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991.
L Carnevali F Mastorci E Audero G Graiani S Rossi E Macchi S Callegari A Bartolomucci E Nalivaiko F Quaini C Gross A Sgoifo 《PloS one》2012,7(7):e41184
In humans, chronic stressors have long been linked to cardiac morbidity. Altered serotonergic neurotransmission may represent a crucial pathophysiological mechanism mediating stress-induced cardiac disturbances. Here, we evaluated the physiological role of serotonin (5-HT) 1A receptors in the autonomic regulation of cardiac function under acute and chronic stress conditions, using 5-HT(1A) receptor knockout mice (KOs). When exposed to acute stressors, KO mice displayed a higher tachycardic stress response and a larger reduction of vagal modulation of heart rate than wild type counterparts (WTs). During a protocol of chronic psychosocial stress, 6 out of 22 (27%) KOs died from cardiac arrest. Close to death, they displayed a severe bradycardia, a lengthening of cardiac interval (P wave, PQ and QRS) duration, a notched QRS complex and a profound hypothermia. In the same period, the remaining knockouts exhibited higher values of heart rate than WTs during both light and dark phases of the diurnal rhythm. At sacrifice, KO mice showed a larger expression of cardiac muscarinic receptors (M2), whereas they did not differ for gross cardiac anatomy and the amount of myocardial fibrosis compared to WTs. This study demonstrates that chronic genetic loss of 5-HT(1A) receptors is detrimental for cardiovascular health, by intensifying acute, stress-induced heart rate rises and increasing the susceptibility to sudden cardiac death in mice undergoing chronic stress. 相似文献
992.
Helena Svensson Veronica Olofsson Samuel Lundin Chakradhar Yakkala Stellan Bj?rck Lars B?rjesson Bengt Gustavsson Marianne Quiding-J?rbrink 《PloS one》2012,7(2)
Background
Colorectal cancer usually gives rise to a specific anti-tumor immune response, but for unknown reasons the resulting immunity is not able to clear the tumor. Recruitment of activated effector lymphocytes to the tumor is important for efficient anti-tumor responses, while the presence of regulatory T cells (Treg) down-modulate tumor-specific immunity. We therefore aimed to determine homing mechanisms and activation stage of Treg and effector T cell infiltrating colon tumors compared to cells from the unaffected mucosa in patients suffering from colon adenocarcinoma.Methodology/Principal Findings
Lymphocytes were isolated from unaffected and tumor mucosa from patients with colon adenocarcinoma, and flow cytometry, immunohistochemistry, and quantitative PCR was used to investigate the homing mechanisms and activation stage of infiltrating Treg and conventional lymphocytes. We detected significantly higher frequencies of CD25highFOXP3+CD127low putative Treg in tumors than unaffected mucosa, which had a complete demethylation in the FOXP3 promotor. Tumor-associated Treg had a high expression of CTLA-4, and some appeared to be antigen experienced effector/memory cells based on their expression of αEβ7 (CD103). There were also significantly fewer activated T cells and more CTLA-4+ conventional T cells susceptible to immune regulation in the tumor-associated mucosa. In contrast, CD8+granzyme B+ putative cytotoxic cells were efficiently recruited to the tumors. The frequencies of cells expressing α4β7 and the Th1 associated chemokine receptor CXCR3 were significantly decreased among CD4+ T cells in the tumor, while frequencies of CD4+CCR4+ lymphocytes were significantly increased.Conclusions/Significance
This study shows that CCR4+CTLA4hi Treg accumulate in colon tumors, while the frequencies of activated conventional Th1 type T cells are decreased. The altered lymphocyte composition in colon tumors will probably diminish the ability of the immune system to effectively attack tumor cells, and reducing the Treg activity is an important challenge for future immunotherapy protocols. 相似文献993.
