全文获取类型
收费全文 | 1486篇 |
免费 | 157篇 |
专业分类
1643篇 |
出版年
2023年 | 11篇 |
2022年 | 23篇 |
2021年 | 33篇 |
2020年 | 24篇 |
2019年 | 29篇 |
2018年 | 41篇 |
2017年 | 35篇 |
2016年 | 52篇 |
2015年 | 70篇 |
2014年 | 79篇 |
2013年 | 105篇 |
2012年 | 108篇 |
2011年 | 95篇 |
2010年 | 49篇 |
2009年 | 66篇 |
2008年 | 56篇 |
2007年 | 62篇 |
2006年 | 58篇 |
2005年 | 67篇 |
2004年 | 52篇 |
2003年 | 52篇 |
2002年 | 50篇 |
2001年 | 30篇 |
2000年 | 32篇 |
1999年 | 39篇 |
1998年 | 18篇 |
1997年 | 19篇 |
1996年 | 16篇 |
1995年 | 17篇 |
1994年 | 10篇 |
1993年 | 10篇 |
1992年 | 14篇 |
1991年 | 18篇 |
1990年 | 16篇 |
1989年 | 22篇 |
1988年 | 18篇 |
1987年 | 15篇 |
1986年 | 6篇 |
1985年 | 11篇 |
1984年 | 6篇 |
1983年 | 7篇 |
1982年 | 9篇 |
1980年 | 11篇 |
1979年 | 7篇 |
1978年 | 7篇 |
1977年 | 8篇 |
1975年 | 7篇 |
1973年 | 13篇 |
1970年 | 6篇 |
1965年 | 3篇 |
排序方式: 共有1643条查询结果,搜索用时 0 毫秒
51.
Gabriela B. Gomez Nicola Foster Daniella Brals Heleen E. Nelissen Oladimeji A. Bolarinwa Marleen E. Hendriks Alexander C. Boers Diederik van Eck Nicole Rosendaal Peju Adenusi Kayode Agbede Tanimola M. Akande Michael Boele van Hensbroek Ferdinand W. Wit Catherine A. Hankins Constance Schultsz 《PloS one》2015,10(9)
Background
While the Nigerian government has made progress towards the Millennium Development Goals, further investments are needed to achieve the targets of post-2015 Sustainable Development Goals, including Universal Health Coverage. Economic evaluations of innovative interventions can help inform investment decisions in resource-constrained settings. We aim to assess the cost and cost-effectiveness of maternal care provided within the new Kwara State Health Insurance program (KSHI) in rural Nigeria.Methods and Findings
We used a decision analytic model to simulate a cohort of pregnant women. The primary outcome is the incremental cost effectiveness ratio (ICER) of the KSHI scenario compared to the current standard of care. Intervention cost from a healthcare provider perspective included service delivery costs and above-service level costs; these were evaluated in a participating hospital and using financial records from the managing organisations, respectively. Standard of care costs from a provider perspective were derived from the literature using an ingredient approach. We generated 95% credibility intervals around the primary outcome through probabilistic sensitivity analysis (PSA) based on a Monte Carlo simulation. We conducted one-way sensitivity analyses across key model parameters and assessed the sensitivity of our results to the performance of the base case separately through a scenario analysis. Finally, we assessed the sustainability and feasibility of this program’s scale up within the State’s healthcare financing structure through a budget impact analysis. The KSHI scenario results in a health benefit to patients at a higher cost compared to the base case. The mean ICER (US$46.4/disability-adjusted life year averted) is considered very cost-effective compared to a willingness-to-pay threshold of one gross domestic product per capita (Nigeria, US$ 2012, 2,730). Our conclusion was robust to uncertainty in parameters estimates (PSA: median US$49.1, 95% credible interval 21.9–152.3), during one-way sensitivity analyses, and when cost, quality, cost and utilization parameters of the base case scenario were changed. The sustainability of this program’s scale up by the State is dependent on further investments in healthcare.Conclusions
This study provides evidence that the investment made by the KSHI program in rural Nigeria is likely to have been cost-effective; however, further healthcare investments are needed for this program to be successfully expanded within Kwara State. Policy makers should consider supporting financial initiatives to reduce maternal mortality tackling both supply and demand issues in the access to care. 相似文献52.
53.
The retromer complex, composed of sorting nexin subunits and a Vps26/Vps29/Vps35 trimer, mediates sorting of retrograde cargo from the endosome to the trans-Golgi network. The retromer trimer subcomplex is an effector of Rab7 (Ypt7 in yeast). Whereas endosome targeting of human retromer has been shown to require Rab7-GTP, targeting of yeast retromer to the endosome is independent of Ypt7-GTP and requires the Vps5 and Vps17 retromer sorting nexin subunits. An evolutionarily conserved amino acid segment within Vps35 is required for Ypt7/Rab7 recognition in vivo by both yeast and human retromer, establishing that Rab recognition is a conserved feature of this subunit. Recognition of Ypt7 by retromer is required for its function in retrograde sorting, and in yeast cells lacking the guanine nucleotide exchange factor for Ypt7, retrograde cargo accumulates in endosomes that are decorated with retromer, revealing an additional role for Rab recognition at the cargo export stage of the retromer functional cycle. In addition, yeast retromer trimer antagonizes Ypt7-regulated organelle tethering and fusion of endosomes/vacuoles via recognition of Ypt7. Thus retromer has dual roles in retrograde cargo export and in controlling the fusion dynamics of the late endovacuolar system. 相似文献
54.
