全文获取类型
收费全文 | 2282篇 |
免费 | 98篇 |
专业分类
2380篇 |
出版年
2024年 | 6篇 |
2023年 | 7篇 |
2022年 | 37篇 |
2021年 | 61篇 |
2020年 | 39篇 |
2019年 | 41篇 |
2018年 | 52篇 |
2017年 | 53篇 |
2016年 | 73篇 |
2015年 | 82篇 |
2014年 | 130篇 |
2013年 | 169篇 |
2012年 | 204篇 |
2011年 | 190篇 |
2010年 | 107篇 |
2009年 | 96篇 |
2008年 | 128篇 |
2007年 | 127篇 |
2006年 | 143篇 |
2005年 | 87篇 |
2004年 | 87篇 |
2003年 | 93篇 |
2002年 | 85篇 |
2001年 | 15篇 |
2000年 | 12篇 |
1999年 | 15篇 |
1998年 | 30篇 |
1997年 | 13篇 |
1996年 | 6篇 |
1995年 | 14篇 |
1994年 | 8篇 |
1993年 | 9篇 |
1992年 | 14篇 |
1991年 | 15篇 |
1990年 | 9篇 |
1989年 | 10篇 |
1988年 | 10篇 |
1987年 | 11篇 |
1986年 | 6篇 |
1985年 | 8篇 |
1984年 | 15篇 |
1983年 | 4篇 |
1982年 | 9篇 |
1981年 | 4篇 |
1980年 | 6篇 |
1979年 | 11篇 |
1976年 | 3篇 |
1973年 | 5篇 |
1972年 | 7篇 |
1971年 | 4篇 |
排序方式: 共有2380条查询结果,搜索用时 0 毫秒
81.
Anantha R. Nookala Junhao Li Anusha Ande Lei Wang Naveen K. Vaidya Weihua Li Santosh Kumar Anil Kumar 《PloS one》2016,11(1)
Cytochrome P450 3A4 (CYP3A4) is the major drug metabolic enzyme, and is involved in the metabolism of antiretroviral drugs, especially protease inhibitors (PIs). This study was undertaken to examine the effect of methamphetamine on the binding and metabolism of PIs with CYP3A4. We showed that methamphetamine exhibits a type I spectral change upon binding to CYP3A4 with δAmax and KD of 0.016±0.001 and 204±18 μM, respectively. Methamphetamine-CYP3A4 docking showed that methamphetamine binds to the heme of CYP3A4 in two modes, both leading to N-demethylation. We then studied the effect of methamphetamine binding on PIs with CYP3A4. Our results showed that methamphetamine alters spectral binding of nelfinavir but not the other type I PIs (lopinavir, atazanavir, tipranavir). The change in spectral binding for nelfinavir was observed at both δAmax (0.004±0.0003 vs. 0.0068±0.0001) and KD (1.42±0.36 vs.2.93±0.08 μM) levels. We further tested effect of methamphetamine on binding of 2 type II PIs; ritonavir and indinavir. Our results showed that methamphetamine alters the ritonavir binding to CYP3A4 by decreasing both the δAmax (0.0038±0.0003 vs. 0.0055±0.0003) and KD (0.043±0.0001 vs. 0.065±0.001 nM), while indinavir showed only reduced KD in presence of methamphetamine (0.086±0.01 vs. 0.174±0.03 nM). Furthermore, LC-MS/MS studies in high CYP3A4 human liver microsomes showed a decrease in the formation of hydroxy ritonavir in the presence of methamphetamine. Finally, CYP3A4 docking with lopinavir and ritonavir in the absence and presence of methamphetamine showed that methamphetamine alters the docking of ritonavir, which is consistent with the results obtained from spectral binding and metabolism studies. Overall, our results demonstrated differential effects of methamphetamine on the binding and metabolism of PIs with CYP3A4. These findings have clinical implication in terms of drug dose adjustment of antiretroviral medication, especially with ritonavir-boosted antiretroviral therapy, in HIV-1-infected individuals who abuse methamphetamine. 相似文献
82.