Veronica De Micco Giovanna Battipaglia Willi A. Brand Petra Linke Matthias Saurer Giovanna Aronne Paolo Cherubini 《Trees - Structure and Function》2012,26(2):513-524
Intra-annual density fluctuations (IADFs) are anomalies of tree rings where wood density is abruptly altered after sudden
changes in environmental conditions. Their characterisation can provide information about the relationship between environmental
factors and eco-physiological processes during tree growth. This paper reports about the variability of anatomical traits
and stable carbon isotopic composition along tree rings as resulting from the application of two different methodological
approaches: (a) the separation of each ring into different regions (earlywood, latewood and IADF) and the comparison of anatomical
and isotopic parameters measured in those specific sectors and (b) the analysis of such features in continuum along ring width. Moreover, different parameters of vessels (i.e. ecd—equivalent circle diameter, elongation, sphericity
and convexity of vessel lumen) were considered to identify those more appropriate for the representation of intra-annual anatomical
variations. The analysis was conducted on Arbutus unedo L. growing on the Elba Island (Italy); tree rings of this species form IADFs with features clearly responsive to the environmental
conditions experienced during plant growth. Results showed that the first approach, although more suitable to obtain data
for subsequent statistical comparisons and for the calculation of correlations with environmental parameters, suffers from
elements of subjectivity due to the size and position of the selected tree-ring regions. The in continuum method allows a clearer identification of the variation of tree-ring properties along ring width. Regarding anatomical parameters,
shape indexes were not suitable indicators of intra-annual variability. The overall analysis suggested that using both methodologies
in synergy helps to gain complete information and avoid misleading interpretations of IADFs in tree rings. 相似文献
994.
Nyström V Humphrey J Skoglund P McKeown NJ Vartanyan S Shaw PW Lidén K Jakobsson M Barnes I Angerbjörn A Lister A Dalén L 《Molecular ecology》2012,21(14):3391-3402
The last glaciation was a dynamic period with strong impact on the demography of many species and populations. In recent years, mitochondrial DNA sequences retrieved from radiocarbon-dated remains have provided novel insights into the history of Late Pleistocene populations. However, genotyping of loci from the nuclear genome may provide enhanced resolution of population-level changes. Here, we use four autosomal microsatellite DNA markers to investigate the demographic history of woolly mammoths (Mammuthus primigenius) in north-eastern Siberia from before 60 000 years ago up until the species' final disappearance c.4000 years ago. We identified two genetic groups, implying a marked temporal genetic differentiation between samples with radiocarbon ages older than 12 thousand radiocarbon years before present (ka) and those younger than 9ka. Simulation-based analysis indicates that this dramatic change in genetic composition, which included a decrease in individual heterozygosity of approximately 30%, was due to a multifold reduction in effective population size. A corresponding reduction in genetic variation was also detected in the mitochondrial DNA, where about 65% of the diversity was lost. We observed no further loss in genetic variation during the Holocene, which suggests a rapid final extinction event. 相似文献
995.
F-spondin, an extracellular matrix protein, is an important player in embryonic morphogenesis and CNS development, but its presence and role later in life remains largely unknown. We generated a transgenic zebrafish in which GFP is expressed under the control of the F-spondin (spon1b) promoter, and used it in combination with complementary techniques to undertake a detailed characterization of the expression patterns of F-spondin in developing and adult brain and periphery. We found that F-spondin is often associated with structures forming long neuronal tracts, including retinal ganglion cells, the olfactory bulb, the habenula, and the nucleus of the medial longitudinal fasciculus (nMLF). F-spondin expression coincides with zones of adult neurogenesis and is abundant in CSF-contacting secretory neurons, especially those in the hypothalamus. Use of this new transgenic model also revealed F-spondin expression patterns in the peripheral CNS, notably in enteric neurons, and in peripheral tissues involved in active patterning or proliferation in adults, including the endoskeleton of zebrafish fins and the continuously regenerating pharyngeal teeth. Moreover, patterning of the regenerating caudal fin following fin amputation in adult zebrafish was associated with F-spondin expression in the blastema, a proliferative region critical for tissue reconstitution. Together, these findings suggest major roles for F-spondin in the CNS and periphery of the developing and adult vertebrate. 相似文献
996.
997.