Olga P. Nyssen Angeles Perez‐Aisa Luis Rodrigo Manuel Castro Pilar Mata Romero Juan Ortuo Jesus Barrio Jose Maria Huguet Ines Modollel Noelia Alcaide Alfredo Lucendo Xavier Calvet Monica Perona Barbara Gomez Blas Jose Gomez Rodriguez Pilar Varela Manuel Jimenez‐Moreno Manuel Dominguez‐Cajal Liliana Pozzati Diego Burgos Luis Bujanda Jenifer Hinojosa Javier Molina‐Infante Tommaso Di Maira Luis Ferrer Luis Fernndez‐Salazar Ariadna Figuerola Llucia Tito Cristobal de la Coba Judith Gomez‐Camarero Nuria Fernandez Maria Caldas Ana Garre Elena Resina Ignasi Puig Colm OMorain Francis Megraud Javier P. Gisbert 《Helicobacter》2020,25(5)
55.
A series of 5-aminosubstituted 4-fluorobenzyl-8-hydroxy-[1,6]naphthyridine-7-carboxamide HIV-1 integrase inhibitors 总被引:2,自引:0,他引:2
Guare JP Wai JS Gomez RP Anthony NJ Jolly SM Cortes AR Vacca JP Felock PJ Stillmock KA Schleif WA Moyer G Gabryelski LJ Jin L Chen IW Hazuda DJ Young SD 《Bioorganic & medicinal chemistry letters》2006,16(11):2900-2904
A series of 5-amino derivatives of 8-hydroxy[1,6]-naphthyridine-7-carboxamide exhibiting sub-micromolar potency against replication of HIV-1 in cell culture was identified. One of these analogs, compound 12, displayed excellent pharmacokinetic properties when dosed orally in rats and in monkeys. This compound was demonstrated to be efficacious against replication of simian-human immunodeficiency virus (SHIV) 89.6P in infected rhesus macaques. 相似文献
56.
Mnica Arias Marianne Elias Christine Andraud Serge Berthier Doris Gomez 《Journal of evolutionary biology》2020,33(2):247-252
Predation is a ubiquitous and strong selective pressure on living organisms. Transparency is a predation defence widespread in water but rare on land. Some Lepidoptera display transparent patches combined with already cryptic opaque patches. A recent study showed that transparency reduced detectability of aposematic prey with conspicuous patches. However, whether transparency has any effect at reducing detectability of already cryptic prey is still unknown. We conducted field predation experiments with free avian predators where we monitored and compared survival of a fully opaque grey artificial form (cryptic), a form including transparent windows and a wingless artificial butterfly body. Survival of the transparent forms was similar to that of wingless bodies and higher than that of fully opaque forms, suggesting a reduction of detectability conferred by transparency. This is the first evidence that transparency decreases detectability in cryptic terrestrial prey. Future studies should explore the organization of transparent and opaque patches in animals and their interplay on survival, as well as the costs and other potential benefits associated with transparency on land. 相似文献
57.
Miguel Camacho‐Sanchez Pablo Burraco Ivan Gomez‐Mestre Jennifer A. Leonard 《Molecular ecology resources》2013,13(4):663-673
Ecological and conservation genetics require sampling of organisms in the wild. Appropriate preservation of the collected samples, usually by cryostorage, is key to the quality of the genetic data obtained. Nevertheless, cryopreservation in the field to ensure RNA and DNA stability is not always possible. We compared several nucleic acid preservation solutions appropriate for field sampling and tested them on rat (Rattus rattus) blood, ear and tail tip, liver, brain and muscle. We compared the efficacy of a nucleic acid preservation (NAP) buffer for DNA preservation against 95% ethanol and Longmire buffer, and for RNA preservation against RNAlater (Qiagen) and Longmire buffer, under simulated field conditions. For DNA, the NAP buffer was slightly better than cryopreservation or 95% ethanol, but high molecular weight DNA was preserved in all conditions. The NAP buffer preserved RNA as well as RNAlater. Liver yielded the best RNA and DNA quantity and quality; thus, liver should be the tissue preferentially collected from euthanized animals. We also show that DNA persists in nonpreserved muscle tissue for at least 1 week at ambient temperature, although degradation is noticeable in a matter of hours. When cryopreservation is not possible, the NAP buffer is an economical alternative for RNA preservation at ambient temperature for at least 2 months and DNA preservation for at least 10 months. 相似文献
58.
