全文获取类型
收费全文 | 918篇 |
免费 | 112篇 |
学科分类
生物科学 | 1030篇 |
出版年
2023年 | 8篇 |
2021年 | 21篇 |
2020年 | 15篇 |
2019年 | 16篇 |
2018年 | 13篇 |
2017年 | 12篇 |
2016年 | 18篇 |
2015年 | 42篇 |
2014年 | 37篇 |
2013年 | 40篇 |
2012年 | 48篇 |
2011年 | 56篇 |
2010年 | 33篇 |
2009年 | 19篇 |
2008年 | 43篇 |
2007年 | 44篇 |
2006年 | 43篇 |
2005年 | 32篇 |
2004年 | 30篇 |
2003年 | 36篇 |
2002年 | 20篇 |
2001年 | 27篇 |
2000年 | 25篇 |
1999年 | 36篇 |
1998年 | 8篇 |
1997年 | 9篇 |
1996年 | 11篇 |
1995年 | 12篇 |
1994年 | 14篇 |
1992年 | 32篇 |
1991年 | 21篇 |
1990年 | 16篇 |
1989年 | 19篇 |
1988年 | 15篇 |
1987年 | 13篇 |
1986年 | 17篇 |
1985年 | 23篇 |
1984年 | 13篇 |
1983年 | 5篇 |
1982年 | 12篇 |
1981年 | 7篇 |
1980年 | 3篇 |
1979年 | 8篇 |
1978年 | 4篇 |
1977年 | 7篇 |
1976年 | 6篇 |
1975年 | 5篇 |
1974年 | 6篇 |
1973年 | 3篇 |
1972年 | 4篇 |
排序方式: 共有1030条查询结果,搜索用时 15 毫秒
91.
Leana Doherty Adrianna Vlachos Valerie Choesmel Marie-Françoise O'Donohue Catherine Clinton Colin A. Sieff Peter E. Newburger Edyta Niewiadomska Bertil Glader Jason E. Farrar Jeffrey M. Lipton Pierre-Emmanuel Gleizes Hanna T. Gazda 《American journal of human genetics》2010,86(2):222-6951
Diamond-Blackfan anemia (DBA), an inherited bone marrow failure syndrome characterized by anemia that usually presents before the first birthday or in early childhood, is associated with birth defects and an increased risk of cancer. Although anemia is the most prominent feature of DBA, the disease is also characterized by growth retardation and congenital malformations, in particular craniofacial, upper limb, heart, and urinary system defects that are present in ∼30%–50% of patients. DBA has been associated with mutations in seven ribosomal protein (RP) genes, RPS19, RPS24, RPS17, RPL35A, RPL5, RPL11, and RPS7, in about 43% of patients. To continue our large-scale screen of RP genes in a DBA population, we sequenced 35 ribosomal protein genes, RPL15, RPL24, RPL29, RPL32, RPL34, RPL9, RPL37, RPS14, RPS23, RPL10A, RPS10, RPS12, RPS18, RPL30, RPS20, RPL12, RPL7A, RPS6, RPL27A, RPLP2, RPS25, RPS3, RPL41, RPL6, RPLP0, RPS26, RPL21, RPL36AL, RPS29, RPL4, RPLP1, RPL13, RPS15A, RPS2, and RPL38, in our DBA patient cohort of 117 probands. We identified three distinct mutations of RPS10 in five probands and nine distinct mutations of RPS26 in 12 probands. Pre-rRNA analysis in lymphoblastoid cells from patients bearing mutations in RPS10 and RPS26 showed elevated levels of 18S-E pre-rRNA. This accumulation is consistent with the phenotype observed in HeLa cells after knockdown of RPS10 or RPS26 expression with siRNAs, which indicates that mutations in the RPS10 and RPS26 genes in DBA patients affect the function of the proteins in rRNA processing. 相似文献
92.
