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排序方式: 共有542条查询结果,搜索用时 15 毫秒
1.
Transthyretin (TTR) protects against A-Beta toxicity by binding the peptide thus inhibiting its aggregation. Previous work showed different TTR mutations interact differently with A-Beta, with increasing affinities correlating with decreasing amyloidogenecity of the TTR mutant; this did not impact on the levels of inhibition of A-Beta aggregation, as assessed by transmission electron microscopy. Our work aimed at probing differences in binding to A-Beta by WT, T119M and L55P TTR using quantitative assays, and at identifying factors affecting this interaction. We addressed the impact of such factors in TTR ability to degrade A-Beta. Using a dot blot approach with the anti-oligomeric antibody A11, we showed that A-Beta formed oligomers transiently, indicating aggregation and fibril formation, whereas in the presence of WT and T119M TTR the oligomers persisted longer, indicative that these variants avoided further aggregation into fibrils. In contrast, L55PTTR was not able to inhibit oligomerization or to prevent evolution to aggregates and fibrils. Furthermore, apoptosis assessment showed WT and T119M TTR were able to protect against A-Beta toxicity. Because the amyloidogenic potential of TTR is inversely correlated with its stability, the use of drugs able to stabilize TTR tetrameric fold could result in increased TTR/A-Beta binding. Here we showed that iododiflunisal, 3-dinitrophenol, resveratrol, [2-(3,5-dichlorophenyl)amino] (DCPA) and [4-(3,5-difluorophenyl)] (DFPB) were able to increase TTR binding to A-Beta; however only DCPA and DFPB improved TTR proteolytic activity. Thyroxine, a TTR ligand, did not influence TTR/A-Beta interaction and A-Beta degradation by TTR, whereas RBP, another TTR ligand, not only obstructed the interaction but also inhibited TTR proteolytic activity. Our results showed differences between WT and T119M TTR, and L55PTTR mutant regarding their interaction with A-Beta and prompt the stability of TTR as a key factor in this interaction, which may be relevant in AD pathogenesis and for the design of therapeutic TTR-based therapies. 相似文献
2.
Natalia Cadaxo Rochael Luize Gon?alves Lima Sandra Maria Pereira de Oliveira Marcello André Barcinski Elvira Maria Saraiva Robson Queiroz Monteiro Lucia Helena Pinto-da-Silva 《Memórias do Instituto Oswaldo Cruz》2013,108(6):679-685
Leishmania parasites expose phosphatidylserine (PS) on their
surface, a process that has been associated with regulation of host''s immune
responses. In this study we demonstrate that PS exposure by metacyclic
promastigotes of Leishmania amazonensis favours blood
coagulation. L. amazonensis accelerates in vitro coagulation of
human plasma. In addition, L. amazonensis supports the assembly
of the prothrombinase complex, thus promoting thrombin formation. This process
was reversed by annexin V which blocks PS binding sites. During blood meal,
Lutzomyia longipalpis sandfly inject saliva in the bite
site, which has a series of pharmacologically active compounds that inhibit
blood coagulation. Since saliva and parasites are co-injected in the host during
natural transmission, we evaluated the anticoagulant properties of sandfly
saliva in counteracting the procoagulant activity of L.
amazonensis . Lu. longipalpis saliva reverses
plasma clotting promoted by promastigotes. It also inhibits thrombin formation
by the prothrombinase complex assembled either in phosphatidylcholine (PC)/PS
vesicles or in L. amazonensis . Sandfly saliva inhibits factor
X activation by the intrinsic tenase complex assembled on PC/PS vesicles and
blocks factor Xa catalytic activity. Altogether our results show that metacyclic
promastigotes of L. amazonensis are procoagulant due to PS
exposure. Notably, this effect is efficiently counteracted by sandfly
saliva. 相似文献
3.
The effects of implementing Directive 91/271/EEC of 21 May 1991 (Waste Water Treatment Plan Directive) and Directive 91/676/EEC
of 12 December (Nitrates Directive) are analysed in 7 Portuguese estuaries (Minho, Lima, Douro, Mondego, Tagus, Sado and Guadiana)
and two coastal lagoons (Ria de Aveiro and Ria Formosa), with a modelling approach. MOHID Water Modelling System was used
to perform simulations with three nitrogen load scenarios for each system: a reference scenario, a 50% nitrate removal by
agriculture scenario and another with a 100% nutrients removal by waste water treatment plants (WWTP). It is shown that the
interaction between hydrodynamic and ecological processes is an important feature to study trophic problems in estuaries.
