全文获取类型
收费全文 | 1775篇 |
免费 | 165篇 |
出版年
2023年 | 17篇 |
2022年 | 14篇 |
2021年 | 38篇 |
2020年 | 34篇 |
2019年 | 45篇 |
2018年 | 42篇 |
2017年 | 30篇 |
2016年 | 58篇 |
2015年 | 88篇 |
2014年 | 90篇 |
2013年 | 105篇 |
2012年 | 161篇 |
2011年 | 154篇 |
2010年 | 70篇 |
2009年 | 85篇 |
2008年 | 113篇 |
2007年 | 105篇 |
2006年 | 93篇 |
2005年 | 88篇 |
2004年 | 76篇 |
2003年 | 93篇 |
2002年 | 94篇 |
2001年 | 18篇 |
2000年 | 12篇 |
1999年 | 26篇 |
1998年 | 20篇 |
1997年 | 14篇 |
1996年 | 11篇 |
1995年 | 14篇 |
1994年 | 10篇 |
1993年 | 7篇 |
1992年 | 8篇 |
1991年 | 10篇 |
1990年 | 3篇 |
1989年 | 6篇 |
1988年 | 3篇 |
1987年 | 12篇 |
1986年 | 7篇 |
1985年 | 7篇 |
1984年 | 9篇 |
1983年 | 8篇 |
1982年 | 5篇 |
1981年 | 3篇 |
1979年 | 4篇 |
1975年 | 3篇 |
1973年 | 4篇 |
1972年 | 2篇 |
1971年 | 3篇 |
1968年 | 3篇 |
1963年 | 2篇 |
排序方式: 共有1940条查询结果,搜索用时 15 毫秒
931.
Iris Lansdorp-Vogelaar Stacey Fedewa Chun Chieh Lin Katherine S. Virgo Ahmedin Jemal 《PloS one》2014,9(11)
Background
Surveillance in patients with previous polypectomy was underused in the Medicare population in 1994. This study investigates whether expansion of Medicare reimbursement for colonoscopy screening in high-risk individuals has reduced the inappropriate use of surveillance.Methods
We used Kaplan-Meier analysis to estimate time to surveillance and polyp recurrence rates for Medicare beneficiaries with a colonoscopy with polypectomy between 1998 and 2003 who were followed through 2008 for receipt of surveillance colonoscopy. Generalized Estimating Equations were used to estimate risk factors for: 1) failing to undergo surveillance and 2) polyp recurrence among these individuals. Analyses were stratified into three 2-year cohorts based on baseline colonoscopy date.Results
Medicare beneficiaries undergoing a colonoscopy with polypectomy in the 1998–1999 (n = 4,136), 2000–2001 (n = 3,538) and 2002–2003 (n = 4,655) cohorts had respective probabilities of 30%, 26% and 20% (p<0.001) of subsequent surveillance events within 3 years. At the same time, 58%, 52% and 45% (p<0.001) of beneficiaries received a surveillance event within 5 years. Polyp recurrence rates after 5 years were 36%, 30% and 26% (p<0.001) respectively. Older age (≥ 70 years), female gender, later cohort (2000–2001 & 2002–2003), and severe comorbidity were the most important risk factors for failure to undergo a surveillance event. Male gender and early cohort (1998–1999) were the most important risk factors for polyp recurrence.Conclusions
Expansion of Medicare reimbursement for colonoscopy screening in high-risk individuals has not reduced underutilization of surveillance in the Medicare population. It is important to take action now to improve this situation, because polyp recurrence is substantial in this population. 相似文献932.
