全文获取类型
收费全文 | 1414篇 |
免费 | 153篇 |
国内免费 | 1篇 |
出版年
2023年 | 14篇 |
2022年 | 24篇 |
2021年 | 62篇 |
2020年 | 29篇 |
2019年 | 26篇 |
2018年 | 45篇 |
2017年 | 40篇 |
2016年 | 51篇 |
2015年 | 95篇 |
2014年 | 87篇 |
2013年 | 104篇 |
2012年 | 139篇 |
2011年 | 111篇 |
2010年 | 77篇 |
2009年 | 53篇 |
2008年 | 79篇 |
2007年 | 59篇 |
2006年 | 60篇 |
2005年 | 58篇 |
2004年 | 46篇 |
2003年 | 40篇 |
2002年 | 38篇 |
2001年 | 6篇 |
2000年 | 12篇 |
1999年 | 6篇 |
1998年 | 9篇 |
1997年 | 4篇 |
1996年 | 5篇 |
1995年 | 11篇 |
1994年 | 6篇 |
1992年 | 18篇 |
1991年 | 6篇 |
1990年 | 15篇 |
1989年 | 11篇 |
1988年 | 8篇 |
1987年 | 9篇 |
1986年 | 5篇 |
1985年 | 9篇 |
1984年 | 7篇 |
1983年 | 10篇 |
1982年 | 10篇 |
1981年 | 5篇 |
1980年 | 5篇 |
1979年 | 5篇 |
1977年 | 3篇 |
1976年 | 5篇 |
1975年 | 6篇 |
1973年 | 4篇 |
1972年 | 3篇 |
1970年 | 5篇 |
排序方式: 共有1568条查询结果,搜索用时 15 毫秒
991.
Dynorphin A 1–17 (Dyn A 1–17) is an endogenous neuropeptide known to act at the kappa opioid receptor; it has been implicated in a number of neurological disorders, including neuropathic pain, stress, depression, and Alzheimer's and Parkinson's diseases. The investigation of Dyn A 1–17 metabolism at the blood–brain barrier (BBB) is important since the metabolites exhibit unique biological functions compared to the parent compound. In this work, Dyn A 1–6 is identified as a metabolite of Dyn A 1–17 in the presence of bovine brain microvessel endhothelial cells (BBMECs), using LC–MS/MS. The transport of Dyn A 1–6 at the BBB was examined using this in vitro cell culture model of the BBB. Furthermore, the permeation of the BBB by the low molecular weight permeability marker fluorescein was characterized in the presence and absences of Dyn A 1–6. 相似文献
992.
993.
Corley CD Lancaster MJ Brigantic RT Chung JS Walters RA Arthur RR Bruckner-Lea CJ Calapristi A Dowling G Hartley DM Kennedy S Kircher A Klucking S Lee EK McKenzie T Nelson NP Olsen J Pancerella C Quitugua TN Reed JT Thomas CS 《Biosecurity and bioterrorism : biodefense strategy, practice, and science》2012,10(1):131-141
994.
Our objective was to determine if sexual orientation groups differ in accuracy of BMI (kg/m(2)) calculated from self-reported height and weight and if weight status modifies possible differences. Using gender-stratified multiple linear regression to analyze Wave III of the National Longitudinal Study of Adolescent Health (n = 12,197), we examined the association of sexual orientation with BMI calculated from self-reported height and weight (self-reported BMI), controlling for BMI calculated from objectively measured height and weight (objectively measured BMI) as well as demographic, health, and behavioral variables. We tested for effect modification of the relationship between sexual orientation and self-reported BMI by objectively measured BMI. The population underestimated their BMI (females: β = 0.87, P < 0.001; males = 0.86, P < 0.001). Sexual orientation groups differed little in their accuracy of reporting; only gay males had significant underreporting (β = -0.37, P = 0.038) relative to their heterosexual peers. We found no evidence of effect modification of the relationship of sexual orientation and self-reported BMI by objectively measured BMI. With the exception of gay males, sexual orientation groups are consistent in their underreporting of BMI thus providing confidence in most comparisons of weight status based on self-report. Self-reporting of weight and height by gay males may exaggerate the differences in BMI between gay and heterosexual males. 相似文献
995.
