全文获取类型
收费全文 | 6719篇 |
免费 | 482篇 |
出版年
2023年 | 31篇 |
2022年 | 46篇 |
2021年 | 151篇 |
2020年 | 70篇 |
2019年 | 114篇 |
2018年 | 139篇 |
2017年 | 128篇 |
2016年 | 201篇 |
2015年 | 305篇 |
2014年 | 316篇 |
2013年 | 419篇 |
2012年 | 540篇 |
2011年 | 478篇 |
2010年 | 272篇 |
2009年 | 255篇 |
2008年 | 361篇 |
2007年 | 392篇 |
2006年 | 343篇 |
2005年 | 291篇 |
2004年 | 243篇 |
2003年 | 237篇 |
2002年 | 236篇 |
2001年 | 128篇 |
2000年 | 133篇 |
1999年 | 113篇 |
1998年 | 60篇 |
1997年 | 58篇 |
1996年 | 46篇 |
1995年 | 50篇 |
1994年 | 38篇 |
1993年 | 42篇 |
1992年 | 97篇 |
1991年 | 76篇 |
1990年 | 75篇 |
1989年 | 65篇 |
1988年 | 50篇 |
1987年 | 54篇 |
1986年 | 46篇 |
1985年 | 44篇 |
1984年 | 44篇 |
1983年 | 49篇 |
1982年 | 21篇 |
1981年 | 21篇 |
1979年 | 36篇 |
1978年 | 21篇 |
1975年 | 26篇 |
1974年 | 22篇 |
1973年 | 19篇 |
1970年 | 21篇 |
1967年 | 21篇 |
排序方式: 共有7201条查询结果,搜索用时 15 毫秒
901.
Csilla Krausz Claudia Giachini Deborah Lo Giacco Fabrice Daguin Chiara Chianese Elisabet Ars Eduard Ruiz-Castane Gianni Forti Elena Rossi 《PloS one》2012,7(10)
Context
The role of CNVs in male infertility is poorly defined, and only those linked to the Y chromosome have been the object of extensive research. Although it has been predicted that the X chromosome is also enriched in spermatogenesis genes, no clinically relevant gene mutations have been identified so far.Objectives
In order to advance our understanding of the role of X-linked genetic factors in male infertility, we applied high resolution X chromosome specific array-CGH in 199 men with different sperm count followed by the analysis of selected, patient-specific deletions in large groups of cases and normozoospermic controls.Results
We identified 73 CNVs, among which 55 are novel, providing the largest collection of X-linked CNVs in relation to spermatogenesis. We found 12 patient-specific deletions with potential clinical implication. Cancer Testis Antigen gene family members were the most frequently affected genes, and represent new genetic targets in relationship with altered spermatogenesis. One of the most relevant findings of our study is the significantly higher global burden of deletions in patients compared to controls due to an excessive rate of deletions/person (0.57 versus 0.21, respectively; p = 8.785×10−6) and to a higher mean sequence loss/person (11.79 Kb and 8.13 Kb, respectively; p = 3.435×10−4).Conclusions
By the analysis of the X chromosome at the highest resolution available to date, in a large group of subjects with known sperm count we observed a deletion burden in relation to spermatogenic impairment and the lack of highly recurrent deletions on the X chromosome. We identified a number of potentially important patient-specific CNVs and candidate spermatogenesis genes, which represent novel targets for future investigations. 相似文献902.
Jeffrey R. Kugelman Michael S. Lee Cynthia A. Rossi Sarah E. McCarthy Sheli R. Radoshitzky John M. Dye Lisa E. Hensley Anna Honko Jens H. Kuhn Peter B. Jahrling Travis K. Warren Chris A. Whitehouse Sina Bavari Gustavo Palacios 《PloS one》2012,7(11)
To identify polymorphic sites that could be used as biomarkers of Ebola virus passage history, we repeatedly amplified Ebola virus (Kikwit variant) in vitro and in vivo and performed deep sequencing analysis of the complete genomes of the viral subpopulations. We then determined the sites undergoing selection during passage in Vero E6 cells. Four locations within the Ebola virus Kikwit genome were identified that together segregate cell culture-passaged virus and virus obtained from infected non-human primates. Three of the identified sites are located within the glycoprotein gene (GP) sequence: the poly-U (RNA editing) site at position 6925, as well as positions 6677, and 6179. One site was found in the VP24 gene at position 10833. In all cases, in vitro and in vivo, both populations (majority and minority variants) were maintained in the viral swarm, with rapid selections occurring after a few passages or infections. This analysis approach will be useful to differentiate whether filovirus stocks with unknown history have been passaged in cell culture and may support filovirus stock standardization for medical countermeasure development. 相似文献
903.
