全文获取类型
收费全文 | 765篇 |
免费 | 57篇 |
国内免费 | 1篇 |
专业分类
823篇 |
出版年
2023年 | 5篇 |
2022年 | 14篇 |
2021年 | 23篇 |
2020年 | 16篇 |
2019年 | 10篇 |
2018年 | 17篇 |
2017年 | 15篇 |
2016年 | 21篇 |
2015年 | 36篇 |
2014年 | 43篇 |
2013年 | 78篇 |
2012年 | 68篇 |
2011年 | 67篇 |
2010年 | 33篇 |
2009年 | 33篇 |
2008年 | 56篇 |
2007年 | 45篇 |
2006年 | 40篇 |
2005年 | 32篇 |
2004年 | 36篇 |
2003年 | 21篇 |
2002年 | 38篇 |
2001年 | 2篇 |
2000年 | 10篇 |
1999年 | 7篇 |
1998年 | 4篇 |
1997年 | 1篇 |
1996年 | 1篇 |
1995年 | 2篇 |
1994年 | 2篇 |
1993年 | 5篇 |
1992年 | 3篇 |
1991年 | 3篇 |
1990年 | 2篇 |
1989年 | 4篇 |
1988年 | 5篇 |
1987年 | 5篇 |
1986年 | 1篇 |
1985年 | 3篇 |
1984年 | 2篇 |
1983年 | 1篇 |
1981年 | 2篇 |
1977年 | 1篇 |
1975年 | 1篇 |
1973年 | 1篇 |
1972年 | 1篇 |
1971年 | 1篇 |
1969年 | 2篇 |
1966年 | 1篇 |
1962年 | 2篇 |
排序方式: 共有823条查询结果,搜索用时 15 毫秒
11.
Ashwin Sankar Kevin Thorpe Daniel I. McIsaac Jin Luo Duminda N. Wijeysundera Andrea S. Gershon 《CMAJ》2023,195(2):E62
Background:Chronic obstructive pulmonary disease (COPD) is common among surgical patients, and patients with COPD have higher risk for complications and death within 30 days after surgery. We sought to describe the longer-term postoperative survival and costs of patients with COPD compared with those without COPD within 1 year after inpatient elective surgery.Methods:In this retrospective population-based cohort study, we used linked health administrative databases to identify all patients undergoing inpatient elective surgery in Ontario, Canada, from 2005 to 2019. We ascertained COPD status using validated definitions. We followed participants for 1 year after surgery to evaluate survival and costs to the health system. We quantified the association of COPD with survival (Cox proportional hazards models) and costs (linear regression model with log-transformed costs) with partial adjustment (for sociodemographic factors and procedure type) and full adjustment (also adjusting for comorbidities). We assessed for effect modification by frailty, cancer and procedure type.Results:We included 932 616 patients, of whom 170 482 (18%) had COPD. With respect to association with risk of death, COPD had a partially adjusted hazard ratio (HR) of 1.61 (95% confidence interval [CI] 1.58–1.64), and a fully adjusted HR of 1.26 (95% CI 1.24–1.29). With respect to impact on health system costs, COPD was associated with a partially adjusted relative increase of 13.1% (95% CI 12.7%–13.4%), and an increase of 4.6% (95% CI 4.3%–5.0%) with full adjustment. Frailty, cancer and procedure type (such as orthopedic and lower abdominal surgery) modified the association between COPD and outcomes.Interpretation:Patients with COPD have decreased survival and increased costs in the year after surgery. Frailty, cancer and the type of surgical procedure modified associations between COPD and outcomes, and must be considered when risk-stratifying surgical patients with COPD.Contemporary estimates suggest that more than 10% of surgical patients have COPD.1 Patients with COPD are at increased risk for complications and death within 30 days after surgery;2–4 previous work estimates a 35% increase in odds of morbidity and a 30% increase in odds of death attributable to COPD after risk adjustment.3 However, existing studies have substantial shortcomings. Several included select hospitals, which limits generalizability, while others were narrow in scope and studied selected surgical procedures; most did not follow up patients for more than 30 days after surgery.2–7Patients with COPD may be at increased risk over the longer term owing to age and other comorbidities.8,9 Understanding the longer-term outcomes of surgical patients with COPD is critically important to accurately guide informed consent discussions and project care needs. The costs to health systems to care for patients with COPD after surgery are also unknown;10 delineating these costs would facilitate system-level budgeting and resource allocation. We sought to compare survival and health care costs up to 1 year after inpatient elective surgery between patients with and without COPD in a large, real-world surgical population in a health system where hospital and physician care are government-funded. 相似文献
12.