Takedachi M Oohara H Smith BJ Iyama M Kobashi M Maeda K Long CL Humphrey MB Stoecker BJ Toyosawa S Thompson LF Murakami S 《Journal of cellular physiology》2012,227(6):2622-2631
CD731 is a GPI-anchored cell surface protein with ecto-5'-nucleotidase enzyme activity that plays a crucial role in adenosine production. While the roles of adenosine receptors (AR) on osteoblasts and osteoclasts have been unveiled to some extent, the roles of CD73 and CD73-generated adenosine in bone tissue are largely unknown. To address this issue, we first analyzed the bone phenotype of CD73-deficient (cd73(-/-)) mice. The mutant male mice showed osteopenia, with significant decreases of osteoblastic markers. Levels of osteoclastic markers were, however, comparable to those of wild-type mice. A series of in vitro studies revealed that CD73 deficiency resulted in impairment in osteoblast differentiation but not in the number of osteoblast progenitors. In addition, over expression of CD73 on MC3T3-E1 cells resulted in enhanced osteoblastic differentiation. Moreover, MC3T3-E1 cells expressed adenosine A(2A) receptors (A(2A)AR) and A(2B) receptors (A(2B)AR) and expression of these receptors increased with osteoblastic differentiation. Enhanced expression of osteocalcin (OC) and bone sialoprotein (BSP) observed in MC3T3-E1 cells over expressing CD73 were suppressed by treatment with an A(2B)AR antagonist but not with an A(2A) AR antagonist. Collectively, our results indicate that CD73 generated adenosine positively regulates osteoblast differentiation via A(2B)AR signaling. 相似文献
996.
Giordano CR Mueller KL Terlecky LJ Krentz KA Bollig-Fischer A Terlecky SR Boerner JL 《Experimental cell research》2012,318(16):2014-2021
Gefitinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) of potential use in patients with breast cancer. Unfortunately, in clinical studies, gefitinib is often ineffective indicating that resistance to EGFR inhibitors may be a common occurrence in cancer of the breast. EGFR has been shown to be overexpressed in breast cancer, and in particular remains hyperphosphorylated in cell lines such as MDA-MB-468 that are resistant to EGFR inhibitors. Here, we investigate the cause of this sustained phosphorylation and the molecular basis for the ineffectiveness of gefitinib. We show that reactive oxygen species (ROS), known to damage cellular macromolecules and to modulate signaling cascades in a variety of human diseases including cancers, appear to play a critical role in mediating EGFR TKI-resistance. Furthermore, elimination of these ROS through use of a cell-penetrating catalase derivative sensitizes the cells to gefitinib. These results suggest a new approach for the treatment of TKI-resistant breast cancer patients specifically, the targeting of ROS and attendant downstream oxidative stress and their effects on signaling cascades. 相似文献
997.
SD Brown M Podar DM Klingeman CM Johnson ZK Yang SM Utturkar ML Land JJ Mosher RA Hurt TJ Phelps AV Palumbo AP Arkin TC Hazen DA Elias 《Journal of bacteriology》2012,194(18):5147-5148
Pelosinus fermentans 16S rRNA gene sequences have been reported from diverse geographical sites since the recent isolation of the type strain. We present the genome sequence of the P. fermentans type strain R7 (DSM 17108) and genome sequences for two new strains with different abilities to reduce iron, chromate, and uranium. 相似文献
998.
