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81.
Itzik Cooper Keren Sasson Vivian I. Teichberg Michal Schnaider-Beeri Mati Fridkin Yoram Shechter 《The Journal of biological chemistry》2012,287(53):44676-44683
Most chemotherapeutic agents are blood-brain barrier (BBB) impermeants. HIV-1-derived TAT protein variants contain a transmembrane domain, which may enable them to cross the BBB and reach the brain. Here we synthesized CAYGRKKRRQRRR, a peptide containing a cysteine moiety attached to the N terminus of the transmembrane domain (C-TAT peptide), and studied its effects in an in vitro BBB model, which we found to reflect penetration by a receptor-independent pathway. Incubation of the brain capillary endothelial cell monolayer with 0.3–0.6 μmol/ml of this C-TAT peptide, for a period of 1–2 h, destabilizes brain capillary endothelial cell monolayer and introduces the ability of impermeant therapeutic agents including high molecular weight proteins to penetrate it substantially. The cysteinyl moiety at position 1 of the C-TAT peptide contributes largely to the destabilizing potency and the penetration efficacy of impermeant substances. The destabilizing effect was reversed using heparin. In summary, experimental conditions allowing a significant increase in entry of impermeant low and high molecular weight substances from the luminal (blood) to the abluminal side (brain) were found in an in vitro BBB model reflecting in vivo protein penetrability by a receptor-independent pathway. 相似文献
82.
R Zamora N Azhar R Namas MR Metukuri T Clermont C Gladstone RA Namas L Hermus C Megas G Constantine TR Billiar MP Fink Y Vodovotz 《The Journal of biological chemistry》2012,287(37):31003-31014
Extracellular β-nicotinamide adenine dinucleotide (NAD(+)) is anti-inflammatory. We hypothesized that NAD(+) would modulate the anti-inflammatory cytokine Transforming Growth Factor (TGF)-β1. Indeed, NAD(+) led to increases in both active and latent cell-associated TGF-β1 in RAW 264.7 mouse macrophages as well as in primary peritoneal macrophages isolated from both C3H/HeJ (TLR4-mutant) and C3H/HeOuJ (wild-type controls for C3H/HeJ) mice. NAD(+) acts partially via cyclic ADP-ribose (cADPR) and subsequent release of Ca(2+). Treatment of macrophages with the cADPR analog 3-deaza-cADPR or Ca(2+) ionophores recapitulated the effects of NAD(+) on TGF-β1, whereas the cADPR antagonist 8-Br-cADPR, Ca(2+) chelation, and antagonism of L-type Ca(2+) channels suppressed these effects. The time and dose effects of NAD(+) on TGF-β1 were complex and could be modeled both statistically and mathematically. Model-predicted levels of TGF-β1 protein and mRNA were largely confirmed experimentally but also suggested the presence of other mechanisms of regulation of TGF-β1 by NAD(+). Thus, in vitro and in silico evidence points to NAD(+) as a novel modulator of TGF-β1. 相似文献
83.
Robert Smith Harald T. Johansen Hilde Nilsen Mads H. Haugen Solveig J. Pettersen Gunhild M. Mælandsmo Magnus Abrahamson Rigmor Solberg 《Biochimie》2012
Legumain, an asparaginyl endopeptidase, is up-regulated in tumour and tumour-associated cells, and is linked to the processing of cathepsin B, L, and proMMP-2. Although legumain is mainly localized to the endosomal/lysosomal compartments, legumain has been reported to be localized extracellularly in the tumour microenvironment and associated with extracellular matrix and cell surfaces. The most potent endogenous inhibitor of legumain is cystatin E/M, which is a secreted protein synthesised with an export signal. Therefore, we investigated the cellular interplay between legumain and cystatin E/M. As a cell model, HEK293 cells were transfected with legumain cDNA, cystatin E/M cDNA, or both, and over-expressing monoclonal cell lines were selected (termed M38L, M4C, and M3CL, respectively). Secretion of prolegumain from M38L cells was inhibited by treatment with brefeldin A, whereas bafilomycin A1 enhanced the secretion. Cellular processing of prolegumain to the 46 and 36 kDa enzymatically active forms was reduced by treatment with either substance alone. M38L cells showed increased, but M4C cells decreased, cathepsin L processing suggesting a crucial involvement of legumain activity. Furthermore, we observed internalization of cystatin E/M and subsequently decreased intracellular legumain activity. Also, prolegumain was shown to internalize followed by increased intracellular legumain processing and activation. In addition, in M4C cells incomplete processing of the internalized prolegumain was observed, as well as nuclear localized cystatin E/M. Furthermore, auto-activation of secreted prolegumain was inhibited by cystatin E/M, which for the first time shows a regulatory role of cystatin E/M in controlling both intra- and extracellular legumain activity. 相似文献
84.
