全文获取类型
收费全文 | 191篇 |
免费 | 11篇 |
专业分类
耳鼻咽喉 | 2篇 |
儿科学 | 7篇 |
妇产科学 | 1篇 |
基础医学 | 33篇 |
口腔科学 | 2篇 |
临床医学 | 11篇 |
内科学 | 58篇 |
皮肤病学 | 8篇 |
神经病学 | 18篇 |
外科学 | 20篇 |
预防医学 | 6篇 |
眼科学 | 1篇 |
药学 | 9篇 |
肿瘤学 | 26篇 |
出版年
2022年 | 2篇 |
2021年 | 8篇 |
2020年 | 4篇 |
2019年 | 7篇 |
2018年 | 6篇 |
2017年 | 9篇 |
2016年 | 3篇 |
2015年 | 6篇 |
2014年 | 8篇 |
2013年 | 12篇 |
2012年 | 10篇 |
2011年 | 12篇 |
2010年 | 15篇 |
2009年 | 7篇 |
2008年 | 9篇 |
2007年 | 9篇 |
2006年 | 4篇 |
2005年 | 4篇 |
2004年 | 6篇 |
2003年 | 2篇 |
2002年 | 8篇 |
2001年 | 3篇 |
2000年 | 9篇 |
1999年 | 3篇 |
1998年 | 4篇 |
1997年 | 2篇 |
1995年 | 2篇 |
1993年 | 1篇 |
1992年 | 6篇 |
1991年 | 4篇 |
1990年 | 3篇 |
1989年 | 3篇 |
1987年 | 2篇 |
1986年 | 2篇 |
1985年 | 1篇 |
1984年 | 1篇 |
1983年 | 1篇 |
1980年 | 1篇 |
1978年 | 1篇 |
1968年 | 1篇 |
1967年 | 1篇 |
排序方式: 共有202条查询结果,搜索用时 15 毫秒
21.
22.
Caux F Dubosclard E Lascols O Buendia B Chazouillères O Cohen A Courvalin JC Laroche L Capeau J Vigouroux C Christin-Maitre S 《The Journal of clinical endocrinology and metabolism》2003,88(3):1006-1013
A-Type lamins, arising from the LMNA gene, are intermediate filaments proteins that belong to the lamina, a ubiquitous nuclear network. Naturally occurring mutations in these proteins have been shown to be responsible for several distinct diseases that display skeletal and/or cardiac muscle or peripheral nerve involvement. These include familial partial lipodystrophy of the Dunnigan type and the mandibuloacral dysplasia syndrome. The pathophysiology of this group of diseases, often referred to as laminopathies, remains elusive. We report a new condition in a 30-yr-old man exhibiting a previously undescribed heterozygous R133L LMNA mutation. His phenotype associated generalized acquired lipoatrophy with insulin-resistant diabetes, hypertriglyceridemia, hepatic steatosis, hypertrophic cardiomyopathy with valvular involvement, and disseminated whitish papules. Immunofluorescence microscopic analysis of the patient's cultured skin fibroblasts revealed nuclear disorganization and abnormal distribution of A-type lamins, similar to that observed in patients harboring other LMNA mutations. This observation broadens the clinical spectrum of laminopathies, pointing out the clinical variability of lipodystrophy and the unreported possibility of hypertrophic cardiomyopathy and skin involvement. It emphasizes the fact that the diagnosis of genetic alterations in A-type lamins requires careful and complete clinical and morphological investigations in patients regardless of the presenting signs. 相似文献
23.
Somatic mutations of the β-catenin gene are frequent in mouse and human hepatocellular carcinomas
下载免费PDF全文
![点击此处可从《Proceedings of the National Academy of Sciences of the United States of America》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Alix de La Coste Batrice Romagnolo Pierre Billuart Claire-Anglique Renard Marie-Annick Buendia Olivier Soubrane Monique Fabre Jamel Chelly Cherif Beldjord Axel Kahn Christine Perret 《Proceedings of the National Academy of Sciences of the United States of America》1998,95(15):8847-8851
Hepatocellular carcinoma (HCC) is the major primary malignant tumor in the human liver, but the molecular changes leading to liver cell transformation remain largely unknown. The Wnt-β-catenin pathway is activated in colon cancers and some melanoma cell lines, but has not yet been investigated in HCC. We have examined the status of the β-catenin gene in different transgenic mouse lines of HCC obtained with the oncogenes c-myc or H-ras. Fifty percent of the hepatic tumors in these transgenic mice had activating somatic mutations within the β-catenin gene similar to those found in colon cancers and melanomas. These alterations in the β-catenin gene (point mutations or deletions) lead to a disregulation of the signaling function of β-catenin and thus to carcinogenesis. We then analyzed human HCCs and found similar mutations in eight of 31 (26%) human liver tumors tested and in HepG2 and HuH6 hepatoma cells. The mutations led to the accumulation of β-catenin in the nucleus. Thus alterations in the β-catenin gene frequently are selected for during liver tumorigenesis and suggest that disregulation of the Wnt-β-catenin pathway is a major event in the development of HCC in humans and mice. 相似文献
24.