Ecological processes such as primary production only occur inside the system if the residence time of water is high enough
to enable organismal activity and if the adequate conditions are found (e.g. light, nutrients, temperature). From the model
results it is possible to conclude: (i) in systems with short residence time a reduction in nutrient load will only produce
a decrease in nutrient transit and will not affect the system’s global ecological status (e.g. Douro Estuary); (ii) in systems
with long residence time the effects will range from significant, when primary production is mostly limited by nutrients (e.g.
Ria de Aveiro), to non-significant, when primary production in the system is light-limited (e.g. Tagus Estuary). 相似文献
4.
Marina Burgos-Silva Patricia Semedo-Kuriki Cassiano Donizetti-Oliveira Priscilla Barbosa Costa Marco Antonio Cenedeze Meire Ioshie Hiyane Alvaro Pacheco-Silva Niels Olsen Saraiva Camara 《PloS one》2015,10(11)
Acute and chronic kidney injuries (AKI and CKI) constitute syndromes responsible for a large part of renal failures, and are today still associated with high mortality rates. Given the lack of more effective therapies, there has been intense focus on the use stem cells for organ protective and regenerative effects. Mesenchymal stem cells (MSCs) have shown great potential in the treatment of various diseases of immune character, although there is still debate on its mechanism of action. Thus, for a greater understanding of the role of MSCs, we evaluated the effect of adipose tissue-derived stem cells (AdSCs) in an experimental model of nephrotoxicity induced by folic acid (FA) in FVB mice. AdSC-treated animals displayed kidney functional improvement 24h after therapy, represented by reduced serum urea after FA. These data correlated with cell cycle regulation and immune response modulation via reduced chemokine expression and reduced neutrophil infiltrate. Long-term analyses, 4 weeks after FA, indicated that AdSC treatment reduced kidney fibrosis and chronic inflammation. These were demonstrated by reduced interstitial collagen deposition and tissue chemokine and cytokine expression. Thus, we concluded that AdSC treatment played a protective role in the framework of nephrotoxic injury via modulation of inflammation and cell cycle regulation, resulting in reduced kidney damage and functional improvement, inhibiting organ fibrosis and providing long-term immune regulation. 相似文献
5.
6.
Timmers LF Ducati RG Sánchez-Quitian ZA Basso LA Santos DS de Azevedo WF 《Journal of molecular modeling》2012,18(2):467-479
Cytidine Deaminase (CD) is an evolutionarily conserved enzyme that participates in the pyrimidine salvage pathway recycling cytidine and deoxycytidine
into uridine and deoxyuridine, respectively. Here, our goal is to apply computational techniques in the pursuit of potential
inhibitors of Mycobacterium tuberculosis CD (MtCDA) enzyme activity. Molecular docking simulation was applied to find the possible hit compounds. Molecular dynamics simulations
were also carried out to investigate the physically relevant motions involved in the protein-ligand recognition process, aiming
at providing estimates for free energy of binding. The proposed approach was capable of identifying a potential inhibitor,
which was experimentally confirmed by IC50 evaluation. Our findings open up the possibility to extend this protocol to different databases in order to find new potential
inhibitors for promising targets based on a rational drug design process. 相似文献
7.
H Furuya M J Saraiva M A Gawinowicz I L Alves P P Costa H Sasaki I Goto Y Sakaki 《Biochemistry》1991,30(9):2415-2421
Transthyretin (TTR) is a plasma protein interacting with thyroxine T4 and retinol binding protein (RBP). Several variants of TTR with single amino acid substitutions have been identified as the major components of the amyloid fibrils of familial amyloidotic polyneuropathy (FAP), a fetal, autosomal dominant genetic disease. The elucidation of the molecular nature of the variants distinct from that of the wild-type TTR is crucial for understanding the amyloidogenesis in FAP, but our understanding is very poor mainly because of the unavailability of pure variant TTRs. In the present study, we used an Escherichia coli OmpA secretion vector (Ghrayeb et al., 1984) and achieved an effective production of the variant TTRs related to FAP including Met-30, Ile-33, Ala-60, Tyr-77, Met-111, and Ile-122 types. The variant TTRs produced in this system were efficiently secreted to the culture media. The chemical analysis showed that the secreted TTR (Met-30 type) has the same N-terminus as the native one. IEF analyses also indicated that the secreted product is properly processed as assessed by its pI. Furthermore, the secreted TTR was shown to have biological activities, namely, the thyroxin binding activity and the ability to associate with retinol binding protein, indicating that the secreted TTR polypeptide is properly folded. The present work also demonstrated that the processing/secretion of the recombinant TTR molecules in E. coli was strongly affected by single amino acid substitutions. 相似文献
8.