Background
Precision medicine aims to combat the variability of the therapeutic response to a given medicine by delivering the right medicine to the right patient. However, the application of precision medicine is predicated on a prior quantitation of the variance of the reference range of normality. Airway pathophysiology provides a good example due to a very variable first line of defence against airborne assault. Humans differ in their susceptibility to inhaled pollutants and pathogens in part due to the magnitude of trans-epithelial resistance that determines the degree of epithelial penetration to the submucosal space. This initial ‘set-point’ may drive a sentinel event in airway disease pathogenesis. Epithelia differentiated in vitro from airway biopsies are commonly used to model trans-epithelial resistance but the ‘reference range of normality’ remains problematic. We investigated the range of electrophysiological characteristics of human airway epithelia grown at air-liquid interface in vitro from healthy volunteers focusing on the inter- and intra-subject variability both at baseline and after sequential exposure to drugs modulating ion transport.Methodology/Principal Findings
Brushed nasal airway epithelial cells were differentiated at air-liquid interface generating 137 pseudostratified ciliated epithelia from 18 donors. A positively-skewed baseline range exists for trans-epithelial resistance (Min/Max: 309/2963 Ω·cm2), trans-epithelial voltage (-62.3/-1.8 mV) and calculated equivalent current (-125.0/-3.2 μA/cm2; all non-normal, P<0.001). A minority of healthy humans manifest a dramatic amiloride sensitivity to voltage and trans-epithelial resistance that is further discriminated by prior modulation of cAMP-stimulated chloride transport.Conclusions/Significance
Healthy epithelia show log-order differences in their ion transport characteristics, likely reflective of their initial set-points of basal trans-epithelial resistance and sodium transport. Our data may guide the choice of the background set point in subjects with airway diseases and frame the reference range for the future delivery of precision airway medicine. 相似文献83.
Objective
To describe the prevalence, characteristics, and predictors of safety-net use for primary care among non-Medicaid insured adults (i.e., those with private insurance or Medicare).Methods
Cross-sectional analysis using the 2006–2010 National Ambulatory Medical Care Surveys, annual probability samples of outpatient visits in the U.S. We estimated national prevalence of safety-net visits using weighted percentages to account for the complex survey design. We conducted bivariate and multivariate logistic regression analyses to examine characteristics associated with safety-net clinic use.Results
More than one-third (35.0%) of all primary care safety-net clinic visits were among adults with non-Medicaid primary insurance, representing 6,642,000 annual visits nationally. The strongest predictors of safety-net use among non-Medicaid insured adults were: being from a high-poverty neighborhood (AOR 9.53, 95% CI 4.65–19.53), being dually eligible for Medicare and Medicaid (AOR 2.13, 95% CI 1.38–3.30), and being black (AOR 1.97, 95% CI 1.06–3.66) or Hispanic (AOR 2.28, 95% CI 1.32–3.93). Compared to non-safety-net users, non-Medicaid insured adults who used safety-net clinics had a higher prevalence of diabetes (23.5% vs. 15.0%, p<0.001), hypertension (49.4% vs. 36.0%, p<0.001), multimorbidity (≥2 chronic conditions; 53.5% vs. 40.9%, p<0.001) and polypharmacy (≥4 medications; 48.8% vs. 34.0%, p<0.001). Nearly one-third (28.9%) of Medicare beneficiaries in the safety-net were dual eligibles, compared to only 6.8% of Medicare beneficiaries in non-safety-net clinics (p<0.001).Conclusions
Safety net clinics are important primary care delivery sites for non-Medicaid insured minority and low-income populations with a high burden of chronic illness. The critical role of safety-net clinics in care delivery is likely to persist despite expanded insurance coverage under the Affordable Care Act. 相似文献84.
Karoline Kragelund Nielsen Peter Damm Anil Kapur Vijayam Balaji Madhuri S. Balaji Veerasamy Seshiah Ib C. Bygbjerg 《PloS one》2016,11(3)
Introduction
Hyperglycaemia in pregnancy (HIP), i.e. gestational diabetes mellitus (GDM) and diabetes in pregnancy (DIP), increases the risk of various short- and long-term adverse outcomes. However, much remains to be understood about the role of different risk factors in development of HIP.Objective
The aims of this observational study were to examine the role of potential risk factors for HIP, and to investigate whether any single or accumulated risk factor(s) could be used to predict HIP among women attending GDM screening at three centres in urban, semi-urban and rural Tamil Nadu, India.Methodology
Pregnant women underwent a 75 g oral glucose tolerance test. Data on potential risk factors was collected and analysed using logistical regression analysis. Receiver operating characteristic (ROC) curves, sensitivity, specificity and predictive values were calculated for significant risk factors and a risk factor scoring variable was constructed.Results
HIP was prevalent in 18.9% of the study population (16.3% GDM; 2.6% DIP). Increasing age and BMI as well as having a mother only or both parents with diabetes were significant independent risk factors for HIP. Among women attending the rural health centre a doubling of income corresponded to an 80% increased risk of HIP (OR 1.80, 95%CI 1.10–2.93; p = 0.019), whereas it was not significantly associated with HIP among women attending the other health centres. The performance of the individual risk factors and the constructed scoring variable differed substantially between the three health centres, but none of them were good enough to discriminate between those with and without HIP.Conclusions
The findings highlight the importance of socio-economic circumstances and intergenerational risk transmission in the occurrence of HIP as well as the need for universal screening. 相似文献85.