Resistin has been proposed as both an anti-adipogenic factor and an inducer of insulin resistance. During late pregnancy, white adipose tissue mass increases and insulin sensitivity decreases. To check for the involvement of resistin in these processes, we measured plasma resistin in pregnant and non-pregnant rats and in lactating dams. Plasma resistin increased by day 15 of pregnancy and remained high 5 days post partum. The simultaneous increase in plasma resistin concentration and the decrease in insulin sensitivity is compatible with resistin depressing maternal insulin sensitivity. Resistin expression increased 5-15 times in visceral white adipose tissue depots by day 8 of pregnancy but was similar to pre-pregnancy values by day 19. Resistin expression in the placenta and mammary gland was similar to that in the parametrial adipose depot by day 8 but was almost null by day 19. There was therefore a time-lag between the peaks in expression and in plasma concentration. White adipose tissue mass increased without changes in adipocyte size once peaks in resistin expression had passed, which is compatible with an anti-adipogenic role for enhanced resistin expression. A bolus injection of chorionic gonadotrophin - which peaks in early pregnancy - to non-pregnant rats increased resistin expression in white adipose tissue, indicating that this hormone is involved in controlling resistin expression. Resistin was not detected in cerebrospinal fluid. Our results have suggested a role for resistin in pregnancy. 相似文献
25.
Prieto E Lecumberri P Pagola M Gómez M Bilbao I Ecay M Peñuelas I Martí-Climent JM 《Physics in medicine and biology》2012,57(12):3963-3980
Tumor volume delineation over positron emission tomography (PET) images is of great interest for proper diagnosis and therapy planning. However, standard segmentation techniques (manual or semi-automated) are operator dependent and time consuming while fully automated procedures are cumbersome or require complex mathematical development. The aim of this study was to segment PET images in a fully automated way by implementing a set of 12 automated thresholding algorithms, classical in the fields of optical character recognition, tissue engineering or non-destructive testing images in high-tech structures. Automated thresholding algorithms select a specific threshold for each image without any a priori spatial information of the segmented object or any special calibration of the tomograph, as opposed to usual thresholding methods for PET. Spherical (18)F-filled objects of different volumes were acquired on clinical PET/CT and on a small animal PET scanner, with three different signal-to-background ratios. Images were segmented with 12 automatic thresholding algorithms and results were compared with the standard segmentation reference, a threshold at 42% of the maximum uptake. Ridler and Ramesh thresholding algorithms based on clustering and histogram-shape information, respectively, provided better results that the classical 42%-based threshold (p < 0.05). We have herein demonstrated that fully automated thresholding algorithms can provide better results than classical PET segmentation tools. 相似文献
26.
Epidemiological studies have provided overwhelming evidence for a causal role of chronic HBV infection in the development of hepatocellular carcinoma (HCC), but the molecular mechanisms underlying virally-induced tumorigenesis remain largely debated. In the absence of a dominant oncogene encoded by the HBV genome, indirect roles have been proposed, including insertional activation of cellular oncogenes by HBV DNA integration, induction of genetic instability by viral integration or by the regulatory protein HBx, and long term effects of viral proteins in enhancing immune-mediated liver disease. In this chapter, we discuss different models of HBV-mediated liver cell transformation based on animal systems of hepadnavirus infection as well as functional studies in hepatocyte and hepatoma cell lines. These studies might help identifying the cellular effectors connecting HBV infection and liver cell transformation. 相似文献
27.
Alberto Arnedo-Pena Luis García-Marcos Ignacio Carvajal Urueña Rosa Busquets Monge María Morales Suárez-Varela Izaskun Miner Canflanca José Batlles Garrido Alfredo Blanco Quirós Ángel López-Silvarrey Varela Gloria García Hernández Inés Aguinaga Ontoso Carlos González Díaz 《Archivos de bronconeumología》2009
Objective
The objective of the study was to analyze the relationship between air pollutants and the prevalence of recent symptoms of asthma, allergic rhinitis, and atopic eczema in schoolchildren aged between 6 and 7 years.Patients and Methods
The prevalence of recent (previous 12 months) symptoms of allergic diseases was obtained by means of the questionnaire of the International Study of Asthma and Allergies in Childhood (ISAAC), Spain, with the participation of 7 centers (Asturias, Barcelona, Bilbao, Cartagena, La Coruña, Madrid, and Valencia) and 20 455 schoolchildren aged between 6 and 7 years, from 2002 to 2003. The pollutant detection systems of the aforementioned centers provided the mean annual concentrations of sulfur dioxide (SO2), nitrogen dioxide (NO2), carbon monoxide (CO), and total suspended particulate matter.Results
The annual average concentration of SO2 showed a significant association with a higher prevalence of recent severe asthma (adjusted odds ratio [aOR] between level-1 and level-3 pollution, 1.32; 95% confidence interval [CI], 1.01–1.73), rhinitis (aOR, 1.56; 95% CI, 1.39–1.75), and rhinoconjunctivitis (aOR, 1.70; 95% CI, 1.45–2.00). The annual average concentration of CO was associated with a higher prevalence of rhinitis (aOR, 1.65; 95% CI, 1.34–2.04), rhinoconjunctivitis (aOR, 1.76; 95% CI, 1.31–2.37), and eczema (aOR, 1.55; 95% CI, 1.17–2.04). The annual average concentration for NO2 and total suspended particulate matter showed inverse associations with the prevalence of nocturnal dry cough.Conclusions
Findings suggest that air pollutants such as SO2 and CO increase the risk of recent symptoms of asthma and allergic rhinitis in schoolchildren aged between 6 and 7 years in Spain. 相似文献28.
