全文获取类型
收费全文 | 2196篇 |
免费 | 133篇 |
专业分类
2329篇 |
出版年
2024年 | 3篇 |
2023年 | 3篇 |
2022年 | 21篇 |
2021年 | 40篇 |
2020年 | 23篇 |
2019年 | 39篇 |
2018年 | 64篇 |
2017年 | 37篇 |
2016年 | 46篇 |
2015年 | 94篇 |
2014年 | 141篇 |
2013年 | 177篇 |
2012年 | 225篇 |
2011年 | 175篇 |
2010年 | 112篇 |
2009年 | 114篇 |
2008年 | 166篇 |
2007年 | 124篇 |
2006年 | 115篇 |
2005年 | 125篇 |
2004年 | 106篇 |
2003年 | 99篇 |
2002年 | 77篇 |
2001年 | 15篇 |
2000年 | 12篇 |
1999年 | 22篇 |
1998年 | 32篇 |
1997年 | 21篇 |
1996年 | 13篇 |
1995年 | 10篇 |
1994年 | 13篇 |
1993年 | 8篇 |
1992年 | 4篇 |
1991年 | 5篇 |
1990年 | 6篇 |
1989年 | 5篇 |
1988年 | 9篇 |
1987年 | 3篇 |
1986年 | 3篇 |
1985年 | 2篇 |
1984年 | 2篇 |
1983年 | 2篇 |
1982年 | 2篇 |
1981年 | 3篇 |
1980年 | 2篇 |
1979年 | 2篇 |
1978年 | 4篇 |
1976年 | 1篇 |
1972年 | 2篇 |
排序方式: 共有2329条查询结果,搜索用时 15 毫秒
991.
Roberto Littera Luchino Chessa Simona Onali Francesco Figorilli Sara Lai Luca Secci Giorgio La Nasa Giovanni Caocci Marcella Arras Maurizio Melis Sara Cappellini Cinzia Balestrieri Giancarlo Serra Maria Conti Teresa Zolfino Michele Casale Stefania Casu Maria Cristina Pasetto Lucia Barca Claudia Salustro Laura Matta Rosetta Scioscia Fausto Zamboni Gavino Faa Sandro Orrù Carlo Carcassi 《PloS one》2016,11(1)
Background
Natural killer cells are involved in the complex mechanisms underlying autoimmune diseases but few studies have investigated their role in autoimmune hepatitis. Killer immunoglobulin-like receptors are key regulators of natural killer cell-mediated immune responses.Methods and Findings
KIR gene frequencies, KIR haplotypes, KIR ligands and combinations of KIRs and their HLA Class I ligands were investigated in 114 patients diagnosed with type 1 autoimmune hepatitis and compared with a group of 221 healthy controls. HLA Class I and Class II antigen frequencies were compared to those of 551 healthy unrelated families representative of the Sardinian population. In our cohort, type 1 autoimmune hepatitis was strongly associated with the HLA-B18, Cw5, DR3 haplotype. The KIR2DS1 activating KIR gene and the high affinity HLA-C2 ligands were significantly higher in patients compared to controls. Patients also had a reduced frequency of HLA-Bw4 ligands for KIR3DL1 and HLA-C1 ligands for KIR2DL3. Age at onset was significantly associated with the KIR2DS1 activating gene but not with HLA-C1 or HLA-C2 ligand groups.Conclusions
The activating KIR gene KIR2DS1 resulted to have an important predictive potential for early onset of type 1 autoimmune hepatitis. Additionally, the low frequency of the KIR-ligand combinations KIR3DL1/HLA-Bw4 and KIR2DL3/HLA-C1 coupled to the high frequency of the HLA-C2 high affinity ligands for KIR2DS1 could contribute to unwanted NK cell autoreactivity in AIH-1. 相似文献992.
Alessio Boattini Stefania Sarno Carla Bini Valeria Pesci Chiara Barbieri Sara De Fanti Andrea Quagliariello Luca Pagani Qasim Ayub Gianmarco Ferri Davide Pettener Donata Luiselli Susi Pelotti 《PloS one》2016,11(11)
Rapidly Mutating Y-STRs (RM Y-STRs) were recently introduced in forensics in order to increase the differentiation of Y-chromosomal profiles even in case of close relatives. We estimate RM Y-STRs mutation rates and their power to discriminate between related individuals by using samples extracted from a wide set of paternal pedigrees and by comparing RM Y-STRs results with those obtained from the Y-filer set. In addition, we tested the ability of RM Y-STRs to discriminate between unrelated individuals carrying the same Y-filer haplotype, using the haplogroup R-M269 (reportedly characterised by a strong resemblance in Y-STR profiles) as a case study. Our results, despite confirming the high mutability of RM Y-STRs, show significantly lower mutation rates than reference germline ones. Consequently, their power to discriminate between related individuals, despite being higher than the one of Y-filer, does not seem to improve significantly the performance of the latter. On the contrary, when considering R-M269 unrelated individuals, RM Y-STRs reveal significant discriminatory power and retain some phylogenetic signal, allowing the correct classification of individuals for some R-M269-derived sub-lineages. These results have important implications not only for forensics, but also for molecular anthropology, suggesting that RM Y-STRs are useful tools for exploring subtle genetic variability within Y-chromosomal haplogroups. 相似文献
993.
