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41.
This compendium focuses on functionalised sugar amino acids (SAAs) and their 3- to 6-membered nitrogen heterocyclic and carbocyclic analogues. The main benefit of using SAAs and their related nitrogen and carbon congeners in the production of peptidomimetics and glycomimetics is that their properties can be readily altered via modification of their ring size, chemical manipulation of their numerous functional groups and fine-tuning of the stereochemical arrangement of their ring substituents. These building blocks provide access to hydrophilic and hydrophobic peptide isosteres whose physical properties allow entry to a region of chemotherapeutic space which is still under-explored by medicinal chemists. These building blocks are also important in providing amino acids whose inherent conformational bias leads to predisposition to secondary structure upon oligomerisation in relatively short sequences. These foldamers, particularly those containing ω-amino acids, provide an additional opportunity to expand access to the control of structures by artificial peptides. The synthesis and biological evaluation of these building blocks in glycomimetics and peptidomimetics systems keep expanding the reach of the glycosciences to the medical sciences, provide a greater outlook onto the wide range of cellular functions of saccharides and their derivatives involved and greater insight into the nature of oligosaccharide and protein folding. 相似文献
42.
Emanuele Ferrari Mireille Engelen Enrico Monzani Michela Sturini Stefania Girotto Luigi Bubacco Luigi Zecca Luigi Casella 《Journal of biological inorganic chemistry》2013,18(1):81-93
Elucidating the structure and biosynthesis of neuromelanin (NM) would be an important step towards understanding its putative role in the pathogenesis of Parkinson’s disease. A useful complement to studies aimed at unraveling the origin and properties of this essentially insoluble natural substance is the preparation of synthetic derivatives that resemble NM. With this aim in mind, water-soluble conjugates between dopamine-derived melanin and bovine serum albumin (BSA) were synthesized. Melanin–BSA adducts were prepared with both eumelanic oligomers obtained through the oxidative polymerization of dopamine and pheomelanic oligomers obtained under the same conditions from dopamine and cysteine. Iron ions were added during the synthesis to understand the interaction between the pigment and this metal ion, as the NM in neurons in several human brain regions contains significant amounts of iron. The structures of the conjugates were analyzed by 1H NMR spectroscopy and controlled proteolysis/MS experiments. The binding of iron(III) ions was evaluated by ICP analysis and EPR spectroscopy. The EPR signal from bound iron(III) indicated high-spin octahedral sites and, as also seen for NM, the signal is coupled to a signal from a radical associated with the melanic components of the conjugates. However, the intensity of the EPR signal from iron suggested a reduced fraction of the total iron, indicating that most of the iron is strongly coupled in clusters within the matrix. The amount of paramagnetic, mononuclear iron(III) was greater in the pheomelanin–BSA conjugates, suggesting that iron clustering is reduced in the sulfur-containing pigment. Thus, the melanin–BSA conjugates appear to be good models for the natural pigment. 相似文献
43.
Background
Efforts to prevent and respond to heat-related illness would benefit by quantifying the impact of summer heat on acute population mortality. We estimated years of life lost due to heat in 14 European cities during the 1990s accounting for harvesting.Methods
We combined the number of deaths attributable to heat estimated by the PHEWE project with life expectancy derived from population life tables. The degree of harvesting was quantified by comparing the cumulative effect of heat up to lagged day 30 with the immediate effect of heat, by geographical region and age. Next, an evaluation of years of life lost adjusted for harvesting was obtained.Results
Without accounting for harvesting, we estimated more than 23,000 years of life lost per year, 55% of which was among individuals younger than 75. When 30 day mortality displacement was taken into account, the overall impact reduced on average by 75%. Harvesting was more pronounced in North-continental cities than in Mediterranean cities and was stronger among young people than among elderly.Conclusions
High ambient temperatures during summer were responsible for many deaths in European cities during the 1990s, but a large percentage of these deaths likely involved frail persons whose demise was only briefly hastened by heat exposure. Differences in harvesting across regions and classes of age could reflect different proportions of frail individuals in the population or could be indicative of heterogeneous dynamics underlying the entry and exit of individuals from the high-risk pool which is subject to mortality displacement. 相似文献44.
Batool Shannan Quan Chen Andrea Watters Michela Perego Clemens Krepler Rakhee Thombre Ling Li Geena Rajan Scott Peterson Phyllis A. Gimotty Melissa Wilson Katherine L. Nathanson Tara C. Gangadhar Lynn M. Schuchter Ashani T. Weeraratna Meenhard Herlyn Adina Vultur 《Pigment cell & melanoma research》2016,29(3):317-328
Targeted therapies for mutant BRAF metastatic melanoma are effective but not curative due to acquisition of resistance. PI3K signaling is a common mediator of therapy resistance in melanoma; thus, the need for effective PI3K inhibitors is critical. However, testing PI3K inhibitors in adherent cultures is not always reflective of their potential in vivo. To emphasize this, we compared PI3K inhibitors of different specificity in two‐ and three‐dimensional (2D, 3D) melanoma models and show that drug response predictions gain from evaluation using 3D models. Our results in 3D demonstrate the anti‐invasive potential of PI3K inhibitors and that drugs such as PX‐866 have beneficial activity in physiological models alone and when combined with BRAF inhibition. These assays finally help highlight pathway effectors that could be involved in drug response in different environments (e.g. p4E‐BP1). Our findings show the advantages of 3D melanoma models to enhance our understanding of PI3K inhibitors. 相似文献
45.