Delbarre E Tramier M Coppey-Moisan M Gaillard C Courvalin JC Buendia B 《Human molecular genetics》2006,15(7):1113-1122
Hutchinson-Gilford progeria syndrome (HGPS) is a dominant autosomal premature aging syndrome caused by the expression of a truncated prelamin A designated progerin (Pgn). A-type and B-type lamins are intermediate filament proteins that polymerize to form the nuclear lamina network apposed to the inner nuclear membrane of vertebrate somatic cells. It is not known if in vivo both type of lamins assemble independently or co-assemble. The blebbing and disorganization of the nuclear envelope and adjacent heterochromatin in cells from patients with HGPS is a hallmark of the disease, and the ex vivo reversal of this phenotype is considered important for the development of therapeutic strategies. Here, we investigated the alterations in the lamina structure that may underlie the disorganization caused in nuclei by Pgn expression. We studied the polymerization of enhanced green fluorescent protein- and red fluorescent protein-tagged wild-type and mutated lamins in the nuclear envelope of living cells by measuring fluorescence resonance energy transfer (FRET) that occurs between the two fluorophores when tagged lamins interact. Using time domain fluorescence lifetime imaging microscopy that allows a quantitative analysis of FRET signals, we show that wild-type lamins A and B1 polymerize in distinct homopolymers that further interact in the lamina. In contrast, expressed Pgn co-assembles with lamin B1 and lamin A to form a mixed heteropolymer in which A-type and B-type lamin segregation is lost. We propose that such structural lamina alterations may be part of the primary mechanisms leading to HGPS, possibly by impairing functions specific for each lamin type such as nuclear membrane biogenesis, signal transduction, nuclear compartmentalization and gene regulation. 相似文献
29.
Dietrich MO Spuch C Antequera D Rodal I de Yébenes JG Molina JA Bermejo F Carro E 《Neurobiology of aging》2008,29(6):902-912
Leptin, a peptide hormone secreted by adipose tissue, exhibits a large range of central and peripheral actions. It has been proposed that the participation of leptin in diseases such as obesity is due to, at least in part, its impaired transport across the blood–brain barrier (BBB). Since, the mechanisms by which brain takes up leptin remain unclear, we set out to study how leptin may cross the BBB. We have used different immunoassays and lentiviral vectors to analyze the role of megalin in the transport of leptin in rodents and humans. We demonstrate that circulating leptin is transported into the brain by binding to megalin at the choroid plexus epithelium. Indeed, the downregulation of megalin expression in physiological and pathological situations such as aging and Alzheimer's disease was correlated with poor entry of leptin into the brain. Moreover, amyloid beta (Aβ) deposits of choroid plexus could be disturbing megalin function. The present data indicate that leptin represents a novel megalin ligand of importance in the levels and therapeutic actions of leptin into the brain. 相似文献
30.
Fernando Alfonso Parounak Zelveian Jean-Jacques Monsuez Michael Aschermann Michael Boehm Alfonso Buendia Hernandez Tzung-Dau Wang Ariel Cohen Sebija Izetbegovic Anton Doubell Dario Echeverri Nuray Enç Ignacio Ferreira-González Anetta Undas Ulrike Fortmüller Plamen Gatzov Carmen Ginghina Lino Goncalves Valentyn Shumakov 《Revista portuguesa de cardiologia》2019,38(7):519-525
The Editors’ Network of the European Society of Cardiology (ESC) provides a dynamic forum for editorial discussions and endorses the recommendations of the International Committee of Medical Journal Editors (ICMJE) to improve the scientific quality of biomedical journals. Authorship confers credit and important academic rewards. Recently, however, the ICMJE emphasized that authorship also requires responsibility and accountability. These issues are now covered by the new (fourth) criterion for authorship. Authors should agree to be accountable and ensure that questions regarding the accuracy and integrity of the entire work will be appropriately addressed. This review discusses the implications of this paradigm shift on authorship requirements with the aim of increasing awareness on good scientific and editorial practices. 相似文献