Kari Bj?rneraas Ivar Herfindal Erling Johan Solberg Bernt-Erik S?ther Bram van Moorter Christer Moe Rolandsen 《Oecologia》2012,168(1):231-243
Identifying factors shaping variation in resource selection is central for our understanding of the behaviour and distribution
of animals. We examined summer habitat selection and space use by 108 Global Positioning System (GPS)-collared moose in Norway
in relation to sex, reproductive status, habitat quality, and availability. Moose selected habitat types based on a combination
of forage quality and availability of suitable habitat types. Selection of protective cover was strongest for reproducing
females, likely reflecting the need to protect young. Males showed strong selection for habitat types with high quality forage,
possibly due to higher energy requirements. Selection for preferred habitat types providing food and cover was a positive
function of their availability within home ranges (i.e. not proportional use) indicating functional response in habitat selection.
This relationship was not found for unproductive habitat types. Moreover, home ranges with high cover of unproductive habitat
types were larger, and smaller home ranges contained higher proportions of the most preferred habitat type. The distribution
of moose within the study area was partly related to the distribution of different habitat types. Our study shows how distribution
and availability of habitat types providing cover and high-quality food shape ungulate habitat selection and space use. 相似文献
85.
Samuni-Blank M Izhaki I Dearing MD Gerchman Y Trabelcy B Lotan A Karasov WH Arad Z 《Current biology : CB》2012,22(13):1218-1220
Plant secondary metabolites (SMs) acting as defensive chemicals in reproductive organs such as fruit tissues play roles in both mutualistic and antagonistic interactions between plants and seed dispersers/predators. The directed-deterrence hypothesis states that SMs in ripe fruits deter seed predators but have little or no effect on seed dispersers. Indeed, studies have demonstrated that birds are able to cope with fruit SMs whereas rodents are deterred by them. However, this mechanism was only demonstrated at the class level, i.e., between birds and mammals, based on differences in the vanilloid receptors. Here we present experimental and behavioral data demonstrating the use of the broad-range, class-independent "mustard oil bomb" mechanism in Ochradenus baccatus fruits to force a behavioral change at an ecological timescale, converting rodents from seed predators to seed dispersers. This is achieved by a unique compartmentalization of the mustard oil bomb, causing activation of the system only upon seed and pulp coconsumption, encouraging seed dispersal via seed spitting by rodents. Our findings demonstrate the power of SMs to shift the animal-plant relationship from predation to mutualism and provide support for the directed-deterrence hypothesis at the intraspecific level, in addition to the interspecific level. 相似文献
86.
87.
Raveau M Lignon JM Nalesso V Duchon A Groner Y Sharp AJ Dembele D Brault V Hérault Y 《PLoS genetics》2012,8(5):e1002724
Down syndrome (DS) leads to complex phenotypes and is the main genetic cause of birth defects and heart diseases. The Ts65Dn DS mouse model is trisomic for the distal part of mouse chromosome 16 and displays similar features with post-natal lethality and cardiovascular defects. In order to better understand these defects, we defined electrocardiogram (ECG) with a precordial set-up, and we found conduction defects and modifications in wave shape, amplitudes, and durations in Ts65Dn mice. By using a genetic approach consisting of crossing Ts65Dn mice with Ms5Yah mice monosomic for the App-Runx1 genetic interval, we showed that the Ts65Dn viability and ECG were improved by this reduction of gene copy number. Whole-genome expression studies confirmed gene dosage effect in Ts65Dn, Ms5Yah, and Ts65Dn/Ms5Yah hearts and showed an overall perturbation of pathways connected to post-natal lethality (Coq7, Dyrk1a, F5, Gabpa, Hmgn1, Pde10a, Morc3, Slc5a3, and Vwf) and heart function (Tfb1m, Adam19, Slc8a1/Ncx1, and Rcan1). In addition cardiac connexins (Cx40, Cx43) and sodium channel sub-units (Scn5a, Scn1b, Scn10a) were found down-regulated in Ts65Dn atria with additional down-regulation of Cx40 in Ts65Dn ventricles and were likely contributing to conduction defects. All these data pinpoint new cardiac phenotypes in the Ts65Dn, mimicking aspects of human DS features and pathways altered in the mouse model. In addition they highlight the role of the App-Runx1 interval, including Sod1 and Tiam1, in the induction of post-natal lethality and of the cardiac conduction defects in Ts65Dn. These results might lead to new therapeutic strategies to improve the care of DS people. 相似文献
88.
