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71.
P R Lowe C E Sansom C H Schwalbe M F Stevens A S Clark 《Journal of medicinal chemistry》1992,35(18):3377-3382
The antitumor imidazotetrazinone, temozolomide (5), C6H6N6O2, forms crystals with unit cell dimensions a = 17.332 (3), b = 7.351 (2), c = 13.247 (1), beta = 109.56 (1) degree and space group P21/c. A doubly hydrogen-bonded dimer constitutes the asymmetric unit. One carboxamide group forms an additional intermolecular NH...O hydrogen bond; in both molecules the carboxamide group is coplanar with the heterocycle and its NH2 group interacts with the imidazole nitrogen atom N(7). Molecular orbital calculations show the carbonyl carbon C(4) to be the most electron deficient atom, with relatively weak N(3)-C(4) and C(4)-N(5) bonds confirming that temozolomide should ring-open at this position in solution. The energy barrier to carboxamide group rotation of approximately 20 kJ mol-1 should permit interconversion between rotamers. In temozolomide and the related drug mitozolomide (4), N(7) is more negatively charged than N(1), which favors the formation of hydrogen bonds to the former atom in spite of their poor geometry. The relevance of these structural features to the action of temozolomide as a major-groove-directed prodrug of the alkylating agent MTIC (3) is discussed. 相似文献
72.
Berry JM Bradshaw TD Fichtner I Ren R Schwalbe CH Wells G Chew EH Stevens MF Westwell AD 《Journal of medicinal chemistry》2005,48(2):639-644
A series of substituted 4-(1-arylsulfonylindol-2-yl)-4-hydroxycyclohexa-2,5-dien-1-ones (indolylquinols) has been synthesized on the basis of the discovery of lead compound 1a and screened for antitumor activity. Synthesis of this novel series was accomplished via the "one-pot" addition of lithiated (arylsulfonyl)indoles to 4,4-dimethoxycyclohexa-2,5-dienone followed by deprotection under acidic conditions. Similar methodology gave rise to the related naphtho-, 1H-indole-, and benzimidazole-substituted quinols. A number of compounds in this new series were found to possess in vitro human tumor cell line activity substantially more potent than the recently reported antitumor 4-substituted 4-hydroxycyclohexa-2,5-dien-1-ones(1) with similar patterns of selectivity against colon, renal, and breast cell lines. The most potent compound in the series in vitro, 4-(1-benzenesulfonyl-6-fluoro-1H-indol-2-yl)-4-hydroxycyclohexa-2,5-dienone (1h), exhibits a mean GI(50) value of 16 nM and a mean LC(50) value of 2.24 muM in the NCI 60-cell-line screen, with LC(50) activity in the HCT 116 human colon cancer cell line below 10 nM. The crystal structure of the unsubstituted indolylquinol 1a exhibits two independent molecules, both participating in intermolecular hydrogen bonds from quinol OH to carbonyl O, but one OH group also interacts intramolecularly with a sulfonyl O atom. This interaction, which strengthens upon ab initio optimization, may influence the chemical environment of the bioactive quinol moiety. In vivo, significant antitumor activity was recorded (day 28) in mice bearing subcutaneously implanted MDA-MB-435 xenografts, following intraperitoneal treatment of mice with compound 1a at 50 mg/kg. 相似文献
73.
Molloy KJ Thompson MM Schwalbe EC Bell PR Naylor AR Loftus IM 《The American journal of cardiology》2004,94(1):144-146
We performed an observational study on 137 patients undergoing carotid endarterectomy (CEA). Patients on statins were less likely to have had symptoms in the 4 weeks before CEA (p = 0.0049) and were less likely to have spontaneous cerebral embolization detected by transcranial Doppler (p = 0.0459). Carotid plaques retrieved at CEA from patients taking statins revealed significantly lower concentrations of matrix metalloproteinase-1 (p = 0.0176), matrix metalloproteinase-9 (p = 0.0018), and interleukin-6 (p = 0.0005). 相似文献
74.
Differential dynamics in the G protein-coupled receptor rhodopsin revealed by solution NMR
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Klein-Seetharaman J Yanamala NV Javeed F Reeves PJ Getmanova EV Loewen MC Schwalbe H Khorana HG 《Proceedings of the National Academy of Sciences of the United States of America》2004,101(10):3409-3413
G protein-coupled receptors are cell-surface seven-helical membrane proteins that undergo conformational changes on activation. The mammalian photoreceptor, rhodopsin, is the best-studied member of this superfamily. Here, we provide the first evidence that activation in rhodopsin may involve differential dynamic properties of side-chain versus backbone atoms. High-resolution NMR studies of alpha-(15)N-labeled receptor revealed large backbone motions in the inactive dark state. In contrast, indole side-chain (15)N groups of tryptophans showed well resolved, equally intense NMR signals, suggesting restriction to a single specific conformation. 相似文献
75.
