全文获取类型
收费全文 | 2725篇 |
免费 | 199篇 |
国内免费 | 1篇 |
出版年
2023年 | 13篇 |
2022年 | 32篇 |
2021年 | 64篇 |
2020年 | 21篇 |
2019年 | 46篇 |
2018年 | 89篇 |
2017年 | 56篇 |
2016年 | 82篇 |
2015年 | 123篇 |
2014年 | 153篇 |
2013年 | 188篇 |
2012年 | 219篇 |
2011年 | 229篇 |
2010年 | 148篇 |
2009年 | 122篇 |
2008年 | 143篇 |
2007年 | 184篇 |
2006年 | 164篇 |
2005年 | 137篇 |
2004年 | 131篇 |
2003年 | 136篇 |
2002年 | 108篇 |
2001年 | 42篇 |
2000年 | 22篇 |
1999年 | 34篇 |
1998年 | 20篇 |
1997年 | 13篇 |
1996年 | 9篇 |
1995年 | 16篇 |
1994年 | 11篇 |
1993年 | 10篇 |
1992年 | 17篇 |
1991年 | 18篇 |
1990年 | 6篇 |
1989年 | 10篇 |
1988年 | 9篇 |
1987年 | 10篇 |
1986年 | 8篇 |
1985年 | 4篇 |
1984年 | 5篇 |
1983年 | 6篇 |
1982年 | 5篇 |
1980年 | 4篇 |
1979年 | 5篇 |
1978年 | 6篇 |
1975年 | 5篇 |
1973年 | 5篇 |
1972年 | 4篇 |
1971年 | 5篇 |
1968年 | 8篇 |
排序方式: 共有2925条查询结果,搜索用时 343 毫秒
121.
Rossello A Nuti E Orlandini E Carelli P Rapposelli S Macchia M Minutolo F Carbonaro L Albini A Benelli R Cercignani G Murphy G Balsamo A 《Bioorganic & medicinal chemistry》2004,12(9):2441-2450
New N-arylsulfonyl-substituted alkoxyaminoaceto hydroxamic acid derivatives of types 8 and 10 designed as oxa-analogues of known sulfonamide-based MMPi of types 2 and 7 were synthesized and tested for their inhibitory activities on some matrix metalloproteinases. The combination of a biphenylsulfonamide group with oxyamino oxygen in the pharmacophoric central skeleton of sulfonamide-based MMPi obtained in the new sulfonamides 10 seems to be able to give selectivity for MMP-2 over MMP-1. The most potent derivative of this type, 10a, shows similar anti-invasive properties to the analogue reference drug CGS27023A, 2, in an in vitro model of invasion on matrigel, carried out on cellular lines of fibrosarcoma HT1080 (tumoural cells over-expressing MMP-2 and MMP-9). 相似文献
122.
The two-faced nature of protozoa allowed us to study the relationship between cell cycle and behaviour in Euplotes crassus; the former represents one of the most typical cellular traits, the latter is one of the most significant characteristics of an organism. Dividing cells of E. crassus were isolated on a slide and recorded for 11 h: the classic ethographic parameters were calculated every 60 min. The percentage of mobile cells went from 0-100% in the first 2.5 h. This value was maintained for 6.5 h, but from 9 h the value began to drop, reaching 0% at 11 h. The relative frequency of leftward arcs was very high in the first hour, the radius and length of the arcs increased from 1-7 h; velocity showed a similar trend, peaking at 7 h. All our results showed that the behaviour of this ciliate is heavily affected by its cell-division cycle. 相似文献
123.
Structural characterization of transglutaminase-catalyzed cross-linking between glyceraldehyde 3-phosphate dehydrogenase and polyglutamine repeats 下载免费PDF全文
Ruoppolo M Orrù S Francese S Caputo I Esposito C 《Protein science : a publication of the Protein Society》2003,12(1):170-179
The accumulation of abnormal polyglutamine-containing protein aggregates within the cytosol and nuclei of affected neurons is a hallmark of the progressive neurodegenerative disorders caused by an elongated (CAG)(n) repeat in the genome. The polyglutamine domains are excellent substrates for the enzyme transglutaminase type 2 (tissue), resulting in the formation of cross-links with polypeptides containing lysyl groups. Enzymatic activity toward the Q(n) domains increases greatly upon lengthening of such Q(n) stretches (n > 40). Among the possible amine donors, the glycolytic enzyme glyceraldehyde-3-phosphate-dehydrogenase was shown to tightly bind several proteins involved in polyglutamine expansion diseases. Recently, the authors have shown that K191, K268, and K331, out of the 26 lysines present in glyceraldehyde-3-phosphate-dehydrogenase, are the reactive amine-donor sites forming cross-links with substance P, which bears the simplest Q(n) domain (n = 2). The present study reports that synthetic peptides of both pathological and nonpathological length (n = 43 and 17, respectively) form cross-links with the same K residues located in the C-terminal region of glyceraldehyde-3-phosphate-dehydrogenase. In addition, it is shown that extra K residues present in the C termini of glyceraldehyde-3-phosphate-dehydrogenase are susceptible to cross-linking in the presence of transglutaminase. The present results indicate a possible modulating effect of Q(n) stretches on tissue transglutaminase substrate specificity and mechanism of recognition. 相似文献
124.