Mafalda C. O. Figueiredo Susana A. L. Lobo Sara H. Sousa Fábio P. Pereira Judy D. Wall Lígia S. Nobre Lígia M. Saraiva 《Journal of bacteriology》2013,195(11):2684-2690
Desulfovibrio species are Gram-negative anaerobic sulfate-reducing bacteria that colonize the human gut. Recently, Desulfovibrio spp. have been implicated in gastrointestinal diseases and shown to stimulate the epithelial immune response, leading to increased production of inflammatory cytokines by macrophages. Activated macrophages are key cells of the immune system that impose nitrosative stress during phagocytosis. Hence, we have analyzed the in vitro and in vivo responses of Desulfovibrio vulgaris Hildenborough to nitric oxide (NO) and the role of the hybrid cluster proteins (HCP1 and HCP2) and rubredoxin oxygen oxidoreductases (ROO1 and ROO2) in NO protection. Among the four genes, hcp2 was the gene most highly induced by NO, and the hcp2 transposon mutant exhibited the lowest viability under conditions of NO stress. Studies in murine macrophages revealed that D. vulgaris survives incubation with these phagocytes and triggers NO production at levels similar to those stimulated by the cytokine gamma interferon (IFN-γ). Furthermore, D. vulgaris
hcp and roo mutants exhibited reduced viability when incubated with macrophages, revealing that these gene products contribute to the survival of D. vulgaris during macrophage infection. 相似文献
9.
Valéria Martins Godinho Maria Theresa Rafaela de Paula Débora Amorim Saraiva Silva Karla Paresque Aline Paternostro Martins Pio Colepicolo Carlos Augusto Rosa Luiz Henrique Rosa 《Fungal biology》2019,123(7):507-516
In the present study, we surveyed the distribution and diversity of fungal assemblages associated with 10 species of marine animals from Antarctica. The collections yielded 83 taxa from 27 distinct genera, which were identified using molecular biology methods. The most abundant taxa were Cladosporium sp. 1, Debaryomyces hansenii, Glaciozyma martinii, Metschnikowia australis, Pseudogymnoascus destructans, Thelebolus cf. globosus, Pseudogymnoascus pannorum, Tolypocladium tundrense, Metschnikowia australis, and different Penicillium species. The diversity, richness, and dominance of fungal assemblages ranged among the host; however, in general, the fungal community, which was composed of endemic and cold-adapted cosmopolitan taxa distributed across the different sites of Antarctic Peninsula, displayed high diversity, richness, and dominance indices. Our results contribute to knowledge about fungal diversity in the marine environment across the Antarctic Peninsula and their phylogenetic relationships with species that occur in other cold, temperate, and tropical regions of the World. Additionally, despite their extreme habitats, marine Antarctic animals shelter cryptic and complex fungal assemblages represented by endemic and cosmopolitan cold-adapted taxa, which may represent interesting models to study different symbiotic associations between fungi and their animal hosts in the extreme conditions of Antarctica. 相似文献
10.
Patrícia T. Borges Célia V. Romão Lígia M. Saraiva Vera L. Gonçalves Maria A. Carrondo Miguel Teixeira Carlos Frazão 《Journal of structural biology》2019,205(1):91-102
Flavodiiron proteins (FDPs) play key roles in biological response mechanisms against oxygen and/or nitric oxide; in particular they are present in oxygenic phototrophs (including cyanobacteria and gymnosperms). Two conserved domains define the core of this family of proteins: a N-terminal metallo-β-lactamase-like domain followed by a C-terminal flavodoxin-like one, containing the catalytic diiron centre and a FMN cofactor, respectively. Members of the FDP family may present extra modules in the C-terminus, and were classified into several classes according to their distribution and composition. The cyanobacterium Synechocystis sp. PCC6803 contains four Class C FDPs (Flv1-4) that include at the C-terminus an additional NAD(P)H:flavin oxidoreductase (FlR) domain. Two of them (Flv3 and Flv4) have the canonical diiron ligands (Class C, Type 1), while the other two (Flv1 and Flv2) present different residues in that region (Class C, Type 2). Most phototrophs, either Bacterial or Eukaryal, contain at least two FDP genes, each encoding for one of those two types. Crystals of the Flv1 two core domains (Flv1-ΔFlR), without the C-terminal NAD(P)H:flavin oxidoreductase extension, were obtained and the structure was determined. Its pseudo diiron site contains non-canonical basic and neutral residues, and showed anion moieties, instead. The presented structure revealed for the first time the structure of the two-domain core of a Class C-Type 2 FDP. 相似文献