全文获取类型
收费全文 | 13739篇 |
免费 | 1108篇 |
国内免费 | 8篇 |
专业分类
14855篇 |
出版年
2023年 | 52篇 |
2022年 | 121篇 |
2021年 | 185篇 |
2020年 | 116篇 |
2019年 | 147篇 |
2018年 | 212篇 |
2017年 | 203篇 |
2016年 | 313篇 |
2015年 | 531篇 |
2014年 | 568篇 |
2013年 | 767篇 |
2012年 | 913篇 |
2011年 | 886篇 |
2010年 | 606篇 |
2009年 | 585篇 |
2008年 | 725篇 |
2007年 | 817篇 |
2006年 | 757篇 |
2005年 | 727篇 |
2004年 | 692篇 |
2003年 | 685篇 |
2002年 | 663篇 |
2001年 | 154篇 |
2000年 | 151篇 |
1999年 | 187篇 |
1998年 | 220篇 |
1997年 | 172篇 |
1996年 | 150篇 |
1995年 | 143篇 |
1994年 | 133篇 |
1993年 | 159篇 |
1992年 | 196篇 |
1991年 | 138篇 |
1990年 | 153篇 |
1989年 | 120篇 |
1988年 | 105篇 |
1987年 | 100篇 |
1986年 | 77篇 |
1985年 | 117篇 |
1984年 | 108篇 |
1983年 | 85篇 |
1982年 | 104篇 |
1981年 | 88篇 |
1980年 | 82篇 |
1979年 | 78篇 |
1978年 | 67篇 |
1977年 | 76篇 |
1976年 | 73篇 |
1975年 | 55篇 |
1973年 | 50篇 |
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
991.
Timofey Kalupov Mich��le Brillard-Bourdet S��bastien Dad�� H��l��ne Serrano Julien Wartelle Nicolas Guyot Luiz Juliano Thierry Moreau Azzaq Belaaouaj Francis Gauthier 《The Journal of biological chemistry》2009,284(49):34084-34091
It is widely accepted that neutrophil serine proteases (NSPs) play a critical role in neutrophil-associated lung inflammatory and tissue-destructive diseases. To investigate NSP pathogenic role(s), various mouse experimental models have been developed that mimic acutely or chronically injured human lungs. We and others are using mouse exposure to cigarette smoke as a model for chronic obstructive pulmonary disease with or without exacerbation. However, the relative contribution of NSPs to lung disease processes as well as their underlying mechanisms remains still poorly understood. And the lack of purified mouse NSPs and their specific substrates have hampered advances in these studies. In this work, we compared mouse and human NSPs and generated three-dimensional models of murine NSPs based on three-dimensional structures of their human homologs. Analyses of these models provided compelling evidence that peptide substrate specificities of human and mouse NSPs are different despite their conserved cleft and close structural resemblance. These studies allowed us to synthesize for the first time novel sensitive fluorescence resonance energy transfer substrates for individual mouse NSPs. Our findings and the newly identified substrates should better our understanding about the role of NSPs in the pathogenesis of cigarette-associated chronic obstructive pulmonary disease as well as other neutrophils-associated inflammatory diseases. 相似文献
992.
Geneviève LeBel Katy Vaillancourt Michel Frenette Marcelo Gottschalk Daniel Grenier 《Applied and environmental microbiology》2014,80(17):5484-5492
Streptococcus suis serotype 2 is known to cause severe infections (meningitis, endocarditis, and septicemia) in pigs and is considered an emerging zoonotic agent. Antibiotics have long been used in the swine industry for disease treatment/prevention and growth promoters. This pattern of utilization resulted in the spread of antibiotic resistance in S. suis worldwide. Interestingly, pigs may harbor S. suis in their tonsils without developing diseases, while North American strains belonging to the sequence type 28 (ST28) are nonvirulent in animal models. Consequently, the aim of this study was to purify and characterize a bacteriocin produced by a nonvirulent strain of S. suis serotype 2, with a view to a potential therapeutic and preventive application. S. suis 90-1330 belonging to ST28 and previously shown to be nonvirulent in an animal model exhibited antibacterial activity toward all S. suis pathogenic isolates tested. The bacteriocin produced by this strain was purified to homogeneity by cationic exchange and reversed-phase fast protein liquid chromatography. Given its properties (molecular mass of <4 kDa, heat, pH and protease stability, and the presence of modified amino acids), the bacteriocin, named suicin 90-1330, belongs to the lantibiotic class. Using a DNA-binding fluorophore, the bacteriocin was found to possess a membrane permeabilization activity. When tested on other swine pathogens, the suicin showed activity against Staphylococcus hyicus and Staphylococcus aureus, whereas it was inactive against all Gram-negative bacteria tested. Amino acid sequencing of the purified bacteriocin showed homology (90.9% identity) with nisin U produced by Streptococcus uberis. The putative gene cluster involved in suicin production was amplified by PCR and sequence analysis revealed the presence of 11 open reading frames, including the structural gene and those required for the modification of amino acids, export, regulation, and immunity. Further studies will evaluate the ability of suicin 90-1330 or the producing strain to prevent experimental S. suis infections in pigs. 相似文献
993.
