全文获取类型
收费全文 | 1913篇 |
免费 | 135篇 |
专业分类
2048篇 |
出版年
2024年 | 2篇 |
2023年 | 20篇 |
2022年 | 47篇 |
2021年 | 99篇 |
2020年 | 49篇 |
2019年 | 65篇 |
2018年 | 75篇 |
2017年 | 55篇 |
2016年 | 81篇 |
2015年 | 133篇 |
2014年 | 142篇 |
2013年 | 165篇 |
2012年 | 197篇 |
2011年 | 170篇 |
2010年 | 102篇 |
2009年 | 85篇 |
2008年 | 110篇 |
2007年 | 86篇 |
2006年 | 73篇 |
2005年 | 60篇 |
2004年 | 61篇 |
2003年 | 44篇 |
2002年 | 29篇 |
2001年 | 10篇 |
2000年 | 6篇 |
1999年 | 2篇 |
1998年 | 5篇 |
1997年 | 5篇 |
1996年 | 5篇 |
1994年 | 2篇 |
1993年 | 3篇 |
1992年 | 6篇 |
1990年 | 5篇 |
1989年 | 4篇 |
1988年 | 4篇 |
1985年 | 11篇 |
1984年 | 4篇 |
1983年 | 2篇 |
1982年 | 1篇 |
1980年 | 3篇 |
1979年 | 1篇 |
1977年 | 2篇 |
1976年 | 5篇 |
1975年 | 2篇 |
1974年 | 3篇 |
1972年 | 1篇 |
1970年 | 2篇 |
1969年 | 1篇 |
1966年 | 1篇 |
1960年 | 1篇 |
排序方式: 共有2048条查询结果,搜索用时 15 毫秒
21.
Adelaide Greco Monica Ragucci Anna Rita Daniela Coda Alessandro Rosa Sara Gargiulo Raffaele Liuzzi Matteo Gramanzini Sandra Albanese Sabina Pappatà Marcello Mancini Arturo Brunetti Marco Salvatore 《PloS one》2013,8(10)
Background
Ultrasound is a valuable non-invasive tool used in obstetrics and gynecology to monitor the growth and well being of the human fetus. The laboratory mouse has recently emerged as an appropriate model for fetal and perinatal studies because morphogenetic processes in mice exhibit adequate homology to those in humans, and genetic manipulations are relatively simple to perform in mice. High-frequency ultrasound (HFUS) has recently become available for small animal preclinical imaging and can be used to study pregnancy and development in the mouse. The objective of the current study was to assess the main applications of HFUS in the evaluation of fetal growth and placental function and to better understand human congenital diseases.Methodology/Principal Findings
On each gestational day, at least 5 dams were monitored with HFUS; a total of ∼200 embryos were examined. Because it is not possible to measure each variable for the entire duration of the pregnancy, the parameters were divided into three groups as a function of the time at which they were measured. Univariate analysis of the relationship between each measurement and the embryonic day was performed using Spearman’s rank correlation (Rs). Continuous linear regression was adopted for multivariate analysis of significant parameters. All statistical tests were two-sided, and a p value of 0.05 was considered statistically significant.Conclusions/Significance
The study describes the main applications of HFUS to assess changes in phenotypic parameters in the developing CD1 mouse embryo and fetus during pregnancy and to evaluating physiological fetal and placental growth and the development of principal organs such as the heart, kidney, liver, brain and eyes in the embryonic mouse. A database of normal structural and functional parameters of mouse development will provide a useful tool for the better understanding of morphogenetic and cardiovascular anomalies in transgenic and mutant mouse models. 相似文献22.
