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71.
Lenore J. Launer Cora E. Lewis Pamela J. Schreiner Steve Sidney Harsha Battapady David R. Jacobs Kelvin O. Lim Mark D’Esposito Qian Zhang Jared Reis Christos Davatzikos R. Nick Bryan 《PloS one》2015,10(3)
Objective
To identify early changes in brain structure and function that are associated with cardiovascular risk factors (CVRF).Design
Cross-sectional brain Magnetic Resonance I (MRI) study.Setting
Community based cohort in three U.S. sites.Participants
A Caucasian and African-American sub-sample (n= 680; mean age 50.3 yrs) attending the 25 year follow-up exam of the Coronary Artery Risk Development in Young Adults Study.Primary and Secondary Outcomes
3T brain MR images processed for quantitative estimates of: total brain (TBV) and abnormal white matter (AWM) volume; white matter fractional anisotropy (WM-FA); and gray matter cerebral blood flow (GM-CBF). Total intracranial volume is TBV plus cerebral spinal fluid (TICV). A Global Cognitive Function (GCF) score was derived from tests of speed, memory and executive function.Results
Adjusting for TICV and demographic factors, current smoking was significantly associated with lower GM-CBF and TBV, and more AWM (all <0.05); SA with lower GM-CBF, WM-FA and TBV (p=0.01); increasing BMI with decreasing GM-CBF (p<0003); hypertension with lower GM-CBF, WM-FA, and TBV and higher AWM (all <0.05); and diabetes with lower TBV (p=0.007). The GCS was lower as TBV decreased, AWM increased, and WM-FA (all p<0.01).Conclusion
In middle age adults, CVRF are associated with brain health, reflected in MRI measures of structure and perfusion, and cognitive functioning. These findings suggest markers of mid-life cardiovascular and brain health should be considered as indication for early intervention and future risk of late-life cerebrovascular disease and dementia. 相似文献72.
Evidence of niche shift and global invasion potential of the Tawny Crazy ant,Nylanderia fulva 下载免费PDF全文
Sunil Kumar Edward G. LeBrun Thomas J. Stohlgren Jared A. Stabach Danny L. McDonald David H. Oi John S. LaPolla 《Ecology and evolution》2015,5(20):4628-4641
Analysis of an invasive species' niche shift between native and introduced ranges, along with potential distribution maps, can provide valuable information about its invasive potential. The tawny crazy ant, Nylanderia fulva, is a rapidly emerging and economically important invasive species in the southern United States. It is originally from east‐central South America and has also invaded Colombia and the Caribbean Islands. Our objectives were to generate a global potential distribution map for N. fulva, identify important climatic drivers associated with its current distribution, and test whether N. fulva's realized climatic niche has shifted across its invasive range. We used MaxEnt niche model to map the potential distribution of N. fulva using its native and invaded range occurrences and climatic variables. We used principal component analysis methods for investigating potential shifts in the realized climatic niche of N. fulva during invasion. We found strong evidence for a shift in the realized climatic niche of N. fulva across its invasive range. Our models predicted potentially suitable habitat for N. fulva in the United States and other parts of the world. Our analyses suggest that the majority of observed occurrences of N. fulva in the United States represent stabilizing populations. Mean diurnal range in temperature, degree days at ≥10°C, and precipitation of driest quarter were the most important variables associated with N. fulva distribution. The climatic niche expansion demonstrated in our study may suggest significant plasticity in the ability of N. fulva to survive in areas with diverse temperature ranges shown by its tolerance for environmental conditions in the southern United States, Caribbean Islands, and Colombia. The risk maps produced in this study can be useful in preventing N. fulva's future spread, and in managing and monitoring currently infested areas. 相似文献
73.
Aditya S. Khanna Sarah T. Roberts Susan Cassels Roger Ying Grace John-Stewart Steven M. Goodreau Jared M. Baeten Pamela M. Murnane Connie Celum Ruanne V. Barnabas 《PloS one》2015,10(8)
Introduction
Prevention of mother-to-child HIV transmission (PMTCT) strategies include combined short-course antiretrovirals during pregnancy (Option A), triple-drug antiretroviral treament (ART) during pregnancy and breastfeeding (Option B), or lifelong ART (Option B+). The WHO also recommends ART for HIV treatment and prevention of sexual transmission of HIV. The impact of PMTCT strategies on prevention of sexual HIV transmission of HIV is not known. We estimated the population-level impact of PMTCT interventions on heterosexual HIV transmission in southwestern Uganda and KwaZulu-Natal, South Africa, two regions with different HIV prevalence and fertility rates.Materials and Methods
We constructed and validated dynamic, stochastic, network-based HIV transmission models for each region. PMTCT Options A, B, and B+ were simulated over ten years under three scenarios: 1) current ART and PMTCT coverage, 2) current ART and high PMTCT coverage, and 3) high ART and PMTCT coverage. We compared adult HIV incidence after ten years of each intervention to Option A (and current ART) at current coverage.Results
At current coverage, Options B and B+ reduced heterosexual HIV incidence by about 5% and 15%, respectively, in both countries. With current ART and high PMTCT coverage, Option B+ reduced HIV incidence by 35% in Uganda and 19% in South Africa, while Option B had smaller, but meaningful, reductions. The greatest reductions in HIV incidence were achieved with high ART and PMTCT coverage. In this scenario, all PMTCT strategies yielded similar results.Discussion
Implementation of Options B/B+ reduces adult HIV incidence, with greater effect (relative to Option A at current levels) in Uganda than South Africa. These results are likely driven by Uganda’s higher fertility rates. 相似文献74.
75.
