全文获取类型
收费全文 | 384篇 |
免费 | 39篇 |
出版年
2022年 | 2篇 |
2021年 | 5篇 |
2020年 | 3篇 |
2019年 | 3篇 |
2018年 | 10篇 |
2017年 | 6篇 |
2016年 | 8篇 |
2015年 | 14篇 |
2014年 | 11篇 |
2013年 | 32篇 |
2012年 | 19篇 |
2011年 | 26篇 |
2010年 | 15篇 |
2009年 | 15篇 |
2008年 | 20篇 |
2007年 | 21篇 |
2006年 | 21篇 |
2005年 | 18篇 |
2004年 | 10篇 |
2003年 | 20篇 |
2002年 | 25篇 |
2001年 | 8篇 |
2000年 | 10篇 |
1999年 | 12篇 |
1998年 | 5篇 |
1997年 | 3篇 |
1996年 | 7篇 |
1994年 | 6篇 |
1992年 | 4篇 |
1991年 | 4篇 |
1990年 | 7篇 |
1989年 | 5篇 |
1988年 | 4篇 |
1987年 | 3篇 |
1985年 | 3篇 |
1984年 | 2篇 |
1983年 | 3篇 |
1982年 | 3篇 |
1981年 | 3篇 |
1979年 | 4篇 |
1977年 | 5篇 |
1975年 | 2篇 |
1974年 | 2篇 |
1971年 | 1篇 |
1970年 | 2篇 |
1969年 | 1篇 |
1968年 | 4篇 |
1967年 | 1篇 |
1966年 | 1篇 |
1951年 | 1篇 |
排序方式: 共有423条查询结果,搜索用时 15 毫秒
101.
Gökçen Eren Serdar Ünlü Maria-Teresa Nuñez Luis Labeaga Francisco Ledo Antonio Entrena Erden Banoğlu Gabriele Costantino M. Fethi Şahin 《Bioorganic & medicinal chemistry》2010,18(17):6367-6376
Three novel series of diaryl heterocyclic derivatives bearing the 2-oxo-5H-furan, 2-oxo-3H-1,3-oxazole, and 1H-pyrazole moieties as the central heterocyclic ring were synthesized and their in vitro inhibitory activities on COX-1 and COX-2 isoforms were evaluated using a purified enzyme assay. The 2-oxo-5H-furan derivative 6b was identified as potent COX inhibitor with selectivity toward COX-1 (COX-1 IC50 = 0.061 μM and COX-2 IC50 = 0.325 μM; selectivity index (SI) = 0.19). Among the 1H-pyrazole derivatives, 11b was found to be a potent COX-2 inhibitor, about 38 times more potent than Rofecoxib (COX-2 IC50 = 0.011 μM and 0.398 μM, respectively), but showed no selectivity for COX-2 isoform. Compound 11c demonstrated strong and selective COX-2 inhibitory activity (COX-1 IC50 = 1 μM, COX-2 IC50 = 0.011 μM; SI = ~92). Molecular docking studies of compounds 6b and 11b–d into the binding sites of COX-1 and COX-2 allowed to shed light on the binding mode of these novel COX inhibitors. 相似文献
102.
Tarantino U Capone A Planta M D'Arienzo M Letizia Mauro G Impagliazzo A Formica A Pallotta F Patella V Spinarelli A Pazzaglia U Zarattini G Roselli M Montanari G Sessa G Privitera M Verdoia C Corradini C Feola M Padolino A Saturnino L Scialdoni A Rao C Iolascon G Brandi ML Piscitelli P 《Arthritis research & therapy》2010,12(6):R226-9
Introduction
We aimed to assess the incidence and hospitalization rate of hip and "minor" fragility fractures in the Italian population.Methods
We carried out a 3-year survey at 10 major Italian emergency departments to evaluate the hospitalization rate of hip, forearm, humeral, ankle, and vertebral fragility fractures in people 45 years or older between 2004 and 2006, both men and women. These data were compared with those recorded in the national hospitalizations database (SDO) to assess the overall incidence of fragility fractures occurring at hip and other sites, including also those events not resulting in hospital admissions.Results
We observed 29,017 fractures across 3 years, with hospitalization rates of 93.0% for hip fractures, 36.3% for humeral fractures, 31.3% for ankle fractures, 22.6% for forearm/wrist fractures, and 27.6% for clinical vertebral fractures. According to the analyses performed with the Italian hospitalization database in year 2006, we estimated an annual incidence of 87,000 hip, 48,000 humeral, 36,000 ankle, 85,000 wrist, and 155,000 vertebral fragility fractures in people aged 45 years or older (thus resulting in almost 410,000 new fractures per year). Clinical vertebral fractures were recorded in 47,000 events per year.Conclusions
The burden of fragility fractures in the Italian population is very high and calls for effective preventive strategies. 相似文献103.