Joshua L. Dooley Todd A. Sanders Jr Paul F. Doherty 《The Journal of wildlife management》2010,74(8):1815-1824
ABSTRACT Spatial and temporal closures of anthropogenic activities are a common management strategy to increase waterfowl usage of an area. However, empirical evidence, specifically how individual waterfowl respond to disturbance, is lacking to support their efficacy. We exposed radiomarked mallards (Anas platyrhynchos) to walk-in, shooting, or no disturbance along the South Platte River corridor in Colorado, USA, from September to February during 2006–2007 and 2007–2008. Mallards exposed to shooting disturbance had greater mean flight distance after disturbance (FDAD) during September-November (4.58 km, 95% CI = 3.55–5.62) than December-February (3.04 km, 95% CI = 2.51–3.58) and were 35% and 17% greater than mean FDAD of mallards exposed to walk-in disturbance, respectively. Walk-in and shooting disturbance had a similar effect on return rates, and disturbed mallards had higher (0.09–0.41) movement probabilities away from and lower (0.15–0.20) probabilities of returning to treatment locations than controls. Probability of presence of disturbed mallards was 37% lower than controls during the daytime but was equal at night. Mallards exposed to walk-in (0.38 [95% CI = 0.30–0.46]) and shooting (0.23 [95% CI = 0.17–0.30] disturbance had low return rates the first afternoon after a disturbance compared to controls (0.71 [95% CI = 0.65–0.77]). A high proportion of mallards exposed to walk-in (0.75 [95% CI = 0.67–0.83]) and shooting (0.70 [95% CI = 0.64–0.76]) disturbance returned to treatment locations in ≤1 day. Managers may be able to more effectively manage disturbance regimes by 1) accounting for surrounding lands within <10 km, especially lands within <5 km, 2) being conscientious when establishing regulations that will affect levels of disturbance 1–2 days after a previous disturbance, and 3) considering shooting and walking disturbance equally for refuge design. 相似文献
93.
Gout is the most prevalent form of inflammatory arthropathy. Several studies suggest that its prevalence and incidence have
risen in recent decades. Numerous risk factors for the development of gout have been established, including hyperuricaemia,
genetic factors, dietary factors, alcohol consumption, metabolic syndrome, hypertension, obesity, diuretic use and chronic
renal disease. Osteoarthritis predisposes to local crystal deposition. Gout appears to be an independent risk factor for all-cause
mortality and cardiovascular mortality and morbidity, additional to the risk conferred by its association with traditional
cardiovascular risk factors. 相似文献
94.
Xavier Calvet Sergio Lario María José Ramírez‐Lázaro Antònia Montserrat Mariela Quesada Lynsey Reeves Helen Masters David Suárez‐Lamas Marta Gallach Mireia Miquel Eva Martínez‐Bauer Isabel Sanfeliu Ferran Segura 《Helicobacter》2010,15(3):201-205
Background: Studies comparing new monoclonal fecal tests for evaluating cure of Helicobacter pylori infection after treatment are scarce. The objective was to compare the diagnostic accuracy of three monoclonal stool tests: two rapid in‐office tools –RAPID Hp StAR and ImmunoCard STAT! HpSA – and an EIA test – Amplified IDEIA Hp StAR. Materials and methods: Diagnostic reliability of the three tests was evaluated in 88 patients at least 8 weeks after H. pylori treatment. Readings of immunochromatographic tests were performed by two different observers. Sensitivity, specificity, positive and negative predictive values and 95% confidence intervals were calculated. Results: All tests presented similar performance for post‐eradication testing. Sensitivity for detecting persistent infection was 100% for both Amplified IDEIA and RAPID Hp StAR and 90% for ImmunoCard STAT! HpSA. Respective specificities were 94.9%, 92.3–93.6% and 94.9%. Negative predictive values were very high (100%, 100% and 98.7% respectively). But positive predictive values were lower, ranging from 62.5 to 71.4%. Conclusion: All monoclonal fecal tests in this series presented similar performance in the post‐treatment setting. A negative test after treatment adequately predicted cure of the infection. However, nearly a third of tests were false positive, showing a poor predictive yield for persistent infection. 相似文献
95.