86.
87.
Feng Zhu Anil Kalra Tal Saif Zaihan Yang King H. Yang Albert I. King 《Computer methods in biomechanics and biomedical engineering》2016,19(10):1053-1059
Traumatic brain injury due to primary blast loading has become a signature injury in recent military conflicts and terrorist activities. Extensive experimental and computational investigations have been conducted to study the interrelationships between intracranial pressure response and intrinsic or ‘input’ parameters such as the head geometry and loading conditions. However, these relationships are very complicated and are usually implicit and ‘hidden’ in a large amount of simulation/test data. In this study, a data mining method is proposed to explore such underlying information from the numerical simulation results. The heads of different species are described as a highly simplified two-part (skull and brain) finite element model with varying geometric parameters. The parameters considered include peak incident pressure, skull thickness, brain radius and snout length. Their interrelationship and coupling effect are discovered by developing a decision tree based on the large simulation data-set. The results show that the proposed data-driven method is superior to the conventional linear regression method and is comparable to the nonlinear regression method. Considering its capability of exploring implicit information and the relatively simple relationships between response and input variables, the data mining method is considered to be a good tool for an in-depth understanding of the mechanisms of blast-induced brain injury. As a general method, this approach can also be applied to other nonlinear complex biomechanical systems. 相似文献
88.
Anil Chekuri Katarzyna Zientara‐Rytter Angel Soto‐Hermida Shyamanga Borooah Marina Voronchikhina Pooja Biswas Virender Kumar David Goodsell Caroline Hayward Peter Shaw Chloe Stanton Donita Garland Suresh Subramani Radha Ayyagari 《Aging cell》2019,18(6)
Late‐onset retinal degeneration (L‐ORD) is an autosomal dominant macular degeneration characterized by the formation of sub‐retinal pigment epithelium (RPE) deposits and neuroretinal atrophy. L‐ORD results from mutations in the C1q‐tumor necrosis factor‐5 protein (CTRP5), encoded by the CTRP5/C1QTNF5 gene. To understand the mechanism underlying L‐ORD pathology, we used a human cDNA library yeast two‐hybrid screen to identify interacting partners of CTRP5. Additionally, we analyzed the Bruch's membrane/choroid (BM‐Ch) from wild‐type (Wt), heterozygous S163R Ctrp5 mutation knock‐in (Ctrp5S163R/wt), and homozygous knock‐in (Ctrp5S163R/S163R) mice using mass spectrometry. Both approaches showed an association between CTRP5 and HTRA1 via its C‐terminal PDZ‐binding motif, stimulation of the HTRA1 protease activity by CTRP5, and CTRP5 serving as an HTRA1 substrate. The S163R‐CTRP5 protein also binds to HTRA1 but is resistant to HTRA1‐mediated cleavage. Immunohistochemistry and proteomic analysis showed significant accumulation of CTRP5 and HTRA1 in BM‐Ch of Ctrp5S163R/S163R and Ctrp5S163R/wt mice compared with Wt. Additional extracellular matrix (ECM) components that are HTRA1 substrates also accumulated in these mice. These results implicate HTRA1 and its interaction with CTRP5 in L‐ORD pathology. 相似文献
89.
90.
Garsa Anita Kumari Choudhury Prasanta Kumar Puniya Anil Kumar Dhewa Tejpal Malik Ravinder Kumar Tomar Sudhir Kumar 《Probiotics and antimicrobial proteins》2019,11(4):1403-1413
Probiotics and Antimicrobial Proteins - Bovicin is a type AII lantibiotic, possessing two β-methyllanthionine and a disulfide bridge encoded by bovA gene hitherto unknown a couple of decades... 相似文献