Viviana Lo Martire Alessandro Silvani Stefano Bastianini Chiara Berteotti Giovanna Zoccoli 《PloS one》2012,7(10)
The central neural pathways underlying the physiological coordination between thermoregulation and the controls of the wake-sleep behavior and cardiovascular function remain insufficiently understood. Growing evidence supports the involvement of hypocretin (orexin) peptides in behavioral, cardiovascular, and thermoregulatory functions. We investigated whether the effects of ambient temperature on wake-sleep behavior and cardiovascular control depend on the hypothalamic neurons that release hypocretin peptides. Orexin-ataxin3 transgenic mice with genetic ablation of hypocretin neurons (n = 11) and wild-type controls (n = 12) were instrumented with electrodes for sleep scoring and a telemetric blood pressure transducer. Simultaneous sleep and blood pressure recordings were performed on freely-behaving mice at ambient temperatures ranging between mild cold (20°C) and the thermoneutral zone (30°C). In both mouse groups, the time spent awake and blood pressure were higher at 20°C than at 30°C. The cold-related increase in blood pressure was significantly smaller in rapid-eye-movement sleep (REMS) than either in non-rapid-eye-movement sleep (NREMS) or wakefulness. Blood pressure was higher in wakefulness than either in NREMS or REMS at both ambient temperatures. This effect was significantly blunted in orexin-ataxin3 mice irrespective of ambient temperature and particularly during REMS. These data demonstrate that hypocretin neurons are not a necessary part of the central pathways that coordinate thermoregulation with wake-sleep behavior and cardiovascular control. Data also support the hypothesis that hypocretin neurons modulate changes in blood pressure between wakefulness and the sleep states. These concepts may have clinical implications in patients with narcolepsy with cataplexy, who lack hypocretin neurons. 相似文献
904.
Francesco Lescai Silvia Bonfiglio Chiara Bacchelli Estelle Chanudet Aoife Waters Sanjay M. Sisodiya Dalia Kasperavi?iūt? Julie Williams Denise Harold John Hardy Robert Kleta Sebahattin Cirak Richard Williams John C. Achermann John Anderson David Kelsell Tom Vulliamy Henry Houlden Nicholas Wood Una Sheerin Gian Paolo Tonini Donna Mackay Khalid Hussain Jane Sowden Veronica Kinsler Justyna Osinska Tony Brooks Mike Hubank Philip Beales Elia Stupka 《PloS one》2012,7(12)
Recent advances in genomics technologies have spurred unprecedented efforts in genome and exome re-sequencing aiming to unravel the genetic component of rare and complex disorders. While in rare disorders this allowed the identification of novel causal genes, the missing heritability paradox in complex diseases remains so far elusive. Despite rapid advances of next-generation sequencing, both the technology and the analysis of the data it produces are in its infancy. At present there is abundant knowledge pertaining to the role of rare single nucleotide variants (SNVs) in rare disorders and of common SNVs in common disorders. Although the 1,000 genome project has clearly highlighted the prevalence of rare variants and more complex variants (e.g. insertions, deletions), their role in disease is as yet far from elucidated.We set out to analyse the properties of sequence variants identified in a comprehensive collection of exome re-sequencing studies performed on samples from patients affected by a broad range of complex and rare diseases (N = 173). Given the known potential for Loss of Function (LoF) variants to be false positive, we performed an extensive validation of the common, rare and private LoF variants identified, which indicated that most of the private and rare variants identified were indeed true, while common novel variants had a significantly higher false positive rate. Our results indicated a strong enrichment of very low-frequency insertion/deletion variants, so far under-investigated, which might be difficult to capture with low coverage and imputation approaches and for which most of study designs would be under-powered. These insertions and deletions might play a significant role in disease genetics, contributing specifically to the underlining rare and private variation predicted to be discovered through next generation sequencing. 相似文献
905.
906.
