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71.
72.
Ibogaine, a putative antiaddictive drug, is remarkable in its apparent ability to downgrade withdrawal symptoms and drug craving for extended periods of time after a single dose. Ibogaine acts as a non-competitive NMDA receptor antagonist, while NMDA has been implicated in long lasting changes in neuronal function and in the physiological basis of drug addiction. The purpose of this study was to verify if persistent changes in NMDA receptors could be shown in vivo and in vitro after a single administration of ibogaine. The time course of ibogaine effects were examined on NMDA-induced seizures and [3H] MK-801 binding to cortical membranes in mice 30min, 24, 48, and 72h post treatment. Ibogaine (80 mg/kg, ip) was effective in inhibiting convulsions induced by NMDA at 24 and 72 hours post administration. Likewise, [3H] MK-801 binding was significantly decreased at 24 and 72 h post ibogaine. No significant differences from controls were found at 30min or 48h post ibogaine. This long lasting and complex pattern of modulation of NMDA receptors prompted by a single dose of ibogaine may be associated to its antiaddictive properties. 相似文献
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74.
Felipe Leal Valentim Simon van Mourik David Posé Min C. Kim Markus Schmid Roeland C. H. J. van Ham Marco Busscher Gabino F. Sanchez-Perez Jaap Molenaar Gerco C. Angenent Richard G. H. Immink Aalt D. J. van Dijk 《PloS one》2015,10(2)
Various environmental signals integrate into a network of floral regulatory genes leading to the final decision on when to flower. Although a wealth of qualitative knowledge is available on how flowering time genes regulate each other, only a few studies incorporated this knowledge into predictive models. Such models are invaluable as they enable to investigate how various types of inputs are combined to give a quantitative readout. To investigate the effect of gene expression disturbances on flowering time, we developed a dynamic model for the regulation of flowering time in Arabidopsis thaliana. Model parameters were estimated based on expression time-courses for relevant genes, and a consistent set of flowering times for plants of various genetic backgrounds. Validation was performed by predicting changes in expression level in mutant backgrounds and comparing these predictions with independent expression data, and by comparison of predicted and experimental flowering times for several double mutants. Remarkably, the model predicts that a disturbance in a particular gene has not necessarily the largest impact on directly connected genes. For example, the model predicts that SUPPRESSOR OF OVEREXPRESSION OF CONSTANS (SOC1) mutation has a larger impact on APETALA1 (AP1), which is not directly regulated by SOC1, compared to its effect on LEAFY (LFY) which is under direct control of SOC1. This was confirmed by expression data. Another model prediction involves the importance of cooperativity in the regulation of APETALA1 (AP1) by LFY, a prediction supported by experimental evidence. Concluding, our model for flowering time gene regulation enables to address how different quantitative inputs are combined into one quantitative output, flowering time. 相似文献
75.
Mette Nyegaard Nanna D. Rendtorff Morten S. Nielsen Thomas J. Corydon Ditte Demontis Anna Starnawska Anne Hedemand Annalisa Buniello Francesco Niola Michael T. Overgaard Suzanne M. Leal Wasim Ahmad Friedrik P. Wikman Kirsten B. Petersen Dorthe G. Crüger Jaap Oostrik Hannie Kremer Niels Tommerup Morten Fr?din Karen P. Steel Lisbeth Tranebj?rg Anders D. B?rglum 《PLoS genetics》2015,11(7)
76.