Gender differences in human immunodeficiency virus type 1-specific CD8 responses in the reproductive tract and colon following nasal peptide priming and modified vaccinia virus Ankara boosting 下载免费PDF全文
Peacock JW Nordone SK Jackson SS Liao HX Letvin NL Yafal AG Gritz L Mazzara GP Haynes BF Staats HF 《Journal of virology》2004,78(23):13163-13172
Induction of mucosal anti-human immunodeficiency virus type 1 (HIV-1) T-cell responses in males and females will be important for the development of a successful HIV-1 vaccine. An HIV-1 envelope peptide, DNA plasmid, and recombinant modified vaccinia virus Ankara (rMVA) expressing the H-2D(d)-restricted cytotoxic T lymphocyte P18 epitope were used as immunogens to test for their ability to prime and boost anti-HIV-1 T-cell responses at mucosal and systemic sites in BALB/c mice. We found of all prime-boost combinations tested, an HIV-1 Env peptide subunit mucosal prime followed by systemic (intradermal) boosting with rMVA yielded the maximal induction of gamma interferon (IFN-gamma) spot-forming cells in the female genital tract and colon. However, this mucosal prime-systemic rMVA boost regimen was minimally immunogenic for the induction of genital, colon, or lung anti-HIV-1 T-cell responses in male mice. We determined that a mucosal Env subunit immunization could optimally prime an rMVA boost in female but not male mice, as determined by the magnitude of antigen-specific IFN-gamma responses in the reproductive tracts, colon, and lung. Defective mucosal priming in male mice could not be overcome by multiple mucosal immunizations. However, rMVA priming followed by an rMVA boost was the optimal prime-boost strategy for male mice as determined by the magnitude of antigen-specific IFN-gamma responses in the reproductive tract and lung. Thus, prime-boost immunization strategies able to induce mucosal antigen-specific IFN-gamma responses were identified for male and female mice. Understanding the cellular and molecular basis of gender-determined immune responses will be important for optimizing induction of anti-HIV-1 mucosal immune responses in both males and females. 相似文献
59.
Lipids are known to play a crucial role both in the normal control of insulin release and in the deterioration of β-cell function, as observed in type 2 diabetes. Despite this established dual role of lipids, little is known about lipid storage and handling in β-cells. Here, we isolated lipid droplets from oleate-incubated INS-1 832/13 cells and characterized the lipid droplet proteome. In a total of four rounds of droplet isolation and proteomic analysis by HPLC-MS/MS, we identified 96 proteins that were specific to droplets. The proteins fall into six categories based on function or previously observed localization: metabolism, endoplasmic reticulum/ribosomes, mitochondria, vesicle formation and transport, signaling, and miscellaneous. The protein profile reinforces the emerging picture of the lipid droplet as an active and dynamic organelle involved in lipid homeostasis and intracellular trafficking. Proteins belonging to the category mitochondria were highly represented, suggesting that the β-cell mitochondria and lipid droplets form a metabolic unit of potential relevance for insulin secretion. 相似文献
60.
J-S Zhang M Herreros-Vilanueva A Koenig Z Deng A A-M de Narvajas T S Gomez X Meng L Bujanda V Ellenrieder X K Li S H Kaufmann D D Billadeau 《Cell death & disease》2014,5(3):e1142
While TRAIL is a promising anticancer agent due to its ability to selectively induce
apoptosis in neoplastic cells, many tumors, including pancreatic ductal adenocarcinoma
(PDA), display intrinsic resistance, highlighting the need for TRAIL-sensitizing agents.
Here we report that TRAIL-induced apoptosis in PDA cell lines is enhanced by
pharmacological inhibition of glycogen synthase kinase-3 (GSK-3) or by shRNA-mediated
depletion of either GSK-3α or GSK-3β. In contrast, depletion
of GSK-3β, but not GSK-3α, sensitized PDA cell lines to
TNFα-induced cell death. Further experiments demonstrated that
TNFα-stimulated IκBα phosphorylation and
degradation as well as p65 nuclear translocation were normal in
GSK-3β-deficient MEFs. Nonetheless, inhibition of GSK-3β
function in MEFs or PDA cell lines impaired the expression of the NF-κB
target genes Bcl-xL and cIAP2, but not IκBα. Significantly,
the expression of Bcl-xL and cIAP2 could be reestablished by expression of
GSK-3β targeted to the nucleus but not GSK-3β targeted to
the cytoplasm, suggesting that GSK-3β regulates NF-κB
function within the nucleus. Consistent with this notion, chromatin immunoprecipitation
demonstrated that GSK-3 inhibition resulted in either decreased p65 binding to the
promoter of BIR3, which encodes cIAP2, or increased p50 binding as well as
recruitment of SIRT1 and HDAC3 to the promoter of BCL2L1, which encodes Bcl-xL.
Importantly, depletion of Bcl-xL but not cIAP2, mimicked the sensitizing effect of GSK-3
inhibition on TRAIL-induced apoptosis, whereas Bcl-xL overexpression ameliorated the
sensitization by GSK-3 inhibition. These results not only suggest that
GSK-3β overexpression and nuclear localization contribute to TNFα
and TRAIL resistance via anti-apoptotic NF-κB genes such as Bcl-xL, but
also provide a rationale for further exploration of GSK-3 inhibitors combined with TRAIL
for the treatment of PDA. 相似文献