Thorsten Klampfl Jelena D. Milosevic Ana Puda Andreas Sch?negger Klaudia Bagienski Tiina Berg Ashot S. Harutyunyan Bettina Gisslinger Elisa Rumi Luca Malcovati Daniela Pietra Chiara Elena Matteo Giovanni Della Porta Lisa Pieri Paola Guglielmelli Christoph Bock Michael Doubek Dana Dvorakova Nada Suvajdzic Dragica Tomin Natasa Tosic Zdenek Racil Michael Steurer Sonja Pavlovic Alessandro M. Vannucchi Mario Cazzola Heinz Gisslinger Robert Kralovics 《PloS one》2013,8(10)
Exome sequencing of primary tumors identifies complex somatic mutation patterns. Assignment of relevance of individual somatic mutations is difficult and poses the next challenge for interpretation of next generation sequencing data. Here we present an approach how exome sequencing in combination with SNP microarray data may identify targets of chromosomal aberrations in myeloid malignancies. The rationale of this approach is that hotspots of chromosomal aberrations might also harbor point mutations in the target genes of deletions, gains or uniparental disomies (UPDs). Chromosome 11 is a frequent target of lesions in myeloid malignancies. Therefore, we studied chromosome 11 in a total of 813 samples from 773 individual patients with different myeloid malignancies by SNP microarrays and complemented the data with exome sequencing in selected cases exhibiting chromosome 11 defects. We found gains, losses and UPDs of chromosome 11 in 52 of the 813 samples (6.4%). Chromosome 11q UPDs frequently associated with mutations of CBL. In one patient the 11qUPD amplified somatic mutations in both CBL and the DNA repair gene DDB1. A duplication within MLL exon 3 was detected in another patient with 11qUPD. We identified several common deleted regions (CDR) on chromosome 11. One of the CDRs associated with de novo acute myeloid leukemia (P=0.013). One patient with a deletion at the LMO2 locus harbored an additional point mutation on the other allele indicating that LMO2 might be a tumor suppressor frequently targeted by 11p deletions. Our chromosome-centered analysis indicates that chromosome 11 contains a number of tumor suppressor genes and that the role of this chromosome in myeloid malignancies is more complex than previously recognized. 相似文献
23.
Gianluca
E.M. Boari Giulia Chiarini Silvia Bonetti Paolo Malerba Gianluca Bianco Cristina Faustini Federico Braglia-Orlandini Daniele Turini Vittoria Guarinoni Michele Saottini Sara Viola Giulia Ferrari-Toninelli Giancarlo Pasini Cristina Mascadri Bianca Bonzi Paolo Desenzani Claudia Tusi Eros Zanotti Matteo Nardin Damiano Rizzoni 《Bioscience reports》2020,40(12)
The aim of the present study was to simultaneously assess several potential predictors of outcome (co-morbidity, previous and in-hospital treatment, radiologic Brixia score) in patients with COVID-19.This retrospective cohort study included 258 consecutive patients with confirmed COVID-19 admitted to a medical ward at Montichiari Hospital, Brescia, Italy from February 28th to April 30rd, 2020. Patients had SARS-CoV-2 related pneumonia with respiratory failure, and were treated with hydroxychloroquine and lopinavir plus ritonavir. In some patients, additional treatment with tocilizumab, dexamethasone and enoxaparin was adopted. Outcomes (death or recovery) were assessed at the end of the discharge period or at the end of the follow-up (August 2020).During hospitalization, 59 patients died, while 6 died after discharge. The following variables were demonstrated to be associated with a worse prognosis: Radiologic Brixia score higher than 8, presence at baseline of hypertension, diabetes, chronic obstructive pulmonary disease, heart disease, cancer, previous treatment with ACE-inhibitors or anti-platelet drugs. Anticoagulant treatment during hospital admission with enoxaparin at a dose higher than 4000 U once daily was associated with a better prognosis.In conclusion, our study demonstrates that some co-morbidities and cardiovascular risk factors may affect prognosis. The radiologic Brixia score may be a useful tool to stratify the risk of death at baseline. Anticoagulant treatment with enoxaparin might be associated to a clinical benefit in terms of survival in patients with COVID-19. 相似文献
24.
Paul Aia Margaret Kal Evelyn Lavu Lucy N. John Karen Johnson Chris Coulter Julia Ershova Olga Tosas Matteo Zignol Shalala Ahmadova Tauhid Islam 《PloS one》2016,11(3)
Background
Reliable estimates of the burden of multidrug-resistant tuberculosis (MDR-TB) are crucial for effective control and prevention of tuberculosis (TB). Papua New Guinea (PNG) is a high TB burden country with limited information on the magnitude of the MDR-TB problem.Methods
A cross-sectional study was conducted in four PNG provinces: Madang, Morobe, National Capital District and Western Province. Patient sputum samples were tested for rifampicin resistance by the Xpert MTB/RIF assay and those showing the presence of resistance underwent phenotypic susceptibility testing to first- and second-line anti-TB drugs including streptomycin, isoniazid, rifampicin, ethambutol, pyrazinamide, ofloxacin, amikacin, kanamycin and capreomycin.Results
Among 1,182 TB patients enrolled in the study, MDR-TB was detected in 20 new (2.7%; 95% confidence intervals [CI] 1.1–4.3%) and 24 previously treated (19.1%; 95%CI: 8.5–29.8%) TB cases. No case of extensively drug-resistant TB (XDR-TB) was detected. Thirty percent (6/20) of new and 33.3% (8/24) of previously treated cases with MDR-TB were detected in a single cluster in Western Province.Conclusion
In PNG the proportion of MDR-TB in new cases is slightly lower than the regional average of 4.4% (95%CI: 2.6–6.3%). A large proportion of MDR-TB cases were identified from a single hospital in Western Province, suggesting that the prevalence of MDR-TB across the country is heterogeneous. Future surveys should further explore this finding. The survey also helped strengthening the use of smear microscopy and Xpert MTB/RIF testing as diagnostic tools for TB in the country. 相似文献25.
