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911.
Krzysztof Lacek Richard A. Urbanowicz Fulvia Troise Claudia De Lorenzo Valeria Severino Antimo Di Maro Alexander W. Tarr Francesca Ferrara Alexander Ploss Nigel Temperton Jonathan K. Ball Alfredo Nicosia Riccardo Cortese Antonello Pessi 《The Journal of biological chemistry》2014,289(50):35015-35028
The broadly neutralizing antibodies HIV 2F5 and 4E10, which bind to overlapping epitopes in the membrane-proximal external region of the fusion protein gp41, have been proposed to use a two-step mechanism for neutralization; first, they bind and preconcentrate at the viral membrane through their long, hydrophobic CDRH3 loops, and second, they form a high affinity complex with the protein epitope. Accordingly, mutagenesis of the CDRH3 can abolish their neutralizing activity, with no change in the affinity for the peptide epitope. We show here that we can mimic this mechanism by conjugating a cholesterol group outside of the paratope of an antibody. Cholesterol-conjugated antibodies bind to lipid raft domains on the membrane, and because of this enrichment, they show increased antiviral potency. In particular, we find that cholesterol conjugation (i) rescues the antiviral activity of CDRH3-mutated 2F5, (ii) increases the antiviral activity of WT 2F5, (iii) potentiates the non-membrane-binding HIV antibody D5 10–100-fold (depending on the virus strain), and (iv) increases synergy between 2F5 and D5. Conjugation can be made at several positions, including variable and constant domains. Cholesterol conjugation therefore appears to be a general strategy to boost the potency of antiviral antibodies, and, because membrane affinity is engineered outside of the antibody paratope, it can complement affinity maturation strategies. 相似文献
912.
913.
Malgorzata Kowalczyk Aleksander Owczarek Renata Suchanek Monika Paul-Samojedny Anna Fila-Danilow Paulina Borkowska Krzysztof Kucia Jan Kowalski 《Cell stress & chaperones》2014,19(2):205-215
HSP70 genes have been considered as promising schizophrenia candidate genes based on their protective role in the central nervous system under stress conditions. In this study, we analyzed the potential implication of HSPA1A +190G/C, HSPA1B +1267A/G, and HSPA1L +2437T/C polymorphisms in the susceptibility to paranoid schizophrenia in a homogenous Caucasian Polish population. In addition, we investigated the association of the polymorphisms with the clinical variables of the disease. Two hundred and three patients with paranoid schizophrenia and 243 healthy controls were enrolled in the study. Polymorphisms of HSPA1A, -1B, and -1L genes were genotyped using the PCR-RFLP technique. Analyses were conducted in entire groups and in subgroups that were stratified according to gender. There were significant differences in the genotype and allele frequencies of HSPA1A polymorphism between the patients and controls. The +190CC genotype and +190C allele were over-represented in the patients and significantly increased the risk for developing schizophrenia (OR = 3.45 and OR = 1.61, respectively). Interestingly, such a risk was higher for females with the +190CC genotype than for males with the +190CC genotype (OR = 5.78 vs. OR = 2.76). We also identified the CGT haplotype as a risk haplotype for schizophrenia and demonstrated the effects of HSPA1A and HSPA1B genotypes on the psychopathology and age of onset. Our study provided the first evidence that the HSPA1A polymorphism may potentially increase the risk of developing paranoid schizophrenia. Further independent analyses in different populations to evaluate the role of gender are needed to replicate these results. 相似文献
914.
915.
Krzysztof Kuchta Lukasz Knizewski Lucjan S. Wyrwicz Leszek Rychlewski Krzysztof Ginalski 《Nucleic acids research》2009,37(22):7701-7714
This article presents a comprehensive review of large and highly diverse superfamily of nucleotidyltransferase fold proteins by providing a global picture about their evolutionary history, sequence-structure diversity and fulfilled functional roles. Using top-of-the-line homology detection method combined with transitive searches and fold recognition, we revised the realm of these superfamily in numerous databases of catalogued protein families and structures, and identified 10 new families of nucleotidyltransferase fold. These families include hundreds of previously uncharacterized and various poorly annotated proteins such as Fukutin/LICD, NFAT, FAM46, Mab-21 and NRAP. Some of these proteins seem to play novel important roles, not observed before for this superfamily, such as regulation of gene expression or choline incorporation into cell membrane. Importantly, within newly detected families we identified 25 novel superfamily members in human genome. Among these newly assigned members are proteins known to be involved in congenital muscular dystrophy, neurological diseases and retinal pigmentosa what sheds some new light on the molecular background of these genetic disorders. Twelve of new human nucleotidyltransferase fold proteins belong to Mab-21 family known to be involved in organogenesis and development. The determination of specific biological functions of these newly detected proteins remains a challenging task. 相似文献
916.
Whole genome sequencing of a single Bos taurus animal for single nucleotide polymorphism discovery 总被引:1,自引:0,他引:1
Sebastian H Eck Anna Benet-Pagès Krzysztof Flisikowski Thomas Meitinger Ruedi Fries Tim M Strom 《Genome biology》2009,10(8):R82-8
Background
The majority of the 2 million bovine single nucleotide polymorphisms (SNPs) currently available in dbSNP have been identified in a single breed, Hereford cattle, during the bovine genome project. In an attempt to evaluate the variance of a second breed, we have produced a whole genome sequence at low coverage of a single Fleckvieh bull. 相似文献917.