Yannick Auclair Raphael Rouget Jonathan M. Belisle Santiago Costantino Elliot A. Drobetsky 《DNA Repair》2010,9(7):754-764
The autosomal recessive disorder Xeroderma pigmentosum-variant (XPV) is characterized (i) at the cellular level by dramatic hypermutability and defective recovery of DNA synthesis following UV exposure, and (ii) clinically by abnormal sunlight sensitivity and remarkable predisposition to skin cancer. These phenotypes are clearly attributable to germline mutations in POLH, encoding DNA polymerase eta (polη) normally required for accurate translesion DNA synthesis (TLS) past UV-induced cyclobutane pyrimidine dimers. Here we demonstrate that patient-derived XPV-skin fibroblasts exposed to 15 J/m2 of UV also exhibit (in addition to abnormal TLS) a significant defect in global-genomic nucleotide excision repair (GG-NER) exclusively during S phase. This cell cycle-specific GG-NER defect can be complemented by ectopic expression of wild-type polη, but not of polη variants deficient in either nuclear relocalization or PCNA interaction. We highlight a previous study from our laboratory demonstrating that UV-exposed, ATR-deficient Seckel syndrome fibroblasts, like XPV fibroblasts, manifest strong attenuation of GG-NER uniquely in S phase populations. We now present further evidence suggesting that deficient S phase repair can be rescued in both XPV- and Seckel syndrome-cells if the formation of blocked replication forks post-UV is either prevented or substantially reduced, i.e., following, respectively, pharmacological inhibition of DNA synthesis prior to UV irradiation, or exposure to a relatively low UV dose (5 J/m2). Our findings in cultured cells permit speculation that abrogation of GG-NER during S phase might partially contribute (in a synergistic manner with defective, atypically error-prone TLS) to the extreme state of UV-hypermutability leading to accelerated skin cancer development in XPV patients. Moreover, based on the overall data, we postulate that loss of either functional polη or -ATR engenders abnormal persistence of stalled replication forks at UV-adducted sites in DNA which, in turn, can actively and/or passively trigger GG-NER inhibition. 相似文献
104.
The bacterial and archaeal communities of the sediments at the base of the Florida Escarpment (Gulf of Mexico, USA) were investigated using molecular phylogenetic analysis. The total microbial community DNA of each of three vertical zones (top, middle and bottom) of a sediment core was extracted and the 16S rRNA genes were amplified by PCR, cloned and sequenced. Shannon–Weaver Diversity measures of bacteria were high in all three zones. For the archaea, diversity was generally low, but increased with depth. The archaeal clonal libraries were dominated by representatives of four groups of organisms involved in the anaerobic oxidation of methane (ANME groups). Phylogenetic analysis of bacteria suggests the dominance of -proteobacteria in the top zone, the -, - and -proteobacteria in the middle zone and the -proteobacteria in the bottom zone of the core. Members of the Cytophaga–Flexibacter–Bacteroidetes group, the Chloroflexi/green non-sulfur bacteria, the Gram+ (Firmicutes), the Planctomyces, candidate division WS3 and Fusobacterium were also detected. Our data suggest that the community structure and diversity of microorganisms can shift greatly within small vertical distances, possibly in response to changes in the physical and chemical conditions. 相似文献
105.
106.
Koblízek M Béjà O Bidigare RR Christensen S Benitez-Nelson B Vetriani C Kolber MK Falkowski PG Kolber ZS 《Archives of microbiology》2003,180(5):327-338
Seven strains of marine aerobic anoxygenic phototrophs belonging to the genus Erythrobacter were isolated. The strains were characterized regarding their physiological and biochemical properties, 16S rDNA and pufM gene sequences, morphological features, substrate preference, as well as pigment and lipid composition. All strains had functional type-2 reaction centers containing bacteriochlorophyll, served by small, light-harvesting complex 1, and were photosynthetically competent. In addition, large pools of carotenoids were found, but only some of the accessory pigments transfer energy to the reaction centers. All of the isolates were facultative photoheterotrophs. They required an organic carbon substrate for growth; however, they are able to supplement a significant fraction of their metabolic requirements with photosynthetically derived energy.Abbreviations BChl Bacteriochlorophyll - Chl Chlorophyll - Erb. Erythrobacter - Erm. Erythromicrobium - FAMEs Fatty acid methyl esters - IRFRR Infrared fast repetition rate - LH1, LH2 Light-harvesting complex 1 and 2, respectively - Por. Porphyrobacter - PUFAs Polyunsaturated fatty acids - Rsb. Roseobacter - RubisCO Ribulose-1,5-bisphosphate carboxylase/oxygenase - µ Growth rate - 470 Functional cross-section of the photosynthetic unit at 470 nm 相似文献
107.