Morán-Barrio J González JM Lisa MN Costello AL Peraro MD Carloni P Bennett B Tierney DL Limansky AS Viale AM Vila AJ 《The Journal of biological chemistry》2007,282(25):18286-18293
Metallo-beta-lactamases (MbetaLs) are zinc-dependent enzymes able to hydrolyze and inactivate most beta-lactam antibiotics. The large diversity of active site structures and metal content among MbetaLs from different sources has limited the design of a pan-MbetaL inhibitor. Here we report the biochemical and biophysical characterization of a novel MbetaL, GOB-18, from a clinical isolate of a Gram-negative opportunistic pathogen, Elizabethkingia meningoseptica. Different spectroscopic techniques, three-dimensional modeling, and mutagenesis experiments, reveal that the Zn(II) ion is bound to Asp120, His121, His263, and a solvent molecule, i.e. in the canonical Zn2 site of dinuclear MbetaLs. Contrasting all other related MbetaLs, GOB-18 is fully active against a broad range of beta-lactam substrates using a single Zn(II) ion in this site. These data further enlarge the structural diversity of MbetaLs. 相似文献
26.
Chiara Salvesi Stefania Silvi Dennis Fiorini Serena Scortichini Gianni Sagratini Francesco A. Palermo Renato De Leone Nadaniela Egidi Lorella Fatone Carlo Cifani Amedeo Amedei Francesca Scocchera Mara Morici Beatrice Gatto Fausto Mannucci Valerio Valeriani Marco Malavasi Sara Servili Andrea Casula Andrea Cresci Ivano Corradetti Francesco Carpi Matteo Picciolini Maria Magdalena Coman Maria Cristina Verdenelli 《Journal of applied microbiology》2022,133(5):2941-2953
27.
Christopher Minteer Marco Morselli Margarita Meer Jian Cao Albert HigginsChen Sabine M. Lang Matteo Pellegrini Qin Yan Morgan
E. Levine 《Aging cell》2022,21(2)
Aging is associated with dramatic changes to DNA methylation (DNAm), although the causes and consequences of such alterations are unknown. Our ability to experimentally uncover mechanisms of epigenetic aging will be greatly enhanced by our ability to study and manipulate these changes using in vitro models. However, it remains unclear whether the changes elicited by cells in culture can serve as a model of what is observed in aging tissues in vivo. To test this, we serially passaged mouse embryonic fibroblasts (MEFs) and assessed changes in DNAm at each time point via reduced representation bisulfite sequencing. By developing a measure that tracked cellular aging in vitro, we tested whether it tracked physiological aging in various mouse tissues and whether anti‐aging interventions modulate this measure. Our measure, termed CultureAGE, was shown to strongly increase with age when examined in multiple tissues (liver, lung, kidney, blood, and adipose). As a control, we confirmed that the measure was not a marker of cellular senescence, suggesting that it reflects a distinct yet progressive cellular aging phenomena that can be induced in vitro. Furthermore, we demonstrated slower epigenetic aging in animals undergoing caloric restriction and a resetting of our measure in lung and kidney fibroblasts when re‐programmed to iPSCs. Enrichment and clustering analysis implicated EED and Polycomb group (PcG) factors as potentially important chromatin regulators in translational culture aging phenotypes. Overall, this study supports the concept that physiologically relevant aging changes can be induced in vitro and used to uncover mechanistic insights into epigenetic aging. 相似文献
28.