Harshad S. Ugamraj Kevin Dang Laure-Hlne Ouisse Benjamin Buelow Eduardo N. Chini Giulia Castello James Allison Starlynn C Clarke Laura M. Davison Roland Buelow Rong Deng Suhasini Iyer Ute Schellenberger Sankar N. Manika Shipra Bijpuria Astrid Musnier Anne Poupon Maria Cristina Cuturi Wim van Schooten Pranjali Dalvi 《MABS-AUSTIN》2022,14(1)
13.
How cells regulate the size of intracellular structures and organelles is a longstanding question. Recent experiments suggest that size control of intracellular structures is achieved through the depletion of a limiting subunit pool in the cytoplasm. While the limiting pool model ensures organelle-to-cell size scaling, it does not provide a mechanism for robust size control of multiple co-existing structures. Here we develop a generalized theory for size-dependent growth of intracellular structures to demonstrate that robust size control of multiple intracellular structures, competing for a limiting subunit pool, is achieved via a negative feedback between the growth rate and the size of the individual structure. This design principle captures size maintenance of a wide variety of subcellular structures, from cytoskeletal filaments to three-dimensional organelles. We identify the feedback motifs for structure size regulation based on known molecular processes, and compare our theory to existing models of size regulation in biological assemblies. Furthermore, we show that positive feedback between structure size and growth rate can lead to bistable size distribution and spontaneous size selection. 相似文献
14.
Nitesh Kumar Somlata Mohit Mazumder Priyanka Dutta Sankar Maiti Samudrala Gourinath 《PLoS pathogens》2014,10(9)
Entamoeba histolytica is a protist parasite that is the causative agent of amoebiasis, and is a highly motile organism. The motility is essential for its survival and pathogenesis, and a dynamic actin cytoskeleton is required for this process. EhCoactosin, an actin-binding protein of the ADF/cofilin family, participates in actin dynamics, and here we report our studies of this protein using both structural and functional approaches. The X-ray crystal structure of EhCoactosin resembles that of human coactosin-like protein, with major differences in the distribution of surface charges and the orientation of terminal regions. According to in vitro binding assays, full-length EhCoactosin binds both F- and G-actin. Instead of acting to depolymerize or severe F-actin, EhCoactosin directly stabilizes the polymer. When EhCoactosin was visualized in E. histolytica cells using either confocal imaging or total internal reflectance microscopy, it was found to colocalize with F-actin at phagocytic cups. Over-expression of this protein stabilized F-actin and inhibited the phagocytic process. EhCoactosin appears to be an unusual type of coactosin involved in E. histolytica actin dynamics. 相似文献
15.
Kelsey Bettridge Subhash Verma Xiaoli Weng Sankar Adhya Jie Xiao 《Molecular microbiology》2021,115(1):12-27
HU (Histone‐like protein from Escherichia coli strain U93) is the most conserved nucleoid‐associated protein in eubacteria, but how it impacts global chromosome organization is poorly understood. Using single‐molecule tracking, we demonstrate that HU exhibits nonspecific, weak, and transitory interactions with the chromosomal DNA. These interactions are largely mediated by three conserved, surface‐exposed lysine residues (triK), which were previously shown to be responsible for nonspecific binding to DNA. The loss of these weak, transitory interactions in a HUα(triKA) mutant results in an over‐condensed and mis‐segregated nucleoid. Mutating a conserved proline residue (P63A) in the HUα subunit, deleting the HUβ subunit, or deleting nucleoid‐associated naRNAs, each previously implicated in HU’s high‐affinity binding to kinked or cruciform DNA, leads to less dramatically altered interacting dynamics of HU compared to the HUα(triKA) mutant, but highly expanded nucleoids. Our results suggest HU plays a dual role in maintaining proper nucleoid volume through its differential interactions with chromosomal DNA. On the one hand, HU compacts the nucleoid through specific DNA structure‐binding interactions. On the other hand, it decondenses the nucleoid through many nonspecific, weak, and transitory interactions with the bulk chromosome. Such dynamic interactions may contribute to the viscoelastic properties and fluidity of the bacterial nucleoid to facilitate proper chromosome functions. 相似文献
16.
17.
Samuel H. Light Sankar N. Krishna Raymond C. Bergan Arnon Lavie Wayne F. Anderson 《Journal of structural and functional genomics》2013,14(1):25-30
Dehydroquinate dehydratase (DHQD) catalyzes the third step in the biosynthetic shikimate pathway. Here we identify a Bifidobacterium longum protein with high sequence homology to type II DHQDs but no detectable DHQD activity under standard assay conditions. A crystal structure reveals that the B. longum protein adopts a DHQD-like tertiary structure but a distinct quaternary state. Apparently forming a dimer, the B. longum protein lacks the active site aspartic acid contributed from a neighboring protomer in the type II DHQD dodecamer. Relating to the absence of protein–protein interactions established in the type II DHQD dodecameric assembly, substantial conformational changes distinguish the would-be active site of the B. longum protein. As B. longum possess no other genes with homology to known DHQDs, these findings imply a unique DHQD activity within B. longum. 相似文献
18.