We investigate the community structure of the global ownership network of transnational corporations. We find a pronounced organization in communities that cannot be explained by randomness. Despite the global character of this network, communities reflect first of all the geographical location of firms, while the industrial sector plays only a marginal role. We also analyze the meta-network in which the nodes are the communities and the links are obtained by aggregating the links among firms belonging to pairs of communities. We analyze the network centrality of the top 50 communities and we provide a quantitative assessment of the financial sector role in connecting the global economy. 相似文献
994.
Stefania Girotto Laura Cendron Marco Bisaglia Isabella Tessari Stefano Mammi Giuseppe Zanotti Luigi Bubacco 《The Journal of biological chemistry》2014,289(15):10887-10899
Lack of oxidative stress control is a common and often prime feature observed in many neurodegenerative diseases. Both DJ-1 and SOD1, proteins involved in familial Parkinson disease and amyotrophic lateral sclerosis, respectively, play a protective role against oxidative stress. Impaired activity and modified expression of both proteins have been observed in different neurodegenerative diseases. A potential cooperative action of DJ-1 and SOD1 in the same oxidative stress response pathway may be suggested based on a copper-mediated interaction between the two proteins reported here. To investigate the mechanisms underlying the antioxidative function of DJ-1 in relation to SOD1 activity, we investigated the ability of DJ-1 to bind copper ions. We structurally characterized a novel copper binding site involving Cys-106, and we investigated, using different techniques, the kinetics of DJ-1 binding to copper ions. The copper transfer between the two proteins was also examined using both fluorescence spectroscopy and specific biochemical assays for SOD1 activity. The structural and functional analysis of the novel DJ-1 copper binding site led us to identify a putative role for DJ-1 as a copper chaperone. Alteration of the coordination geometry of the copper ion in DJ-1 may be correlated to the physiological role of the protein, to a potential failure in metal transfer to SOD1, and to successive implications in neurodegenerative etiopathogenesis. 相似文献
995.
Complementary neutron- and light-scattering results on nine proteins and amino acids reveal the role of rigidity and secondary structure in determining the time- and lengthscales of low-frequency collective vibrational dynamics in proteins. These dynamics manifest in a spectral feature, known as the boson peak (BP), which is common to all disordered materials. We demonstrate that BP position scales systematically with structural motifs, reflecting local rigidity: disordered proteins appear softer than α-helical proteins; which are softer than β-sheet proteins. Our analysis also reveals a universal spectral shape of the BP in proteins and amino acid mixtures; superimposable on the shape observed in typical glasses. Uniformity in the underlying physical mechanism, independent of the specific chemical composition, connects the BP vibrations to nanometer-scale heterogeneities, providing an experimental benchmark for coarse-grained simulations, structure/rigidity relationships, and engineering of proteins for novel applications. 相似文献
996.
Odilon Nouatin Komi Gbédandé Samad Ibitokou Bertin Vianou Parfait Houngbegnon Sem Ezinmegnon Sophie Borgella Carine Akplogan Gilles Cottrell Stefania Varani Achille Massougbodji Kabirou Moutairou Marita Troye-Blomberg Philippe Deloron Adrian J. F. Luty Nadine Fievet 《PloS one》2015,10(11)
Maternal parasitoses modulate fetal immune development, manifesting as altered cellular immunological activity in cord blood that may be linked to enhanced susceptibility to infections in early life. Plasmodium falciparum typifies such infections, with distinct placental infection-related changes in cord blood exemplified by expanded populations of parasite antigen-specific regulatory T cells. Here we addressed whether such early-onset cellular immunological alterations persist through infancy. Specifically, in order to assess the potential impacts of P. falciparum infections either during pregnancy or during infancy, we quantified lymphocyte subsets in cord blood and in infants'' peripheral blood during the first year of life. The principal age-related changes observed, independent of infection status, concerned decreases in the frequencies of CD4+, NKdim and NKT cells, whilst CD8+, Treg and Teff cells'' frequencies increased from birth to 12 months of age. P. falciparum infections present at delivery, but not those earlier in gestation, were associated with increased frequencies of Treg and CD8+ T cells but fewer CD4+ and NKT cells during infancy, thus accentuating the observed age-related patterns. Overall, P. falciparum infections arising during infancy were associated with a reversal of the trends associated with maternal infection i.e. with more CD4+ cells, with fewer Treg and CD8+ cells. We conclude that maternal P. falciparum infection at delivery has significant and, in some cases, year-long effects on the composition of infants'' peripheral blood lymphocyte populations. Those effects are superimposed on separate and independent age- as well as infant infection-related alterations that, respectively, either match or run counter to them. 相似文献
997.