125.
Giacometti A Cirioni O Antonicelli L D'Amato G Silvestri C Del Prete MS Scalise G 《The Journal of parasitology》2003,89(3):490-492
The prevalence of intestinal protozoans and helminths in stool samples of individuals with allergic cutaneous symptoms was evaluated to study a possible link between parasites and allergy. Altogether, 218 patients who had chronic urticaria, atopic dermatitis, or pruritus of unknown origin were included in the study. Standard laboratory tests for the detection of allergic etiology were performed for all patients. The presence of intestinal parasites was investigated using microscopy, immunofluorescence, and immunoenzymatic assays. Overall, protozoans and helminths were recovered from the stools of 48 subjects (P = 0.004), 18 of whom were affected with intestinal symptoms (P = 0.023). The presence of Giardia lamblia in the stools was significantly associated with allergic cutaneous manifestations (P = 0.030). In addition, patients with allergy were significantly more likely to have > or = 5 Blastocystis hominis organisms per field (P = 0.046). There was a set of patients with allergic cutaneous diseases in whom the presence of intestinal parasites may not be incidental. 相似文献
126.
Cicconi S Ventura N Pastore D Bonini P Di Nardo P Lauro R Marlier LN 《Journal of cellular physiology》2003,195(1):27-37
During ischemia/reperfusion (I/R), cardiomyocytes are exposed to sudden lack of nutrients and successively to radical oxygen species (ROS). In the present study, we used the HL-5 cardiac atrial myocyte cell line exposed to serum/glucose depletion added or not in H(2)O(2) to mimic ROS during ischemia, then replaced in their standard culture medium to simulate reperfusion. We investigated the effects of serum/glucose depletion combined or not to ROS exposure on AKT and MAP kinases activation to address the role of each event with respect to apoptosis. We demonstrate that serum/glucose depletion per se did not induce apoptosis when compared to ROS exposure. In particular, ROS recruited p38MAPK and JNK pathways. SB202190 preventing p38MAPK activity, partially protected HL-5 from apoptosis while blocking JNK, thanks to JNKI, further enhanced apoptosis. Blocking phosphatidylinositol (PI) 3-kinase with LY294002 or ERKs with U0126 was without consequence on apoptosis. Finally, BCL-2 and BCL-X(L/S) expression levels were analyzed in cells exposed to 1 h ischemia followed by 12-h reperfusion in the presence or not of SB202190; BCL-2, but not BCL-X(L/S), expression was decreased in ROS treated cells but SB202190 failed to restore BCL-2 level. Our data suggest that p38MAPK activation primarily mediates ROS-induced apoptosis while concomitant JNK activation would represent a scavenger pathway for cells trying to escape apoptosis. 相似文献
127.
Puntoni R Filiberti R Cerrano PG Neri M Andreatta R Bonassi S 《Mutation research》2003,544(2-3):385-396
The carcinogenic effect of asbestos has been reported in the literature since 40 years, and early studies describing the epidemic occurrence of malignant mesothelioma (MM) in asbestos workers, have become a paradigm of occupational cancer research. Research on MM was abandoned for many years since MM was considered as an asbestos-related disease, interesting only from a perspective of disease control and preventive policies. The introduction of new biological endpoints in the epidemiological studies has boosted research in the field, providing new tools for the study of emerging priority in cancer research and in public health. This approach, known as molecular epidemiology has a great potential in the study of MM, contributing to the understanding of susceptibility factors, to the evaluation of cancer risk in people occupationally or environmentally exposed to carcinogens, and to the enhancement of diagnosis and therapy. A comprehensive approach based on the use of banks of biological samples is presented and its advantages discussed here. The application of innovative endpoints, such as oncoproteins in biologic fluids, genetic polimorphisms, or gene function is discussed, and relevant literature reviewed. 相似文献
128.