SE Green M Bosch JE McKenzie DA O'Connor EJ Tavender P Bragge M Chau V Pitt JV Rosenfeld RL Gruen 《Implementation science : IS》2012,7(1):74
ABSTRACT: The Neurotrauma Evidence Translation (NET) program was funded in 2009 to increase the uptake of research evidence in the clinical care of patients who have sustained traumatic brain injury. This paper reports the rationale and plan for this five-year knowledge translation research program. The overarching aims of the program are threefold: to improve outcomes for people with traumatic brain injury; to create a network of neurotrauma clinicians and researchers with expertise in knowledge translation and evidence-based practice; and to contribute knowledge to the field of knowledge translation research. The program comprises a series of interlinked projects spanning varying clinical environments and disciplines relevant to neurotrauma, anchored within four themes representing core knowledge translation activities: reviewing research evidence; understanding practice; developing and testing interventions for practice change; and building capacity for knowledge translation in neurotrauma. The program uses a range of different methods and study designs, including: an evidence fellowship program; conduct of and training in systematic reviews; mixed method study designs to describe and understand factors that influence current practices (e.g., semistructured interviews and surveys); theory-based methods to develop targeted interventions aiming to change practice; a cluster randomised trial to test the effectiveness of a targeted theory-informed intervention; stakeholder involvement activities; and knowledge translation events such as consensus conferences. 相似文献
998.
Molecular Ecology Resources Primer Development Consortium Abreu AG Albaina A Alpermann TJ Apkenas VE Bankhead-Dronnet S Bergek S Berumen ML Cho CH Clobert J Coulon A DE Feraudy D Estonba A Hankeln T Hochkirch A Hsu TW Huang TJ Irigoien X Iriondo M Kay KM Kinitz T Kothera L LE Hénanff M Lieutier F Lourdais O Macrini CM Manzano C Martin C Morris VR Nanninga G Pardo MA Plieske J Pointeau S Prestegaard T Quack M Richard M Savage HM Schwarcz KD Shade J Simms EL Solferini VN Stevens VM Veith M Wen MJ 《Molecular ecology resources》2012,12(2):374-376
This article documents the addition of 139 microsatellite marker loci and 90 pairs of single‐nucleotide polymorphism sequencing primers to the Molecular Ecology Resources Database. Loci were developed for the following species: Aglaoctenus lagotis, Costus pulverulentus, Costus scaber, Culex pipiens, Dascyllus marginatus, Lupinus nanus Benth, Phloeomyzus passerini, Podarcis muralis, Rhododendron rubropilosum Hayata var. taiwanalpinum and Zoarces viviparus. These loci were cross‐tested on the following species: Culex quinquefasciatus, Rhododendron pseudochrysanthum Hay. ssp. morii (Hay.) Yamazaki and R. pseudochrysanthum Hayata. This article also documents the addition of 48 sequencing primer pairs and 90 allele‐specific primers for Engraulis encrasicolus. 相似文献
999.
1000.
David Bruhn Dora B. Madhura Marcus Maddox Robin B. Lee Ashit Trivedi Lei Yang Michael S. Scherman Janet C. Gilliland Veronica Gruppo Michael R. McNeil Anne J. Lenaerts Bernd Meibohm Richard E. Lee 《Bioorganic & medicinal chemistry》2012,20(20):6063-6072
A series of tetracyclic nitrofuran isoxazoline anti-tuberculosis agents was designed and synthesized to improve the pharmacokinetic properties of an initial lead compound, which had potent anti-tuberculosis activity but suffered from poor solubility, high protein binding and rapid metabolism. In this study, structural modifications were carried on the outer phenyl and piperidine rings to introduce solubilizing and metabolically blocking functional groups. The compounds generated were evaluated for their in vitro antitubercular activity, bacterial spectrum of activity, solubility, permeability, microsomal stability and protein binding. Pharmacokinetic profiles for the most promising candidates were then determined. Compounds with phenyl morpholine and pyridyl morpholine outer rings were found to be the most potent anti-tuberculosis agents in the series. These compounds retained a narrow antibacterial spectrum of activity, with weak anti-Gram positive and no Gram negative activity, as well as good activity against non-replicating Mycobacterium tuberculosis in a low oxygen model. Overall, the addition of solubilizing and metabolically blocked outer rings did improve solubility and decrease protein binding as designed. However, the metabolic stability for compounds in this series was generally lower than desired. The best three compounds selected for in vivo pharmacokinetic testing all showed high oral bioavailability, with one notable compound showing a significantly longer half-life and good tolerability supporting its further advancement. 相似文献