Stolzenburg JU Rabenalt R Dietel A Do M Pfeiffer H Schwalbe S Dorschner W 《Journal of laparoendoscopic & advanced surgical techniques. Part A》2003,13(1):27-31
We retrospectively reviewed our experience in performing endoscopic extraperitoneal radical prostatectomy (EERPE) and totally extraperitoneal (TEP) hernia repair in one procedure to evaluate its feasibility and safety. Based on our experience of 70 laparoscopic radical prostatectomies, a total of 60 patients underwent EERPE. Eight of these had 10 hernias repaired with Prolene mesh. The median total operating time for EERPE was 165 minutes. Mesh placement required an additional 15 minutes for a unilateral hernia and 25 minutes for bilateral hernias. The conversion rate and the reoperation rate were 0%. The median duration of vesical catheterization was 8.3 days. One patient required a blood transfusion. The most common minor complications, occurring in eight patients, were edema and hematoma of the penis. No wound infection occurred. The only major complication was a deep venous thrombosis in one patient. No additional complications developed in the hernioplasty group. We conclude that the extraperitoneal approach for radical prostatectomy allows concomitant inguinal hernia repair with a low morbidity rate and within an acceptable operating time. 相似文献
76.
A radioactive antigen-binding assay for the measurement of antibody to Haemophilus influenzae type b capsular polysaccharide 总被引:8,自引:0,他引:8
A new polyethylene glycol (PEG) radioimmunoprecipitation assay was developed for the detection of antibody to Haemophilus influenzae b capsular polysaccharide, polyribosylribitol phosphate (PRP). The radioactive antigen, [3H]PRP, with a high specific activity, was produced by growing the organism in the presence of [3H]ribose and was purified by hydroxylapatite and Sepharose 4B column chromatography. In the assay, PEG (12.5%) was used to separate antibody-bound [3H]PRP from free [3H]PRP. The assay covered the range of 0.5 and 20 ng antibody/assay at a maximum sensitivity of 0.5 approximately 1.0 ng antibody/assay. With various dilutions (1-20 ng antibody/assay) of S. Klein reference antiserum, the within-run coefficient of variation (CV) of 10 replicates ranged from 3.5 to 8.5%. Average CVs of 8.9% and 11.0% were obtained in the between-run and day-to-day reproducibility studies. The binding of [3H]PRP to S. Klein reference antiserum was severely inhibited by a minute amount of non-radioactive PRP; however, no significant interference was found in the presence of high concentrations of polysaccharides from Escherichia coli K100 and Streptococcus pneumoniae indicating that the RIA was highly specific for antibody to H. influenzae b PRP. The present RIA is a simple, specific, sensitive and reproducible procedure for the evaluation of antibody responses of young animals and infants to H. influenzae b vaccines and infections. 相似文献
77.
78.
Interchain hydrogen-bonding interactions may facilitate translocation of K+ ions across the potassium channel selectivity filter, as suggested by synthetic modeling chemistry
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Mareque Rivas JC Schwalbe H Lippard SJ 《Proceedings of the National Academy of Sciences of the United States of America》2001,98(17):9478-9483
A 4-fold symmetric arrangement of TVGYG polypeptides forms the selectivity filter of the K+ channel from Streptomyces lividans (KcsA). We report the synthesis and properties of synthetic models for the filter, p-tert-butyl-calix[4]arene-(OCH(2)CO-XOBz)(4) (X = V, VG, VGY), 1-3. The first cation (Na+, K+) binds to the four -[OCH(2)CO]- units, a region devised to mimic the metal-binding site formed by the four T residues in KcsA. NMR studies reveal that cations and valine amide protons compete for the carbonyl oxygen atoms, converting NH(Val)...O=C hydrogen bonds to M+ ...O=C bonds (M+ = Na+ or K+). The strength of these interchain NH(Val)...O=C hydrogen bonds varies in the order 3 > 2 > 1. We propose that such interchain H-bonding may destabilize metal binding in the selectivity filter and thus help create the low energy barrier needed for rapid cation translocation. 相似文献
79.
The structural and electronic properties of the major groove-binding anti-tumour imidazotetrazinones, mitozolomide and temozolomide were studied using molecular orbital techniques. Structure-activity relationships of mitozolomide derivatives emphasized the importance of a hydrogen bond donor on the C8-substituent and showed that good activity would be expected for derivatives carrying a small C8-substituent with restricted negative potential. The coplanarity of the carboxamide substituent in mitozolomide is unlikely to be disrupted by hydrogen bonding in the major groove. Semi-empirical M.O. calculations gave a very high partial positive charge on C4, indicating an enhanced susceptibility to nucleophilic attack leading to ring opening at this position and the formation of a triazene alkylating agent. 相似文献
80.
Important factors in assessing the development of the trunk are, among others, the relative thoracic data, for example, measurement of the width and depth of the thorax and calculation of the relative thoracic diameter, as well as the thoracic index. The normal values recorded in 196 healthy boys and girls aged 3-6 years, are stated. 相似文献