Janna N. Vrijsen Anne Speckens Alejandro Arias-Vásquez Barbara Franke Eni S. Becker Iris van Oostrom 《PloS one》2014,9(11)
The PCLO rs2522833 candidate polymorphism for depression has been associated to monoaminergic neurotransmission. In healthy and currently depressed individuals, the polymorphism has been found to affect activation of brain areas during memory processing, but no direct association of PCLO with memory bias was found. We hypothesized that the absence of this association might have been obscured by current depressive symptoms or genetically driven individual differences in reactivity to stressful events. Experiencing stressful childhood events fosters dysfunctional assumptions that are related to cognitive biases, and may modulate the predisposition for depression via epigenetic effects. The association between PCLO and memory bias, as well as interaction between PCLO and childhood events was studied in patients remitted from depression (N = 299), as well as a sample of healthy individuals (N = 157). The participants performed an emotional verbal memory task after a sad mood induction. Childhood trauma and adversity were measured with a questionnaire. The Genotype main effect, and Genotype by Childhood Events interaction were analyzed for memory bias in both samples. PCLO risk allele carrying remitted depressed patients did not show more negatively biased memory than non-risk allele carriers, not even patients with stressful childhood events. A similar pattern of results was found in healthy individuals. Memory bias may not be strongly associated with the PCLO rs2522833 polymorphism. We did not find any support for the PCLO-childhood events interaction, but the power of our study was insufficient to exclude this possibility. 相似文献
933.
Zainab AlKhatib Marcel Lagedroste Iris Fey Diana Kleinschrodt André Abts Sander H. J. Smits 《PloS one》2014,9(7)
Nisin, a 3.4 kDa antimicrobial peptide produced by some Lactococcus lactis strains is the most prominent member of the lantibiotic family. Nisin can inhibit cell growth and penetrates the target Gram-positive bacterial membrane by binding to Lipid II, an essential cell wall synthesis precursor. The assembled nisin-Lipid II complex forms pores in the target membrane. To gain immunity against its own-produced nisin, Lactococcus lactis is expressing two immunity protein systems, NisI and NisFEG. Here, we show that the NisI expressing strain displays an IC50 of 73±10 nM, an 8–10-fold increase when compared to the non-expressing sensitive strain. When the nisin concentration is raised above 70 nM, the cells expressing full-length NisI stop growing rather than being killed. NisI is inhibiting nisin mediated pore formation, even at nisin concentrations up to 1 µM. This effect is induced by the C-terminus of NisI that protects Lipid II. Its deletion showed pore formation again. The expression of NisI in combination with externally added nisin mediates an elongation of the chain length of the Lactococcus lactis cocci. While the sensitive strain cell-chains consist mainly of two cells, the NisI expressing cells display a length of up to 20 cells. Both results shed light on the immunity of lantibiotic producer strains, and their survival in high levels of their own lantibiotic in the habitat. 相似文献
934.
Many experiments require early determination of offspring''s sex as well as early marking of newborns for individual recognition. According to animal welfare guidelines, non-invasive techniques should be preferred whenever applicable. In our group, we work on different species of song birds in the lab and in the field, and we successfully apply non-invasive methods to sex and individually mark chicks. This paper presents a comprehensive non-invasive tool-box. Sexing birds prior to the expression of secondary sexual traits requires the collection of DNA-bearing material for PCR. We established a quick and easy method to sex birds of any age (post hatching) by extracting DNA from buccal swabs. Results can be obtained within 3 hours. For individual marking chick''s down feathers are trimmed in specific patterns allowing fast identification within the hatching order. This set of methods is easily applicable in a standard equipped lab and especially suitable for working in the field as no special equipment is required for sampling and storage. Handling of chicks is minimized and marking and sexing techniques are non-invasive thereby supporting the RRR-principle of animal welfare guidelines. 相似文献
935.