Sloboda DM Moss TJ Li S Doherty D Nitsos I Challis JR Newnham JP 《American journal of physiology. Endocrinology and metabolism》2007,292(1):E61-E70
Fetal exposure to synthetic glucocorticoids in sheep results in increased fetal hypothalamic-pituitary-adrenal (HPA) activity persisting to one year of age. We aimed to determine the effects of single or repeated maternal or fetal betamethasone injections on offspring HPA activity at 2 and 3 yr of age and whether changes in adrenal mediators of steroidogenesis contribute to changes in pituitary-adrenal function. Pregnant ewes or their fetuses received either repeated intramuscular saline or betamethasone injections (0.5 mg/kg) at 104, 111, 118, and 124 days of gestation (dG) or a single betamethasone injection at 104 dG followed by saline at 111, 118, and 124 dG. Offspring were catheterized at 2 and 3 yr of age and given corticotrophin-releasing hormone + arginine vasopressin challenges. Adrenal tissue was collected for quantitative RT-PCR mRNA determination at 3.5 yr of age. In 2-yr-old offspring, maternal betamethasone injections did not alter basal ACTH or cortisol levels, but repeated injections elevated ACTH responses. At 3 yr of age, basal ACTH was elevated, and both basal and stimulated cortisol levels were suppressed by repeated maternal injections. Basal and stimulated cortisol-to-ACTH ratios and basal cortisol-to-cytochrome P-450 17alpha-hydroxylase (P450c17) mRNA ratios were suppressed by repeated injections. Repeated fetal betamethasone injections attenuated basal ACTH and cortisol levels in offspring at 2 but not 3 yr of age. Plasma changes were not associated with altered adrenal P450c17, ACTH receptor, beta-hydroxysteroid dehydrogenase, or glucocorticoid receptor mRNA levels. These data suggest that maternal, but not fetal, betamethasone administration results in adrenal suppression in adulthood. 相似文献
96.
Influenza A virus infection of C57BL/6 (B6) mice is characterized by prominent CD8(+) T cell responses to H2D(b) complexed with peptides from the viral nucleoprotein (NP(366), ASNENMETM) and acid polymerase (PA(224), SSLENFRAYV). An in vivo cytotoxicity assay that depends on the adoptive transfer of peptide-pulsed, syngeneic targets was used in this study to quantitate the cytotoxic potential of D(b)NP(366)- and D(b)PA(224)-specific acute and memory CD8(+) T cells following primary or secondary virus challenge. Both T cell populations displayed equivalent levels of in vivo effector function when comparable numbers were transferred into naive B6 hosts. Cytotoxic activity following primary infection clearly correlated with the frequency of tetramer-stained CD8(+) T cells. This relationship looked, however, to be less direct following secondary exposure, partly because the numbers of CD8(+)D(b)NP(366)(+) T cells were greatly in excess. However, calculating the in vivo E:T ratios indicated that in vivo lysis, like many other biological functions, is threshold dependent. Furthermore, the capacity to eliminate peptide-pulsed targets was independent of the differentiation state (i.e., primary or secondary effectors) and was comparable for the two T cell specificities that were analyzed. These experiments provide insights that may be of value for adoptive immunotherapy, where careful consideration of both the activation state and the number of effector cells is required. 相似文献
97.