Pamela Sankar 《New genetics and society》2013,32(3):249-264
Abstract In the United States, research that examines potential genetic contributions to health disparities often relies on racial categories. Some see benefit in this research especially for conditions where disparities in health status seem strongly associated with racial identity, such as heart disease and prostate cancer. But this research calls for close scrutiny. First, despite common optimism about genetic research, it may not be the most productive way to examine health disparities. And second, this research has the potential to contribute to racial stereotypes, arguably a prime cause of the health disparities the genetic research actually seeks to ameliorate. Two articles reporting results about genetics and heart disease are used to illustrate these concerns. Both report strong correlations between increased vulnerability to heart disease and black racial identity. Despite serious sampling and analysis problems in these articles, the findings rapidly entered the scientific and popular literature. A possible reason for their ready acceptance is their congruence with stereotypes that attribute poor health and genetic inferiority to minority US populations. 相似文献
19.
Randeep Singh Aniruddha Majumder Kalyanasundaram Sankar Qamar Qureshi Surendra Prakash Goyal Parag Nigam 《European Journal of Wildlife Research》2013,59(5):629-636
We studied the interbirth interval (IBI) and litter size of the population of free-ranging Bengal tigers (Panthera tigris tigris) in dry tropical deciduous forests in Ranthambhore Tiger Reserve (RTR), Rajasthan, and Pench Tiger Reserve (PTR), Madhya Pradesh, between April 2005 and June 2011. Data on 15 breeding females in RTR and nine breeding females in PTR were collected using camera trapping, direct observation and radio-telemetry. The mean?±?standard error of IBI (months) in RTR was 33.4?±?3.7 and in PTR was 25.2?±?1.8. A significant difference was observed between the mean IBI of tigresses in RTR and those in PTR (df?=?9, P?=?0.04). The estimated mean litter size in RTR was 2.3?±?0.1 and that in PTR was 2.9?±?0.2. There was a significant difference between the litter size in RTR and that in PTR (χ 2?=?12.04, P?=?0.017, df?=?4). Since RTR and PTR are the important source populations of tigers in the Western and Central Indian landscapes, we propose that the tigers in these reserves be monitored, particularly for reproductive traits that are essential for understanding aspects of their population ecology. 相似文献
20.
Dipankar Ray Shirish Shukla Uday Sankar Allam Abigail Helman Susmita Gurjar Ramanand Linda Tran Michael Bassetti Pranathi Meda Krishnamurthy Matthew Rumschlag Michelle Paulsen Lei Sun Thomas P. Shanley Mats Ljungman Mukesh K. Nyati Ming Zhang Theodore S. Lawrence 《PloS one》2013,8(2)
The efficacy of radiation therapy for lung cancer is limited by radiation-induced lung toxicity (RILT). Although tumor necrosis factor-alpha (TNF-α) signaling plays a critical role in RILT, the molecular regulators of radiation-induced TNF-α production remain unknown. We investigated the role of a major TNF-α regulator, Tristetraprolin (TTP), in radiation-induced TNF-α production by macrophages. For in vitro studies we irradiated (4 Gy) either a mouse lung macrophage cell line, MH-S or macrophages isolated from TTP knockout mice, and studied the effects of radiation on TTP and TNF-α levels. To study the in vivo relevance, mouse lungs were irradiated with a single dose (15 Gy) and assessed at varying times for TTP alterations. Irradiation of MH-S cells caused TTP to undergo an inhibitory phosphorylation at Ser-178 and proteasome-mediated degradation, which resulted in increased TNF-α mRNA stabilization and secretion. Similarly, MH-S cells treated with TTP siRNA or macrophages isolated from ttp (−/−) mice had higher basal levels of TNF-α, which was increased minimally after irradiation. Conversely, cells overexpressing TTP mutants defective in undergoing phosphorylation released significantly lower levels of TNF-α. Inhibition of p38, a known kinase for TTP, by either siRNA or a small molecule inhibitor abrogated radiation-induced TNF-α release by MH-S cells. Lung irradiation induced TTPSer178 phosphorylation and protein degradation and a simultaneous increase in TNF-α production in C57BL/6 mice starting 24 h post-radiation. In conclusion, irradiation of lung macrophages causes TTP inactivation via p38-mediated phosphorylation and proteasome-mediated degradation, leading to TNF-α production. These findings suggest that agents capable of blocking TTP phosphorylation or stabilizing TTP after irradiation could decrease RILT. 相似文献