Jana Krauss Silke Geiger‐Rudolph Iris Koch Christiane Nüsslein‐Volhard Uwe Irion 《Pigment cell & melanoma research》2014,27(5):827-830
Melanin biosynthesis in vertebrates depends on the function of three enzymes of the tyrosinase family, tyrosinase (Tyr), tyrosinase‐related protein 1 (Tyrp1), and dopachrome tautomerase (Dct or Tyrp2). Tyrp1 might play an additional role in the survival and proliferation of melanocytes. Here, we describe a mutation in tyrp1A, one of the two tyrp1 paralogs in zebrafish, which causes melanophore death leading to a semi‐dominant phenotype. The mutation, an Arg‐>Cys change in the amino‐terminal part of the protein, is similar to mutations in humans and mice where they lead to blond hair (in melanesians) or dark hair with white bases, respectively. We demonstrate that the phenotype in zebrafish depends on the presence of the mutant protein and on melanin synthesis. Ultrastructural analysis shows that the melanosome morphology and pigment content are altered in the mutants. These structural changes might be the underlying cause for the observed cell death, which, surprisingly, does not result in patterning defects. 相似文献
936.
Michal Entin-Meer Ran Levy Pavel Goryainov Natalie Landa Iris Barshack Camila Avivi Jonathan Semo Gad Keren 《PloS one》2014,9(8)
Purpose
A novel family of transient receptor potential (TRP) channels, that may hold a role in calcium homeostasis, has recently been described. By employing a GeneChip array analysis we have demonstrated a clear and specific upregulation of the TRP vanilloid 2 (TRPV2) mRNA in the left ventricles (LV) 3–5 days post-acute myocardial infarction (MI) compared to sham-operated controls, both in rats and in mice. We sought to characterize the cardiac cellular subpopulations in which TRPV2 is overexpressed upon acute MI.Methods
Lewis rats underwent an acute MI by ligation of the left anterior descending artery or chest opening only (sham). The animals were terminated at various time points and an immunohistochemical (IHC) and immunofloerescent (IFC) staining of the LV sections as well as a flow cytometry analysis of LV-derived cells were carried out, using anti-TRPV2 and anti-monocyte/macrophage antibodies. Rat alveolar macrophage cells, NR8383, transiently transfected with TRPV2 siRNA were allowed to migrate towards hypoxic conditioned media of the rat cardiac myoblast line H9C2 using a trans-well migration assay. The macrophage cells migrating to the bottom side of the inserts were counted.Results
The IHC and IFC staining as well as the flow cytometry data demonstrated a substantial expression of TRPV2 in infiltrating macrophages in the peri-infarct region 3–5 days post-acute MI. The in vitro migration assay data demonstrated that following inhibition of the TRPV2 channel, the number of migrating macrophages towards conditioned medium of hypoxic cardiomyocytes was significantly reduced.Conclusions
TRPV2 is highly expressed on the peri-infarct infiltrating macrophages and may play an important role in post-MI phagocytosis. Better characterization of this channel may pave the way for identifying a new target for modulating the dramatic post-MI immune reactions. 相似文献937.
Iris Jonker Hans C. Klein Hester E. Duivis Robert H. Yolken Judith G. M. Rosmalen Robert A. Schoevers 《PloS one》2014,9(7)
Background
Infections with different herpes viruses have been associated with cognitive functioning in psychiatric patients and healthy adults. The aim of this study was to find out whether antibodies to different herpes viruses are prospectively associated with cognitive functioning in a general adolescent population.Methods
This study was performed in TRAILS, a large prospective general population cohort (N = 1084, 54% female, mean age 16.2 years (SD 0.6)). At age 16, immunoglobulin G antibodies against HSV1, HSV2, CMV and EBV were measured next to high sensitive C-Reactive Protein (hsCRP). Two years later, immediate memory and executive functioning were assessed using the 15 words task and the self ordered pointing task. Multiple linear regression analysis with bootstrapping was performed to study the association between viral infections and cognitive function, adjusting for gender, socioeconomic status, ethnicity, and cannabis use.Results
Presence of HSV1 antibodies was associated with memory function ((B = −0.272, 95% CI = −0.556 to −0.016, p = 0.047)), while the association with executive functioning did not reach statistical significance (B = 0.560, 95% CI is −0.053 to 1.184, p = 0.075). The level of HSV1 antibodies was associated with both memory function (B = −0.160, 95% CI = −0.280 to −0.039, p = 0.014) and executive functioning (B = 0.296, 95% CI = 0.011 to 0.578, p = 0.046). Other herpes viruses and hsCRP were not associated with cognitive functioning.Conclusions
Both presence and level of HSV1 antibodies are prospectively associated with reduced cognitive performance in a large cohort of adolescents. 相似文献938.