Cecconi I Scaloni A Rastelli G Moroni M Vilardo PG Costantino L Cappiello M Garland D Carper D Petrash JM Del Corso A Mura U 《The Journal of biological chemistry》2002,277(44):42017-42027
Aldose reductase (ALR2) is susceptible to oxidative inactivation by copper ion. The mechanism underlying the reversible modification of ALR2 was studied by mass spectrometry, circular dichroism, and molecular modeling approaches on the enzyme purified from bovine lens and on wild type and mutant recombinant forms of the human placental and rat lens ALR2. Two equivalents of copper ion were required to inactivate ALR2: one remained weakly bound to the oxidized protein whereas the other was strongly retained by the inactive enzyme. Cys(303) appeared to be the essential residue for enzyme inactivation, because the human C303S mutant was the only enzyme form tested that was not inactivated by copper treatment. The final products of human and bovine ALR2 oxidation contained the intramolecular disulfide bond Cys(298)-Cys(303). However, a Cys(80)-Cys(303) disulfide could also be formed. Evidence for an intramolecular rearrangement of the Cys(80)-Cys(303) disulfide to the more stable product Cys(298)-Cys(303) is provided. Molecular modeling of the holoenzyme supports the observed copper sequestration as well as the generation of the Cys(80)-Cys(303) disulfide. However, no evidence of conditions favoring the formation of the Cys(298)-Cys(303) disulfide was observed. Our proposal is that the generation of the Cys(298)-Cys(303) disulfide, either directly or by rearrangement of the Cys(80)-Cys(303) disulfide, may be induced by the release of the cofactor from ALR2 undergoing oxidation. The occurrence of a less interactive site for the cofactor would also provide the rationale for the lack of activity of the disulfide enzyme forms. 相似文献
108.
Merendino RA Di Rosa AE Di Pasquale G Minciullo PL Mangraviti C Costantino A Ruello A Gangemi S 《Mediators of inflammation》2002,11(4):265-267
Interleukin-18 (IL-18), a pro-inflammatory cytokine that plays an important role in the T-cell-helper type 1 response, is a new member of the family of cytokines produced in the brain. CD30 is a marker of T-cell-helper type 2 lymphocytes. We evaluated IL-18 and CD30 serum levels in 10 patients affected by moderate-severe depression (MSD). We demonstrated for the first time that serum IL-18 levels of MSD patients were significantly higher than those of healthy donors. On the contrary, no significant difference was found between serum CD30 levels of MSD patients compared with those of healthy donors. These data strengthen the hypothesis that MSD disease is associated with an inflammatory response, mainly T-cell-helper type 1, and suggest an important role for IL-18 in the pathophysiology of MSD. 相似文献
109.
Bacterial plant oncogenes: Therol genes' saga 总被引:1,自引:0,他引:1
P. Costantino I. Capone M. Cardarelli A. De Paolis M. L. Mauro M. Trovato 《Genetica》1994,94(2-3):203-211
Therol genes are part of the T-DNA which is transferred byAgrobacterium rhizogenes in plant cells, causing neoplastic growth and differentiation. Each of these bacterial oncogenes deeply influences plant development and is finely regulated once transferred into the plant host. Both from the study of the effects and biochemical function of therol genes and from the analysis of their regulation, important insight in plant development can be derived. Some of the most intriguing aspects of past, current and future research on this gene system are highlighted and discussed. 相似文献
110.
Costantino Iadecola M.D. Xiaohong Xu Fangyi Zhang Jingru Hu Esam E. El-Fakahany 《Neurochemical research》1994,19(4):501-505
We studied the dose-response characteristics and the temporal profile of inhibition of brain nitric oxide (NO) synthase (NOS) elicited by i.v. administration of the NOS inhibitor nitro-l-arginine methyl ester (L-NAME). L-NAME was administered i.v. in awake rats equipped with a venous cannula. L-NAME was injected in cumulative doses of 5, 10, 20 and 40 mg/kg and rats were sacrificed 30 min after the last dose. NOS catalytic activity was assayed in forebrain cytosol as the conversion of [3H]l-arginine into [3H]l-citrulline. L-NAME attenuated brain NOS activity in a dose-dependent manner but enzyme activity could not be inhibited by more than 50%. After a single 20 mg/kg injection of L-NAME the inhibition of brain NOS activity was time dependent and reached a stable level at 2 hrs (52% of vehicle). Inhibition after a single injection was still present at 96 hrs, albeit to a lower magnitude. We conclude that intravenous administration of L-NAME in rats at concentrations commonly used in physiological experiments leads to a dose and time-dependent but partial inhibition of brain NOS catalytic activity. The finding that the inhibition persists for several days after a single administration is consistent with the hypothesis that nitro-L-arginine, the active principle of L-NAME, binds to NOS irreversibly. 相似文献