Cytogenetic monitoring has been traditionally used for the surveillance of populations exposed to genotoxic agents. In recent years sensitivity problems emerged in surveys of populations exposed to low levels of mutagens, and therefore alternative approaches have been explored. Biomonitoring studies in children are a promising field, since because of evident differences in the uptake, metabolism, distribution and excretion of mutagens this population seems to be more susceptible than adults. Further, the effect of major confounders such as cigarettes smoking, occupation, life-style, and dietary factors plays a minor role. Among cytogenetic assays, the micronucleus assay (MN) has several advantages and is increasingly used. A review was then carried out to synthesize the published data on the occurrence of MN in children and adolescents (age range 0-18 years), and to assess the impact of genotoxic exposure on MN frequency. Overall, 20 papers from international literature and 8 Russian papers were included. An effect of age was found within this age range, while the influence of gender on MN frequency was irrelevant. These results were confirmed by the re-analysis of data for 448 children selected from the HUMN database. An effect of chronic and infectious diseases on MN levels has been reported by various authors. Most studies describing the effect of exposure to genotoxic agents (ionizing radiation, chemicals, drugs, environmental tobacco smoke) found an increase of MN in exposed children. The limited number of published papers indicates that the conduct of properly designed studies on the effect of environmental pollutants in children may be difficult. This review confirmed the usefulness of MN assay in biomonitoring studies conducted in children, revealing that in many circumstances investigating children increases the sensitivity of the study, even with low dose exposures. 相似文献
129.
Blanco AR La Terra Mulè S Babini G Garbisa S Enea V Rusciano D 《Biochimica et biophysica acta》2003,1620(1-3):273-281
The objective of this paper is to assess the gelatinase production by some ocular pathogenic bacterial strains, and evaluate the ability of (-)epigallocatechin-3-gallate (EGCg) to inhibit this gelatinase activity and thus limit bacterial invasion. The effect of EGCg on bacterial gelatinase activity was tested by classic zymography methods, while its effect on bacterial invasion was evaluated through the ability of growing bacteria to liquefy and thus penetrate a semisolid gelatine substrate. It was found that EGCg inhibits bacterial gelatinases with an IC(50) of about 0.2 mM, and limits invasion of gelatinase-positive bacteria at concentrations above 2 mM. These results show for the first time that EGCg, as well as having direct antibacterial activity, can also inhibit bacterial gelatinases, thus limiting their invasion on gelatine. Possible use of EGCg is thus suggested as an adjuvant in antibacterial chemotherapy. 相似文献
130.
Falini G Fermani S Ripamonti A Sabatino P Sparla F Pupillo P Trost P 《Biochemistry》2003,42(16):4631-4639
Photosynthetic glyceraldehyde-3-phosphate dehydrogenase (GAPDH) of Spinacia oleracea belongs to a wide group of GAPDHs found in most organisms displaying oxygenic photosynthesis, including cyanobacteria, green and red algae, and higher plants. As a major catalytic difference with respect to glycolytic GAPDH, photosynthetic GAPDH exhibits dual cofactor specificity toward pyridine nucleotides with a preference for NADP(H). Here we report the crystal structure of NAD-complexed recombinant A(4)-GAPDH (NAD-A(4)-GAPDH) from Spinacia oleracea, expressed in Escherichia coli. Its superimposition onto native A(4)-GAPDH complexed with NADP (NADP-A(4)-GAPDH) pinpoints specific conformational changes resulting from cofactor replacement. In photosynthetic NAD-A(4)-GAPDH, the side chain of Asp32 is oriented toward the coenzyme to interact with the adenine ribose diol, similar to glycolytic GAPDHs (NAD-specific). On the contrary, in NADP-A(4)-GAPDH Asp32 moves away to accommodate the additional 2'-phosphate group of the coenzyme and to minimize electrostatic repulsion. Asp32 rotation is allowed by the presence of the small residue Ala40, conserved in most photosynthetic GAPDHs, replacing bulky amino acid side chains in glycolytic GAPDHs. While in NADP-A(4)-GAPDH two amino acids, Thr33 and Ser188, are involved in hydrogen bonds with the 2'-phosphate group of NADP, in the NAD-complexed enzyme these interactions are lacking. The crystallographic structure of NAD-A(4)-GAPDH highlights that four residues, Thr33, Ala40, Ser188, and Ala187 (Leu, Leu, Pro, and Leu respectively, in glycolytic Bacillus stearothermophilus GAPDH sequence) are of primary importance for the dual cofactor specificity of photosynthetic GAPDH. These modifications seem to trace the minimum evolutionary route for a primitive NAD-specific GAPDH to be converted into the NADP-preferring enzyme of oxygenic photosynthetic organisms. 相似文献