising target for specific therapies. We have
now generated the first monoclonal antibody (6A10) that binds to the catalytic domain of CA XII on vital tumour cells and
inhibits CA XII enzyme activity at nanomolar concentrations and thus much more effective than acetazolamide. In vitro results
demonstrate that inhibition of CA XII by 6A10 inhibits the growth of tumour cells in 3-dimensional structures. In conclusion,
we generated the first specific and efficient biological inhibitor of tumour-associated CA XII. This antibody may serve as
a valuable tool for in vivo diagnosis and adjuvant treatment of different types of cancer. 相似文献