Keating R Yue W Rutigliano JA So J Olivas E Thomas PG Doherty PC 《Journal of immunology (Baltimore, Md. : 1950)》2007,178(5):2737-2745
Influenza A virus infection of C57BL/6 mice is a well-characterized model for studying CD8+ T cell-mediated immunity. Analysis of primary and secondary responses showed that the liver is highly enriched for CD8+ T cells specific for the immunodominant H2D(b)NP(366-374) (D(b)NP(366)) epitope. Functional analysis established that these liver-derived virus-specific CD8+ T cells are fully competent cytotoxic effectors and IFN-gamma secretors. In addition, flow cytometric analysis of early apoptotic cells showed that these influenza-specific CD8+ T cells from liver are as viable as those in the spleen, bronchoalveolar lavage, mediastinal lymph nodes, or lung. Moreover, cytokine profiles of the influenza-specific CD8+ T cells recovered from different sites were consistent with the bronchoalveolar lavage, rather than liver population, being the most susceptible to activation-induced cell death. Importantly, adoptively transferred influenza virus-specific CD8+ T cells from the liver survived and were readily recalled after virus challenge. Together, these results show clearly that the liver is not a "graveyard" for influenza virus-specific CD8+ T cells. 相似文献
98.
Normal levels of wild-type mitochondrial DNA maintain cytochrome c oxidase activity for two pathogenic mitochondrial DNA mutations but not for m.3243A-->G 下载免费PDF全文
Mitochondrial DNA (mtDNA) mutations are a common cause of human disease and accumulate as part of normal ageing and in common neurodegenerative disorders. Cells express a biochemical defect only when the proportion of mutated mtDNA exceeds a critical threshold, but it is not clear whether the actual cause of this defect is a loss of wild-type mtDNA, an excess of mutated mtDNA, or a combination of the two. Here, we show that segments of human skeletal muscle fibers harboring two pathogenic mtDNA mutations retain normal cytochrome c oxidase (COX) activity by maintaining a minimum amount of wild-type mtDNA. For these mutations, direct measurements of mutated and wild-type mtDNA molecules within the same skeletal muscle fiber are consistent with the "maintenance of wild type" hypothesis, which predicts that there is nonselective proliferation of mutated and wild-type mtDNA in response to the molecular defect. However, for the m.3243A-->G mutation, a superabundance of wild-type mtDNA was found in many muscle-fiber sections with negligible COX activity, indicating that the pathogenic mechanism for this particular mutation involves interference with the function of the wild-type mtDNA or wild-type gene products. 相似文献
99.
Conditional deletion of focal adhesion kinase leads to defects in ventricular septation and outflow tract alignment 总被引:1,自引:0,他引:1 下载免费PDF全文
Hakim ZS DiMichele LA Doherty JT Homeister JW Beggs HE Reichardt LF Schwartz RJ Brackhan J Smithies O Mack CP Taylor JM 《Molecular and cellular biology》2007,27(15):5352-5364
To examine a role for focal adhesion kinase (FAK) in cardiac morphogenesis, we generated a line of mice with a conditional deletion of FAK in nkx2-5-expressing cells (herein termed FAKnk mice). FAKnk mice died shortly after birth, likely resulting from a profound subaortic ventricular septal defect and associated malalignment of the outflow tract. Additional less penetrant phenotypes included persistent truncus arteriosus and thickened valve leaflets. Thus, conditional inactivation of FAK in nkx2-5-expressing cells leads to the most common congenital heart defect that is also a subset of abnormalities associated with tetralogy of Fallot and the DiGeorge syndrome. No significant differences in proliferation or apoptosis between control and FAKnk hearts were observed. However, decreased myocardialization was observed for the conal ridges of the proximal outflow tract in FAKnk hearts. Interestingly, chemotaxis was significantly attenuated in isolated FAK-null cardiomyocytes in comparison to genetic controls, and these effects were concomitant with reduced tyrosine phosphorylation of Crk-associated substrate (CAS). Thus, it is possible that ventricular septation and appropriate outflow tract alignment is dependent, at least in part, upon FAK-dependent CAS activation and subsequent induction of polarized myocyte movement into the conal ridges. Future studies will be necessary to determine the precise contributions of the additional nkx2-5-derived lineages to the phenotypes observed. 相似文献
100.