Dagmar Brugger Iris Krondorfer Christopher Shelswell Benjamin Huber-Dittes Dietmar Haltrich Clemens K. Peterbauer 《PloS one》2014,9(10)
Pyranose 2-oxidase (POx), a member of the GMC family of flavoproteins, catalyzes the regioselective oxidation of aldopyranoses at position C2 to the corresponding 2-ketoaldoses. During the first half-reaction, FAD is reduced to FADH2 and reoxidized in the second half-reaction by reducing molecular oxygen to H2O2. Alternative electron acceptors including quinones, radicals or chelated metal ions show significant and in some cases even higher activity. While oxygen as cheap and abundantly available electron acceptor is favored for many processes, reduced oxygen reactivity is desirable for some applications such as in biosensors/biofuel cells because of reduced oxidative damages to the biocatalyst from concomitant H2O2 production as well as reduced electron “leakage” to oxygen. The reactivity of flavoproteins with oxygen is of considerable scientific interest, and the determinants of oxygen activation and reactivity are the subject of numerous studies. We applied site-saturation mutagenesis on a set of eleven amino acids around the active site based on the crystal structure of the enzyme. Using microtiter plate screening assays with peroxidase/2,2′-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid) and 2,6-dichlorophenolindophenol, variants of POx with decreased oxidase activity and maintained dehydrogenase activity were identified. Variants T166R, Q448H, L545C, L547R and N593C were characterized with respect to their apparent steady-state constants with oxygen and the alternative electron acceptors DCPIP, 1,4-benzoquinone and ferricenium ion, and the effect of the mutations was rationalized based on structural properties. 相似文献
939.
Michael Wilschanski Montaser Abbasi Elias Blanco Iris Lindberg Michael Yourshaw David Zangen Itai Berger Eyal Shteyer Orit Pappo Benjamin Bar-Oz Martin G. Martín Orly Elpeleg 《PloS one》2014,9(10)
Four siblings presented with congenital diarrhea and various endocrinopathies. Exome sequencing and homozygosity mapping identified five regions, comprising 337 protein-coding genes that were shared by three affected siblings. Exome sequencing identified a novel homozygous N309K mutation in the proprotein convertase subtilisin/kexin type 1 (PCSK1) gene, encoding the neuroendocrine convertase 1 precursor (PC1/3) which was recently reported as a cause of Congenital Diarrhea Disorder (CDD). The PCSK1 mutation affected the oxyanion hole transition state-stabilizing amino acid within the active site, which is critical for appropriate proprotein maturation and enzyme activity. Unexpectedly, the N309K mutant protein exhibited normal, though slowed, prodomain removal and was secreted from both HEK293 and Neuro2A cells. However, the secreted enzyme showed no catalytic activity, and was not processed into the 66 kDa form. We conclude that the N309K enzyme is able to cleave its own propeptide but is catalytically inert against in trans substrates, and that this variant accounts for the enteric and systemic endocrinopathies seen in this large consanguineous kindred. 相似文献
940.
Siana Nkya Mtatiro Tarjinder Singh Helen Rooks Josephine Mgaya Harvest Mariki Deogratius Soka Bruno Mmbando Evarist Msaki Iris Kolder Swee Lay Thein Stephan Menzel Sharon E. Cox Julie Makani Jeffrey C. Barrett 《PloS one》2014,9(11)