Romeo Romagnoli Filippo Prencipe Luisa Carlota Lopez-Cara Paola Oliva Stefania Baraldi Pier Giovanni Baraldi 《Journal of enzyme inhibition and medicinal chemistry》2018,33(1):727-742
The combination of two pharmacophores into a single molecule represents one of the methods that can be adopted for the synthesis of new anticancer molecules. To investigate the influence of the position of the pyridine nitrogen on biological activity, two different series of α-bromoacryloylamido indolyl pyridinyl propenones 3a–h and 4a–d were designed and synthesized by a pharmacophore hybridization approach and evaluated for their antiproliferative activity against a panel of six human cancer cell lines. These hybrid molecules were prepared to combine the α-bromoacryloyl moiety with two series of indole-inspired chalcone analogues, possessing an indole derivative and a 3- or 4-pyridine ring, respectively, linked on either side of 2-propen-1-one system. The structure-activity relationship was also investigated by the insertion of alkyl or benzyl moieties at the N-1 position of the indole nucleus. We found that most of the newly synthesized displayed high antiproliferative activity against U-937, MOLT-3, K-562, and NALM-6 leukaemia cell lines, with one-digit to double-digit nanomolar IC50 values. The antiproliferative activities of 3-pyridinyl derivatives 3f–h revealed that N-benzyl indole analogues generally exhibited lower activity compared to N-H or N-alkyl derivatives 3a–b and 3c–e, respectively. Moreover, cellular mechanism studies elucidated that compound 4a induced apoptosis along with a decrease of mitochondrial membrane potential and activated caspase-3 in a concentration-dependent manner. 相似文献
998.
S. Gruca Stefania Krzyzowska-Gruca A. Vorbrodt Z. Krawczyk 《Experimental cell research》1978,114(2):462-467
Ultrastructural autoradiography was used to visualize RNA polymerase A activity in parenchymal cell nuclei isolated from normal and regenerating (3, 24, 36 and 48 h after partial hepatectomy) rat liver. High resolution autoradiography showed that the activity of RNA polymerase A which was not inhibited by α-amanitin in a concentration of 0.8 μg/ml, was restricted to the nucleolus. Both the distribution pattern and number of grains were similar in control liver and regenerating liver 3 h after hepatectomy. Twentyfour, 36, and 48 h after hepatectomy nucleoli were enlarged and labeling was distinctly increased. In all experimental groups the activity of RNA polymerase A was located within fibrillar components of the nucleolus. The association of enzyme activity with this component was especially distinct in later stages (36 and 48 h) of liver regeneration. These results suggest that the fibrillar component of the nucleolus contains the active template for ribosomal RNA (rRNA) synthesis in rat liver cell nuclei. 相似文献
999.
1000.
Ruben Ferreira Roberto Artali Adam Benoit Raimundo Gargallo Ramon Eritja David M. Ferguson Yuk Y. Sham Stefania Mazzini 《PloS one》2013,8(3)
G-quadruplexes are higher-order DNA structures formed from guanine-rich sequences, and have been identified as attractive anticancer drug targets. Elucidating the three-dimensional structure of G-quadruplex with 9-amino acridines and the specific interactions involved in binding selectivity are the key to understanding their mechanism of action. Fluorescence titration assays, competitive dialysis and NMR studies have been used to study the binding specificity of 9-amino acridines to DNA. Structural models of the complexes with the telomeric DNA G-quadruplex based on NMR measurements were developed and further examined by molecular dynamics simulations and free energy calculations. Selective binding of 9-amino acridines for G-quadruplex sequences were observed. These compounds bind between A and G-tetrads, involving significant π-π interactions and several strong hydrogen bonds. The specific interactions between different moieties of the 9-amino acridines to the DNA were examined and shown to play a significant role in governing the overall stabilities of DNA G-quadruplex complexes. Both 9-amino acridines, with similar binding affinities to the G-quadruplex, were shown to induce different level of structural stabilization through intercalation. This unique property of altering structural stability is likely a contributing factor for affecting telomerase function and, subsequently, the observed differences in the anticancer activities between the two 9-amino acridines. 相似文献