994.
995.
Michel Sartori 《ZooKeys》2014,(445):97-106
The type material of Epeorella
borneonia Ulmer, 1939, the sole species of the genus Epeorella Ulmer, 1939 is reinvestigated and a lectotype (male imago) is designated. Based on several morphological structures, the synonymy with Epeorus Eaton, 1881 (Rhithrogeninae) is rejected. Epeorella stat. prop., known only at the winged stages, belongs to the subfamily Ecdyonurinae, and is a probable endemic of the island of Borneo. The newly erected genus Darthus Webb & McCafferty, 2007, also endemic to Borneo and only known by one species at the nymphal stage, is shown to be a junior subjective synonym of Epeorella. The new combination Epeorella
vadora (Webb & McCafferty, 2007) is proposed for the species. The distribution of known heptageniid species from the Sunda Islands is discussed. 相似文献
996.
Aït-Aïssa S Billaudel B Poulletier de Gannes F Ruffié G Duleu S Hurtier A Haro E Taxile M Athané A Geffard M Wu T Wiart J Bodet D Veyret B Lagroye I 《Bioelectromagnetics》2012,33(5):410-420
An experimental approach was used to assess immunological biomarkers in the sera of young rats exposed in utero and postnatal to non-ionizing radiofrequency fields. Pregnant rats were exposed free-running, 2 h/day and 5 days/week to a 2.45 GHz Wi-Fi signal in a reverberation chamber at whole-body specific absorption rates (SAR) of 0, 0.08, 0.4, and 4 W/kg (with 10, 10, 12, and 9 rats, respectively), while cage control rats were kept in the animal facility (11 rats). Dams were exposed from days 6 to 21 of gestation and then three newborns per litter were further exposed from birth to day 35 postnatal. On day 35 after birth, all pups were sacrificed and sera collected. The screening of sera for antibodies directed against 15 different antigens related to damage and/or pathological markers was conducted using enzyme-linked immunosorbent assay (ELISA). No change in humoral response of young pups was observed, regardless of the types of biomarker and SAR levels. This study also provided some data on gestational outcome following in utero exposure to Wi-Fi signals. Mass evaluation of dams and pups and the number of pups per litter was monitored, and the genital tracts of young rats were observed for abnormalities by measuring anogenital distance. Under these experimental conditions, our observations suggest a lack of adverse effects of Wi-Fi exposure on delivery and general condition of the animals. 相似文献
997.
Richard Carr III Yang Du Julie Quoyer Reynold A. Panettieri Jr. Jay M. Janz Michel Bouvier Brian K. Kobilka Jeffrey L. Benovic 《The Journal of biological chemistry》2014,289(52):35668-35684
The β2-adrenergic receptor (β2AR) is a prototypical G protein-coupled receptor that mediates many hormonal responses, including cardiovascular and pulmonary function. β-Agonists used to combat hypercontractility in airway smooth muscle stimulate β2AR-dependent cAMP production that ultimately promotes airway relaxation. Chronic stimulation of the β2AR by long acting β-agonists used in the treatment of asthma can promote attenuated responsiveness to agonists and an increased frequency of fatal asthmatic attacks. β2AR desensitization to β-agonists is primarily mediated by G protein-coupled receptor kinases and β-arrestins that attenuate receptor-Gs coupling and promote β2AR internalization and degradation. A biased agonist that can selectively stimulate Gs signaling without promoting receptor interaction with G protein-coupled receptor kinases and β-arrestins should serve as an advantageous asthma therapeutic. To identify such molecules, we screened ∼50 lipidated peptides derived from the intracellular loops of the β2AR, known as pepducins. This screen revealed two classes of Gs-biased pepducins, receptor-independent and receptor-dependent, as well as several β-arrestin-biased pepducins. The receptor-independent Gs-biased pepducins operate by directly stimulating G protein activation. In contrast, receptor-dependent Gs-biased pepducins appear to stabilize a Gs-biased conformation of the β2AR that couples to Gs but does not undergo G protein-coupled receptor kinase-mediated phosphorylation or β-arrestin-mediated internalization. Functional studies in primary human airway smooth muscle cells demonstrate that Gs-biased pepducins are not subject to conventional desensitization and thus may be good candidates for the development of next generation asthma therapeutics. Our study reports the first Gs-biased activator of the β2AR and provides valuable tools for the study of β2AR function. 相似文献
998.