Ana Artero-Castro Mileidys Perez-Alea Andrea Feliciano Jose A Leal Mónica Genestar Josep Castellvi Vicente Peg Santiago Ramón y Cajal Matilde E LLeonart 《Autophagy》2015,11(9):1499-1519
The human ribosomal P complex, which consists of the acidic ribosomal P proteins RPLP0, RPLP1, and RPLP2 (RPLP proteins), recruits translational factors, facilitating protein synthesis. Recently, we showed that overexpression of RPLP1 immortalizes primary cells and contributes to transformation. Moreover, RPLP proteins are overexpressed in human cancer, with the highest incidence in breast carcinomas. It is thought that disruption of the P complex would directly affect protein synthesis, causing cell growth arrest and eventually apoptosis. Here, we report a distinct mechanism by which cancer cells undergo cell cycle arrest and induced autophagy when RPLP proteins are downregulated. We found that absence of RPLP0, RPLP1, or RPLP2 resulted in reactive oxygen species (ROS) accumulation and MAPK1/ERK2 signaling pathway activation. Moreover, ROS generation led to endoplasmic reticulum (ER) stress that involved the EIF2AK3/PERK-EIF2S1/eIF2α-EIF2S2-EIF2S3-ATF4/ATF-4- and ATF6/ATF-6-dependent arms of the unfolded protein response (UPR). RPLP protein-deficient cells treated with autophagy inhibitors experienced apoptotic cell death as an alternative to autophagy. Strikingly, antioxidant treatment prevented UPR activation and autophagy while restoring the proliferative capacity of these cells. Our results indicate that ROS are a critical signal generated by disruption of the P complex that causes a cellular response that follows a sequential order: first ROS, then ER stress/UPR activation, and finally autophagy. Importantly, inhibition of the first step alone is able to restore the proliferative capacity of the cells, preventing UPR activation and autophagy. Overall, our results support a role for autophagy as a survival mechanism in response to stress due to RPLP protein deficiency. 相似文献
77.
María F. Garcés Elizabeth Sanchez Luisa F. Cardona Elkin L. Simanca Iván González Luis G. Leal José A. Mora Andrés Bedoya Juan P. Alzate ángel Y. Sánchez Javier H. Eslava-Schmalbach Roberto Franco-Vega Mario O. Parra Ariel I. Ruíz—Parra Carlos Diéguez Rubén Nogueiras Jorge E. Caminos 《PloS one》2015,10(6)
Background
Meteorin (METRN) is a recently described neutrophic factor with angiogenic properties. This is a nested case-control study in a longitudinal cohort study that describes the serum profile of METRN during different periods of gestation in healthy and preeclamptic pregnant women. Moreover, we explore the possible application of METRN as a biomarker.Methods and Findings
Serum METRN was measured by ELISA in a longitudinal prospective cohort study in 37 healthy pregnant women, 16 mild preeclamptic women, and 20 healthy non-pregnant women during the menstrual cycle with the aim of assessing serum METRN levels and its correlations with other metabolic parameters. Immunostaining for METRN protein was performed in placenta. A multivariate logistic regression model was proposed and a classifier model was formulated for predicting preeclampsia in early and middle pregnancy. The performance in classification was evaluated using measures such as sensitivity, specificity, and the receiver operating characteristic (ROC) curve. In healthy pregnant women, serum METRN levels were significantly elevated in early pregnancy compared to middle and late pregnancy. METRN levels are significantly lower only in early pregnancy in preeclamptic women when compared to healthy pregnant women. Decision trees that did not include METRN levels in the first trimester had a reduced sensitivity of 56% in the detection of preeclamptic women, compared to a sensitivity of 69% when METRN was included.Conclusions
The joint measurements of circulating METRN levels in the first trimester and systolic blood pressure and weight in the second trimester significantly increase the probabilities of predicting preeclampsia. 相似文献78.