Rita Aldini Matteo Micucci Monica Cevenini Romana Fato Christian Bergamini Cristina Nanni Massimiliano Cont Cecilia Camborata Silvia Spinozzi Marco Montagnani Giulia Roda Antonia D'Errico-Grigioni Francesca Rosini Aldo Roda Giuseppe Mazzella Alberto Chiarini Roberta Budriesi 《PloS one》2014,9(9)
Phytosterols, besides hypocholesterolemic effect, present anti-inflammatory properties. Little information is available about their efficacy in Inflammatory Bowel Disease (IBD). Therefore, we have evaluated the effect of a mixture of phytosterols on prevention/induction/remission in a murine experimental model of colitis. Phytosterols were administered x os before, during and after colitis induction with Dextran Sodium Sulfate (DSS) in mice. Disease Activity Index (DAI), colon length, histopathology score, 18F-FDG microPET, oxidative stress in the intestinal tissue (ileum and colon) and gallbladder ileum and colon spontaneous and carbachol (CCh) induced motility, plasma lipids and plasma, liver and biliary bile acids (BA) were evaluated. A similar longitudinal study was performed in a DSS colitis control group. Mice treated with DSS developed severe colitis as shown by DAI, colon length, histopathology score, 18F-FDG microPET, oxidative stress. Both spontaneous and induced ileal and colonic motility were severely disturbed. The same was observed with gallbladder. DSS colitis resulted in an increase in plasma cholesterol, and a modification of the BA pattern. Phytosterols feeding did not prevent colitis onset but significantly reduced the severity of the disease and improved clinical and histological remission. It had strong antioxidant effects, almost restored colon, ileal and gallbladder motility. Plasmatic levels of cholesterol were also reduced. DSS induced a modification in the BA pattern consistent with an increase in the intestinal BA deconjugating bacteria, prevented by phytosterols. Phytosterols seem a potential nutraceutical tool for gastrointestinal inflammatory diseases, combining metabolic systematic and local anti-inflammatory effects. 相似文献
29.
Koen van den Dries Matteo Bolomini-Vittori Alessandra Cambi 《Cell Adhesion & Migration》2014,8(3):268-272
Podosomes are small, circular adhesions formed by cells such as osteoclasts, macrophages, dendritic cells, and endothelial cells. They comprise a protrusive actin core module and an adhesive ring module composed of integrins and cytoskeletal adaptor proteins such as vinculin and talin. Furthermore, podosomes are associated with an actin network and often organize into large clusters. Recent results from our laboratory and others have shed new light on podosome structure and dynamics, suggesting a revision of the classical “core-ring” model. Also, these studies demonstrate that the adhesive and protrusive module are functionally linked by the actin network likely facilitating mechanotransduction as well as providing feedback between these two modules. In this commentary, we briefly summarize these recent advances with respect to the knowledge on podosome structure and discuss force distribution mechanisms within podosomes and their emerging role in mechanotransduction. 相似文献
30.
Human recombinant domain antibodies against multiple sclerosis antigenic peptide CSF114(Glc) 下载免费PDF全文
Francesca Niccheri Feliciana Real‐Fernàndez Matteo Ramazzotti Francesco Lolli Giada Rossi Paolo Rovero Donatella Degl'Innocenti 《Journal of molecular recognition : JMR》2014,27(10):618-626
Multiple sclerosis (MS) is a chronic auto‐immune disease characterized by a damage to the myelin component of the central nervous system. Self‐antigens created by aberrant glycosylation have been described to be a key component in the formation of auto‐antibodies. CSF114(Glc) is a synthetic glucopeptide detecting in vitro MS‐specific auto‐antibodies, and it is actively used in diagnostics and research to monitor and quantify MS‐associated Ig levels. We reasoned that antibodies raised against this probe could have been relevant for MS. We therefore screened a human Domain Antibody library against CSF114(Glc) using magnetic separation as a panning method. We obtained and described several clones, and the one with the highest signals was produced as a 6×His‐tagged protein to properly study the binding properties as a soluble antibody. By surface plasmon resonance measurements, we evidenced that our clone recognized CSF114(Glc) with high affinity and specific for the glucosylated peptide. Kinetic parameters of peptide–clone interaction were calculated obtaining a value of KD in the nanomolar range. Harboring a human framework, this antibody should be very well tolerated by human immune system and may represent a valuable tool for MS diagnosis and therapy, paving the way to new research strategies. Copyright © 2014 John Wiley & Sons, Ltd. 相似文献