Nesher M Vachutinsky Y Fridkin G Schwarz Y Sasson K Fridkin M Shechter Y Lichtstein D 《Bioconjugate chemistry》2008,19(1):342-348
Natriuretic peptides (NP), including atrial natriuretic peptide (ANP), induce potent natriuresis and vasodilation and thereby generate hypotension in vivo. Despite intensive efforts, clinical application of NP as an antihypertensive agent is limited because of their short biological half-life and poor bioavailability. Recently, we have developed a strategy that facilitates slow release of peptides from PEG-peptide inactive conjugates, based on reversible pegylation. Peptides prepared by this approach undergo slow, spontaneous chemical hydrolysis at physiological conditions, releasing the native active peptide/protein drug from the inactive conjugates over prolonged periods. A PEG chain of 30 kDa was linked covalently to the alpha-amino side chain of the hormone via a MAL-Fmoc-NHS spacer, yielding PEG 30-Fmoc-ANP, a prodrug that releases the native hormone upon incubation at physiological conditions. Bolus administration of native ANP to Wistar rats receiving adrenaline yields a short, transitory effect in lowering blood pressure (BP), reaching a maximum at 2 min, and then returning to control values after 12 to 25 min. In contrast, administration of PEG 30-Fmoc-ANP lowered BP following a lag period of 50 min, and maintained low BP for a period exceeding 60 min. Saline or PEG 30-Fmoc-Alanine were not effective in lowering BP in Wistar rats. These results show that the novel compound, PEG 30-Fmoc-ANP, is a reversible pegylated prodrug derivative that facilitates a prolonged BP lowering effect in rats and may be considered as a candidate for development into an antihypertensive drug. 相似文献
89.
Christer M. Rolandsen Erling J. Solberg Morten Heim Frode Holmstrøm May I. Solem Bernt-Erik Sæther 《European Journal of Wildlife Research》2008,54(1):6-14
Optimal research and management of species with age structure often depends on estimates of age-specific population parameters,
which in turn depends on reliable methods for age determination. By counting annuli in the cementum of incisor root tips from
51 known-age moose (Alces alces) between 1 and 12 years old, we examined the variation in accuracy and repeatability of age estimates provided by three research
technicians with different experiences of aging moose. The most experienced technician estimated the moose age correctly in
up to 90% of the cases, while the technician with no prior experience estimated age correctly in up to 73% of the cases. The
medium-experienced technician achieved a lower accuracy (up to 53%), indicating that experience alone is not sufficient if
the basic training or lack of routine checks against other colleagues or a known-age material are not undertaken. The percentage
moose aged within ±1 year from correct age was significantly higher in all technicians (94–98%). After the generally high
accuracy, we also found high repeatability (0.980–0.994) within technicians. We conclude that this method of age-determination
provides reliable estimates that can be used by management and research to gain information about age-specific patterns in
moose populations. However, to obtain estimates of high accuracy the technicians should be well trained, have gained the necessary
experience, and most preferably, have access to a sample of teeth from known-age moose. 相似文献
90.
Nitric oxide (NO), derived from catalysis of inducible NO synthase (iNOS), limits malaria parasite growth in mammals. Transforming growth factor (TGF)-beta1 suppresses iNOS in cells in vitro as well as in vivo in mice, but paradoxically severe malaria in humans is associated with low levels of TGF-beta1. We hypothesized that this paradox is a universal feature of infection and occurs in the mosquito Anopheles stephensi, an invertebrate host for Plasmodium that also regulates parasite development with inducible NO synthase (AsNOS). We show that exogenous human TGF-beta1 dose-dependently regulates mosquito AsNOS expression and that parasite killing by low dose TGF-beta1 depends on AsNOS catalysis. Furthermore, induction of AsNOS expression by TGF-beta1 is regulated by NO synthesis. These results suggest that TGF-beta1 plays similar roles during parasite infection in mammals and mosquitoes and that this role is linked to the effects of TGF-beta1 on inducible NO synthesis. 相似文献