M. Fernanda Lima-Costa James Macinko Juliana Vaz de Melo Mambrini Cibele C. Cesar Sérgio V. Peixoto Wagner C. S. Magalh?es Bernardo L. Horta Mauricio Barreto Erico Castro-Costa Josélia O. A. Firmo Fernando A. Proietti Thiago Peixoto Leal Maira R. Rodrigues Alexandre Pereira Eduardo Tarazona-Santos 《PloS one》2015,10(12)
Background
Self-rated health (SRH) has strong predictive value for mortality in different contexts and cultures, but there is inconsistent evidence on ethnoracial disparities in SRH in Latin America, possibly due to the complexity surrounding ethnoracial self-classification.Materials/Methods
We used 370,539 Single Nucleotide Polymorphisms (SNPs) to examine the association between individual genomic proportions of African, European and Native American ancestry, and ethnoracial self-classification, with baseline and 10-year SRH trajectories in 1,311 community dwelling older Brazilians. We also examined whether genomic ancestry and ethnoracial self-classification affect the predictive value of SRH for subsequent mortality.Results
European ancestry predominated among participants, followed by African and Native American (median = 84.0%, 9.6% and 5.3%, respectively); the prevalence of Non-White (Mixed and Black) was 39.8%. Persons at higher levels of African and Native American genomic ancestry, and those self-identified as Non-White, were more likely to report poor health than other groups, even after controlling for socioeconomic conditions and an array of self-reported and objective physical health measures. Increased risks for mortality associated with worse SRH trajectories were strong and remarkably similar (hazard ratio ~3) across all genomic ancestry and ethno-racial groups.Conclusions
Our results demonstrated for the first time that higher levels of African and Native American genomic ancestry—and the inverse for European ancestry—were strongly correlated with worse SRH in a Latin American admixed population. Both genomic ancestry and ethnoracial self-classification did not modify the strong association between baseline SRH or SRH trajectory, and subsequent mortality. 相似文献79.
Edmond Wonkam-Tingang Isabelle Schrauwen Kevin K Esoh Thashi Bharadwaj Liz M Nouel-Saied Anushree Acharya Abdul Nasir Suzanne M Leal Ambroise Wonkam 《Experimental biology and medicine (Maywood, N.J.)》2021,246(13):1524
Approximately half of congenital hearing impairment cases are inherited, with non-syndromic hearing impairment (NSHI) being the most frequent clinical entity of genetic hearing impairment cases. A family from Cameroon with NSHI was investigated by performing exome sequencing using DNA samples obtained from three family members, followed by direct Sanger sequencing in additional family members and controls participants. We identified an autosomal dominantly inherited novel missense variant [NM_001174116.2:c.918G>T; p.(Q306H)] in DMXL2 gene (MIM:612186) that co-segregates with mild to profound non-syndromic sensorineural hearing impairment . The p.(Q306H) variant which substitutes a highly conserved glutamine residue is predicted deleterious by various bioinformatics tools and is absent from several genome databases. This variant was also neither found in 121 apparently healthy controls without a family history of hearing impairment , nor 112 sporadic NSHI cases from Cameroon. There is one previous report of a large Han Chinese NSHI family that segregates a missense variant in DMXL2. The present study provides additional evidence that DMXL2 is involved in hearing impairment etiology, and we suggest DMXL2 should be considered in diagnostic hearing impairment panels. 相似文献
80.
Bibiana A. Bilbao Alejandra V. Leal Carlos L. Méndez 《Human ecology: an interdisciplinary journal》2010,38(5):663-673
In Canaima National Park (CNP), Venezuela, a protected area inhabited by the Pemón people, socio-cultural and demographic
changes have contributed to the apparent unsustainable use of fire, leading to forest and habitat loss. This over-use of fire,
together with increased forest vulnerability to fire as a result of global climate change, could put both ecosystems and human
well-being at risk. The conflict over fire use derives from the fact that whereas the Pemón depend for their livelihood on
the use of fire for shifting cultivation and hunting, the policy of the CNP government agencies is fire exclusion (although
this is not effectively enforced). Nevertheless, recent ecological studies have revealed that the creation of a mosaic of
patches with different fire histories could be used to create firebreaks that reduce the risk of the wildfires that threaten
the vulnerable and diverse savanna-forest transition areas. This technique imitates the traditional cooperative savanna burning
strategies of the Pemón. By linking research on knowledge systems with management policies, the impasse over fire in the CNP
might be avoided. 相似文献