Nandhakumar Thayanidhi Jared R. Helm Deborah C. Nycz Marvin Bentley Yingjian Liang Jesse C. Hay 《Molecular biology of the cell》2010,21(11):1850-1863
Toxicity of human α-synuclein when expressed in simple organisms can be suppressed by overexpression of endoplasmic reticulum (ER)-to-Golgi transport machinery, suggesting that inhibition of constitutive secretion represents a fundamental cause of the toxicity. Whether similar inhibition in mammals represents a cause of familial Parkinson''s disease has not been established. We tested elements of this hypothesis by expressing human α-synuclein in mammalian kidney and neuroendocrine cells and assessing ER-to-Golgi transport. Overexpression of wild type or the familial disease-associated A53T mutant α-synuclein delayed transport by up to 50%; however, A53T inhibited more potently. The secretory delay occurred at low expression levels and was not accompanied by insoluble α-synuclein aggregates or mistargeting of transport machinery, suggesting a direct action of soluble α-synuclein on trafficking proteins. Co-overexpression of ER/Golgi arginine soluble N-ethylmaleimide-sensitive factor attachment protein receptors (R-SNAREs) specifically rescued transport, indicating that α-synuclein antagonizes SNARE function. Ykt6 reversed α-synuclein inhibition much more effectively than sec22b, suggesting a possible neuroprotective role for the enigmatic high expression of ykt6 in neurons. In in vitro reconstitutions, purified α-synuclein A53T protein specifically inhibited COPII vesicle docking and fusion at a pre-Golgi step. Finally, soluble α-synuclein A53T directly bound ER/Golgi SNAREs and inhibited SNARE complex assembly, providing a potential mechanism for toxic effects in the early secretory pathway. 相似文献
76.
Jared J. Heymann Mario Gabričević Timothy A. Mietzner Alvin L. Crumbliss 《Journal of biological inorganic chemistry》2010,15(2):237-248
The bacterial transferrin ferric binding protein A (FbpA) requires an exogenous anion to facilitate iron sequestration, and
subsequently to shuttle the metal across the periplasm to the cytoplasmic membrane. In the diverse conditions of the periplasm,
numerous anions are known to be present. Prior in vitro experiments have demonstrated the ability of multiple anions to fulfill
the synergistic iron-binding requirement, and the identity of the bound anion has been shown to modulate important physicochemical
properties of iron-bound FbpA (FeFbpA). Here we address the kinetics and mechanism of anion exchange for the FeFbpA–nitrilotriacetate
(NTA) assembly with several biologically relevant anions (citrate, oxalate, phosphate, and pyrophosphate), with nonphysiologic
NTA serving as a representative synergistic anion/chelator. The kinetic data are consistent with an anion-exchange process
that occurs in multiple steps, dependent on the identity of both the entering anion and the leaving anion. The exchange mechanism
may proceed either as a direct substitution or through an intermediate FeFbpA–X* assembly based on anion (X) identity. Our
kinetic results further develop an understanding of exogenous anion lability in the periplasm, as well as address the final
step of the iron-free FbpA (apo-FbpA)/Fe3+ sequestration mechanism. Our results highlight the kinetic significance of the FbpA anion binding site, demonstrating a correlation
between apo-FbpA/anion affinity and the FeFbpA rate of anion exchange, further supporting the requirement of an exogenous
anion to complete tight sequestration of iron by FbpA, and developing a mechanism for anion exchange within FeFbpA that is
dependent on the identity of both the entering anion and the leaving anion. 相似文献
77.
Jared Cumming Suresh Babu Ying Huang Carolyn Carrol Xia Chen Leonard Favreau William Greenlee Tao Guo Matthew Kennedy Reshma Kuvelkar Thuy Le Guoqing Li Nansie McHugh Peter Orth Lynne Ozgur Eric Parker Kurt Saionz Andrew Stamford Corey Strickland Dawit Tadesse Qi Zhang 《Bioorganic & medicinal chemistry letters》2010,20(9):2837-2842
With collaboration between chemistry, X-ray crystallography, and molecular modeling, we designed and synthesized a series of novel piperazine sulfonamide BACE1 inhibitors. Iterative exploration of the non-prime side and S2′ sub-pocket of the enzyme culminated in identification of an analog that potently lowers peripheral Aβ40 in transgenic mice with a single subcutaneous dose. 相似文献
78.
Rong An Gabriela da Silva Xavier Francesca Semplici Saharnaz Vakhshouri Jared Rutter Flavio Meggio Guy A. Rutter 《Biochemical and biophysical research communications》2010,399(2):155-161
Pancreatic and duodenal homeobox 1 (PDX1) regulates pancreatic development and mature β-cell function. We demonstrate by mass spectrometry that serine residue at position 269 in the C-terminal domain of PDX1 is phosphorylated in β-cells. Besides we show that the degree of phosphorylation, assessed with a phospho-Ser-269-specific antibody, is decreased by elevated glucose concentrations in both MIN6 β-cells and primary mouse pancreatic islets. Homeodomain interacting protein kinase 2 (HIPK2) phosphorylates PDX1 in vitro; phosphate incorporation substantially decreases in PDX1 S269A mutant. Silencing of HIPK2 led to a 51 ± 0.2% decrease in Ser-269 phosphorylation in MIN6 β-cells. Mutation of Ser-269 to phosphomimetic residue glutamic acid (S269E) or de-phosphomimetic residue alanine (S269A) exerted no effect on PDX1 half-life. Instead, PDX1 S269E mutant displayed abnormal changes in subnuclear localization in response to high glucose. Our results suggest that HIPK2-mediated phosphorylation of PDX1 at Ser-269 might be a regulatory mechanism connecting signals generated by changes in extracellular glucose concentration to downstream effectors via changes in subnuclear localization of PDX1, thereby influencing islet cell differentiation and function. 相似文献
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80.