Louise Zanella Koko Otsuki Michel Abanto Marin Izidro Bendet Ana Carolina Vicente 《Journal of virology》2012,86(22):12451
Human T-lymphotropic virus type 1 (HTLV-1) has a global spread, and it is estimated that around 20 million persons are infected. Seven major genetic subtypes are recognized. However, there are complete genomes only from the HTLV-1a (cosmopolitan) and HTLV-1c (Melanesian) subtypes. Here, the first full-length genome of an HTLV-1b strain, a subtype so far restricted to Central African countries, is revealed. The genome size of HTLV-1b SF26, a strain isolated in Brazil, was determined to be 8,267 bp. The genomic analysis showed that all characteristic regions and genes of a prototypic HTLV-1 virus are conserved. This genome can provide information for further studies on the evolutionary history and pathogenic potential of this human oncovirus. 相似文献
999.
Aurélie Joly-Amado Rapha?l G P Denis Julien Castel Amélie Lacombe Céline Cansell Claude Rouch Nadim Kassis Julien Dairou Patrice D Cani Renée Ventura-Clapier Alexandre Prola Melissa Flamment Fabienne Foufelle Christophe Magnan Serge Luquet 《The EMBO journal》2012,31(22):4276-4288
Obesity-related diseases such as diabetes and dyslipidemia result from metabolic alterations including the defective conversion, storage and utilization of nutrients, but the central mechanisms that regulate this process of nutrient partitioning remain elusive. As positive regulators of feeding behaviour, agouti-related protein (AgRP) producing neurons are indispensible for the hypothalamic integration of energy balance. Here, we demonstrate a role for AgRP-neurons in the control of nutrient partitioning. We report that ablation of AgRP-neurons leads to a change in autonomic output onto liver, muscle and pancreas affecting the relative balance between lipids and carbohydrates metabolism. As a consequence, mice lacking AgRP-neurons become obese and hyperinsulinemic on regular chow but display reduced body weight gain and paradoxical improvement in glucose tolerance on high-fat diet. These results provide a direct demonstration of a role for AgRP-neurons in the coordination of efferent organ activity and nutrient partitioning, providing a mechanistic link between obesity and obesity-related disorders. 相似文献
1000.
Davy Vancampfort Martien Wampers Alex J. Mitchell Christoph U. Correll Amber De Herdt Michel Probst Marc De Hert 《World psychiatry》2013,12(3):240-250
A meta‐analysis was conducted to explore the risk for cardio‐metabolic abnormalities in drug naïve, first‐episode and multi‐episode patients with schizophrenia and age‐ and gender‐ or cohort‐matched general population controls. Our literature search generated 203 relevant studies, of which 136 were included. The final dataset comprised 185,606 unique patients with schizophrenia, and 28 studies provided data for age‐ and gender‐matched or cohort‐matched general population controls (n=3,898,739). We found that multi‐episode patients with schizophrenia were at increased risk for abdominal obesity (OR=4.43; CI=2.52‐7.82; p<0.001), hypertension (OR=1.36; CI=1.21‐1.53; p<0.001), low high‐density lipoprotein cholesterol (OR=2.35; CI=1.78‐3.10; p<0.001), hypertriglyceridemia (OR=2.73; CI=1.95‐3.83; p<0.001), metabolic syndrome (OR=2.35; CI=1.68‐3.29; p<0.001), and diabetes (OR=1.99; CI=1.55‐2.54; p<0.001), compared to controls. Multi‐episode patients with schizophrenia were also at increased risk, compared to first‐episode (p<0.001) and drug‐naïve (p<0.001) patients, for the above abnormalities, with the exception of hypertension and diabetes. Our data provide further evidence supporting WPA recommendations on screening, follow‐up, health education and lifestyle changes in people with schizophrenia. 相似文献