Kowal K Moniuszko M Zukowski S Bodzenta-Lukaszyk A 《Folia histochemica et cytobiologica / Polish Academy of Sciences, Polish Histochemical and Cytochemical Society》2010,48(4):518-523
Urokinase plasminogen activator (uPA) and its inhibitor (PAI-1) are involved in tiisue remodeling and repair processes associated with acute and chronic inflammation. The aim of the study was to evaluate the effect of allergen challenge on concentration of uPA and PAI-1 in induced sputum of house dust mite allergic asthmatics (HDM-AAs). Thirty HDM-AAs and ten healthy persons (HCs)were recruited for the study. In 24 HDM-AAs bronchial challenge with Dermatophagoides pteronyssinus (Dp) and in 6 HDM-AAs sham challenege with saline were performed. In HDM-AAs sputum was induced 24 hours before (T0) and 24 hours (T24) after the challenge. Concentration of uPA and PAI-1 in induced sputum were determined using immunoenzymatic assays. At T0 in HDM-AAs mean sputum uPA (151 ± 96 pg/ml) and PAI-1 (4341 ± 1262 pg/ml) concentrations were higher than in HC (18.8 ± 6.7 pg/ml; p=0.0002 and 596 ± 180 pg/ml; p<0.0001; for uPA and PAI-1 respectively). After allergen challenge further increase in sputum uPA (187 ± 144 pg/ml; p=0.03) and PAI-1 (6252 ± 2323 pg/ml; p<0.0001) concentrations were observed. Moreover, in Dp challenged, but not in saline challenged HDM-AAs the mean uPA/PAI-1 ratio decreased significantly at T24. No significant increase in the studied parameters were found in sham challenged patients. In HDM-AAs allergen exposure leads to activation of the plasmin system in the airways. Greater increase of the PAI-1 concentration than uPA concentration after allergen challenge may promote airway remodeling and play an important role in the development of bronchial hyperreactivity. 相似文献
918.
Hugo R. Arias Avraham Rosenberg Katarzyna M. Targowska-Duda Krzysztof Jozwiak Stanley D. Glick 《生物化学与生物物理学报:生物膜》2010,1798(6):1153-5278
The interaction of 18-methoxycoronaridine (18-MC) with nicotinic acetylcholine receptors (AChRs) was compared with that for ibogaine and phencyclidine (PCP). The results established that 18-MC: (a) is more potent than ibogaine and PCP inhibiting (±)-epibatidine-induced AChR Ca2+ influx. The potency of 18-MC is increased after longer pre-incubation periods, which is in agreement with the enhancement of [3H]cytisine binding to resting but activatable Torpedo AChRs, (b) binds to a single site in the Torpedo AChR with high affinity and inhibits [3H]TCP binding to desensitized AChRs in a steric fashion, suggesting the existence of overlapping sites. This is supported by our docking results indicating that 18-MC interacts with a domain located between the serine (position 6′) and valine (position 13′) rings, and (c) inhibits [3H]TCP, [3H]ibogaine, and [3H]18-MC binding to desensitized AChRs with higher affinity compared to resting AChRs. This can be partially attributed to a slower dissociation rate from the desensitized AChR compared to that from the resting AChR. The enthalpic contribution is more important than the entropic contribution when 18-MC binds to the desensitized AChR compared to that for the resting AChR, and vice versa. Ibogaine analogs inhibit the AChR by interacting with a luminal domain that is shared with PCP, and by inducing desensitization. 相似文献
919.
Szymon Ziętkiewicz Magdalena J. Ślusarz Rafał Ślusarz Krzysztof Liberek Sylwia Rodziewicz‐Motowidło 《Biopolymers》2010,93(1):47-60
The Escherichia coli heat shock protein ClpB, a member of the Hsp100 family, plays a crucial role in cellular thermotolerance. In co‐operation with the Hsp70 chaperone system, it is able to solubilize proteins aggregated by heat shock conditions and refold them into the native state in an ATP‐dependent way. It was established that the mechanism of ClpB action depends on the formation of a ring‐shaped hexameric structure and the translocation of a protein substrate through an axial channel. The structural aspects of this process are not fully known. By means of homology modeling and protein–protein docking, we obtained a model of the hexameric arrangement of the full‐length ClpB protein complexed with ATP. A molecular dynamics simulation of this model was performed to assess its flexibility and conformational stability. The high mobility of the “linker” M‐domain, essential for the renaturing activity of ClpB, was demonstrated, and the size and shape of central channel were analyzed. In this model, we propose the coordinates for a loop between b4 and B6 structural elements, not defined in previous structural research, which faces the inside of the channel and may therefore play a role in substrate translocation. © 2009 Wiley Periodicals, Inc. Biopolymers 93: 47–60, 2010. This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com 相似文献
920.
Wioleta Dudzinska Anna Lubkowska Barbara Dolegowska Krzysztof Safranow 《Journal of physiology and biochemistry》2010,66(3):189-196
During prolonged maximal exercise, oxygen deficits occur in working muscles. Progressive hypoxia results in the impairment
of the oxidative resynthesis of ATP and increased degradation of purine nucleotides. Moreover, ATP consumption decreases the
conversion of UDP to UTP, to use ATP as a phosphate donor, resulting in an increased concentration of UDP, which enhances
pyrimidine degradation. Because the metabolism of pyrimidine nucleotides is related to the metabolism of purines, in particular
with the cellular concentration of ATP, we decided to investigate the impact of a standardized exercise with increasing intensity
on the concentration of uridine, inosine, hypoxanthine, and uric acid. Twenty-two healthy male subjects volunteered to participate
in this study. Blood concentrations of metabolites were determined at rest, immediately after exercise, and after 30 min of
recovery using high-performance liquid chromatography. We also studied the relationship between the levels of uridine and
indicators of myogenic purine degradation. The results showed that exercise with increasing intensity leads to increased concentrations
of inosine, hypoxanthine, uric acid, and uridine. We found positive correlations between blood uridine levels and indicators
of myogenic purine degradation (hypoxanthine), suggesting that the blood uridine level is related to purine metabolism in
skeletal muscles. 相似文献