Linda Sommese Chiara Pagliuca Bice Avallone Rossana Ippolito Amelia Casamassimi Valerio Costa Roberta Colicchio Raimondo Cerciello Maria D'Armiento Margherita Scarpato Alfonso Giovane Gabiria Pastore Teresa Infante Alfredo Ciccodicola Carmela Fiorito Francesco Paolo D'Armiento Paola Salvatore Claudio Napoli 《PloS one》2012,7(11)
Bartonella henselae is able to internalize endothelial progenitor cells (EPCs), which are resistant to the infection of other common pathogens. Bacteroides fragilis is a gram-negative anaerobe belonging to the gut microflora. It protects from experimental colitis induced by Helicobacter hepaticus through the polysaccharide A (PSA). The aim of our study was to establish: 1) whether B. fragilis colonization could protect from B. henselae infection; if this event may have beneficial effects on EPCs, vascular system and tissues. Our in vitro results establish for the first time that B. fragilis can internalize EPCs and competes with B. henselae during coinfection. We observed a marked activation of the inflammatory response by Real-time PCR and ELISA in coinfected cells compared to B. henselae-infected cells (63 vs 23 up-regulated genes), and after EPCs infection with mutant B. fragilis ΔPSA (≅90% up-regulated genes) compared to B. fragilis. Interestingly, in a mouse model of coinfection, morphological and ultrastructural analyses by hematoxylin-eosin staining and electron microscopy on murine tissues revealed that damages induced by B. henselae can be prevented in the coinfection with B. fragilis but not with its mutant B. fragilis ΔPSA. Moreover, immunohistochemistry analysis with anti-Bartonella showed that the number of positive cells per field decreased of at least 50% in the liver (20±4 vs 50±8), aorta (5±1 vs 10±2) and spleen (25±3 vs 40±6) sections of mice coinfected compared to mice infected only with B. henselae. This decrease was less evident in the coinfection with ΔPSA strain (35±6 in the liver, 5±1 in the aorta and 30±5 in the spleen). Finally, B. fragilis colonization was also able to restore the EPC decrease observed in mice infected with B. henselae (0.65 vs 0.06 media). Thus, our data establish that B. fragilis colonization is able to prevent B. henselae damages through PSA. 相似文献
907.
C Corrado AM Flugy S Taverna S Raimondo G Guggino R Karmali G De Leo R Alessandro 《PloS one》2012,7(8):e42310
The Bcr/Abl kinase has been targeted for the treatment of chronic myelogenous leukaemia (CML) by imatinib mesylate. While imatinib has been extremely effective for chronic phase CML, blast crisis CML are often resistant. New therapeutic options are therefore needed for this fatal disease. Although more common in solid tumors, increased microvessel density was also reported in chronic myelogenous leukaemia and was associated with a significant increase of angiogenic factors, suggesting that vascularity in hematologic malignancies is a controlled process and may play a role in the leukaemogenic process thus representing an alternative therapeutic target. Carboxyamidotriazole-orotate (CTO) is the orotate salt form of carboxyamidotriazole (CAI), an orally bioavailable signal transduction inhibitor that in vitro has been shown to possess antileukaemic activities. CTO, which has a reduced toxicity, increased oral bioavailability and stronger efficacy when compared to the parental compound, was tested in this study for its ability to affect imatinib-resistant CML tumor growth in a xenograft model. The active cross talk between endothelial cells and leukemic cells in the bone marrow involving exosomes plays an important role in modulating the process of neovascularization in CML. We have thus investigated the effects of CTO on exosome-stimulated angiogenesis. Our results indicate that CTO may be effective in targeting both cancer cell growth and the tumor microenvironment, thus suggesting a potential therapeutic utility for CTO in leukaemia patients. 相似文献
908.
Marshall-Pescini S Passalacqua C Miletto Petrazzini ME Valsecchi P Prato-Previde E 《PloS one》2012,7(4):e35437
Dogs appear to be sensitive to human ostensive communicative cues in a variety of situations, however there is still a measure of controversy as to the way in which these cues influence human-dog interactions. There is evidence for instance that dogs can be led into making evaluation errors in a quantity discrimination task, for example losing their preference for a larger food quantity if a human shows a preference for a smaller one, yet there is, so far, no explanation for this phenomenon. Using a modified version of this task, in the current study we investigated whether non-social, social or communicative cues (alone or in combination) cause dogs to go against their preference for the larger food quantity. Results show that dogs' evaluation errors are indeed caused by a social bias, but, somewhat contrary to previous studies, they highlight the potent effect of stimulus enhancement (handling the target) in influencing the dogs' response. A mild influence on the dog's behaviour was found only when different ostensive cues (and no handling of the target) were used in combination, suggesting their cumulative effect. The discussion addresses possible motives for discrepancies with previous studies suggesting that both the intentionality and the directionality of the action may be important in causing dogs' social biases. 相似文献
909.
910.
AC Corte de Araujo H Roschel AR Picanço DM do Prado SM Villares AL de Sá Pinto B Gualano 《PloS one》2012,7(8):e42747