In recent years, tremendous progress has been made in the elucidation of the biological roles and molecular mechanisms of the apolioprotein B mRNA-editing enzyme catalytic polypeptide (APOBEC) family of enzymes. The APOBEC family of cytidine deaminases has important functional roles within the adaptive and innate immune system. Activation induced cytidine deaminase (AID) plays a central role in the biochemical steps of somatic hypermutation and class switch recombination during antibody maturation, and the APOBEC 3 enzymes are able to inhibit the mobility of retroelements and the replication of retroviruses and DNA viruses, such as the human immunodeficiency virus type-1 and hepatitis B virus. Recent advances in structural and functional studies of the APOBEC enzymes provide new biochemical insights for how these enzymes carry out their biological roles. In this review, we provide an overview of these recent advances in the APOBEC field with a special emphasis on AID and APOBEC3G. 相似文献
999.
Franck C. Chatelain Sabrina Gazzarrini Yuichiro Fujiwara Cristina Arrigoni Courtney Domigan Giuseppina Ferrara Carlos Pantoja Gerhard Thiel Anna Moroni Daniel L. Minor Jr. 《PloS one》2009,4(10)
Background
Understanding the interactions between ion channels and blockers remains an important goal that has implications for delineating the basic mechanisms of ion channel function and for the discovery and development of ion channel directed drugs.Methodology/Principal Findings
We used genetic selection methods to probe the interaction of two ion channel blockers, barium and amantadine, with the miniature viral potassium channel Kcv. Selection for Kcv mutants that were resistant to either blocker identified a mutant bearing multiple changes that was resistant to both. Implementation of a PCR shuffling and backcrossing procedure uncovered that the blocker resistance could be attributed to a single change, T63S, at a position that is likely to form the binding site for the inner ion in the selectivity filter (site 4). A combination of electrophysiological and biochemical assays revealed a distinct difference in the ability of the mutant channel to interact with the blockers. Studies of the analogous mutation in the mammalian inward rectifier Kir2.1 show that the T→S mutation affects barium block as well as the stability of the conductive state. Comparison of the effects of similar barium resistant mutations in Kcv and Kir2.1 shows that neighboring amino acids in the Kcv selectivity filter affect blocker binding.Conclusions/Significance
The data support the idea that permeant ions have an integral role in stabilizing potassium channel structure, suggest that both barium and amantadine act at a similar site, and demonstrate how genetic selections can be used to map blocker binding sites and reveal mechanistic features. 相似文献1000.
Peter Berman Malcolm Collins Ingrid Baumgarten Cathal Seoighe Courtney L. Jennings Yael Joffe Estelle V. Lambert Naomi S. Levitt Mirjam V. Faulenbach Steven E. Kahn Julia H. Goedecke 《Obesity (Silver Spring, Md.)》2009,17(6):1298-1300
The objective of the study was to examine the association between a functional 4 bp proinsulin gene insertion polymorphism (IVS‐69), fasting insulin concentrations, and body composition in black South African women. Body composition, body fat distribution, fasting glucose and insulin concentrations, and IVS‐69 genotype were measured in 115 normal‐weight (BMI <25 kg/m2) and 138 obese (BMI ≥30 kg/m2) premenopausal women. The frequency of the insertion allele was significantly higher in the class 2 obese (BMI ≥35kg/m2) compared with the normal‐weight group (P = 0.029). Obese subjects with the insertion allele had greater fat mass (42.3 ± 0.9 vs. 38.9 ± 0.9 kg, P = 0.034) and fat‐free soft tissue mass (47.4 ± 0.6 vs. 45.1 ± 0.6 kg, P = 0.014), and more abdominal subcutaneous adipose tissue (SAT, 595 ± 17 vs. 531 ± 17 cm2, P = 0.025) but not visceral fat (P = 0.739), than obese homozygotes for the wild‐type allele. Only SAT was greater in normal‐weight subjects with the insertion allele (P = 0.048). There were no differences in fasting insulin or glucose levels between subjects with the insertion allele or homozygotes for the wild‐type allele in the normal‐weight or obese groups. In conclusion, the 4 bp proinsulin gene insertion allele is associated with extreme obesity, reflected by greater fat‐free soft tissue mass and fat mass, particularly SAT, in obese black South African women. 相似文献