Patrick Lambert Jose Antonio Campoy Igor Pacheco Jehan-Baptiste Mauroux Cassia Da Silva Linge Diego Micheletti Daniele Bassi Laura Rossini Elisabeth Dirlewanger Thierry Pascal Michela Troggio Maria Jose Aranzana Andrea Patocchi Pere Arús 《Tree Genetics & Genomes》2016,12(6):121
One of the applications of genomics is to identify genetic markers linked to loci responsible for variation in phenotypic traits, which could be used in breeding programs to select individuals with favorable alleles, particularly at the seedling stage. With this aim, in the framework of the European project FruitBreedomics, we selected five main peach fruit characters and a resistance trait, controlled by major genes with Mendelian inheritance: fruit flesh color Y, fruit skin pubescence G, fruit shape S, sub-acid fruit D, stone adhesion-flesh texture F-M, and resistance to green peach aphid Rm2. They were all previously mapped in Prunus. We then selected three F1 and three F2 progenies segregating for these characters and developed genetic maps of the linkage groups including the major genes, using the single nucleotide polymorphism (SNP) genome-wide scans obtained with the International Peach SNP Consortium (IPSC) 9K SNP array v1. We identified SNPs co-segregating with the characters in all cases. Their positions were in agreement with the known positions of the major genes. The number of SNPs linked to each of these, as well as the size of the physical regions encompassing them, varied depending on the maps. As a result, the number of useful SNPs for marker-assisted selection varied accordingly. As a whole, this study establishes a sound basis for further development of MAS on these characters. Additionally, we also discussed some limitations that were observed regarding the SNP array efficiency. 相似文献
46.
Michela Menegon Azucena Bardají Flor Martínez-Espinosa Camila B?tto-Menezes Maria Ome-Kaius Ivo Mueller Inoni Betuela Myriam Arévalo-Herrera Swati Kochar Sanjay K. Kochar Puneet Jaju Dhiraj Hans Chetan Chitnis Norma Padilla María Eugenia Castellanos Lucía Ortiz Sergi Sanz Mireia Piqueras Meghna Desai Alfredo Mayor Hernando del Portillo Clara Menéndez Carlo Severini 《PloS one》2016,11(3)
Plasmodium vivax is the most widely distributed human parasite and the main cause of human malaria outside the African continent. However, the knowledge about the genetic variability of P. vivax is limited when compared to the information available for P. falciparum. We present the results of a study aimed at characterizing the genetic structure of P. vivax populations obtained from pregnant women from different malaria endemic settings. Between June 2008 and October 2011 nearly 2000 pregnant women were recruited during routine antenatal care at each site and followed up until delivery. A capillary blood sample from the study participants was collected for genotyping at different time points. Seven P. vivax microsatellite markers were used for genotypic characterization on a total of 229 P. vivax isolates obtained from Brazil, Colombia, India and Papua New Guinea. In each population, the number of alleles per locus, the expected heterozygosity and the levels of multilocus linkage disequilibrium were assessed. The extent of genetic differentiation among populations was also estimated. Six microsatellite loci on 137 P. falciparum isolates from three countries were screened for comparison. The mean value of expected heterozygosity per country ranged from 0.839 to 0.874 for P. vivax and from 0.578 to 0.758 for P. falciparum. P. vivax populations were more diverse than those of P. falciparum. In some of the studied countries, the diversity of P. vivax population was very high compared to the respective level of endemicity. The level of inter-population differentiation was moderate to high in all P. vivax and P. falciparum populations studied. 相似文献
47.
Michela Silacci Wibke Lembke Richard Woods Isabella Attinger-Toller Nadja Baenziger-Tobler Sarah Batey 《MABS-AUSTIN》2016,8(1):141-149
Biologic treatment options such as tumor necrosis factor (TNF) inhibitors have revolutionized the treatment of inflammatory diseases, including rheumatoid arthritis. Recent data suggest, however, that full and long-lasting responses to TNF inhibitors are limited because of the activation of the pro-inflammatory TH17/interleukin (IL)-17 pathway in patients. Therefore, dual TNF/IL-17A inhibition is an attractive avenue to achieve superior efficacy levels in such diseases. Based on the marketed anti-TNF antibody adalimumab, we generated the bispecific TNF/IL-17A-binding FynomAb COVA322. FynomAbs are fusion proteins of an antibody and a Fyn SH3-derived binding protein. COVA322 was characterized in detail and showed a remarkable ability to inhibit TNF and IL-17A in vitro and in vivo. Through its unique mode-of-action of inhibiting simultaneously TNF and the IL-17A homodimer, COVA322 represents a promising drug candidate for the treatment of inflammatory diseases. COVA322 is currently being tested in a Phase 1b/2a study in psoriasis (ClinicalTrials.gov Identifier: NCT02243787). 相似文献
48.
49.
Robert A. Volkmann Christopher M. Fanger David R. Anderson Venkata Ramana Sirivolu Kathy Paschetto Earl Gordon Caterina Virginio Melanie Gleyzes Bruno Buisson Esther Steidl Susanna B. Mierau Michela Fagiolini Frank S. Menniti 《PloS one》2016,11(2)
GluN2A is the most abundant of the GluN2 NMDA receptor subunits in the mammalian CNS. Physiological and genetic evidence implicate GluN2A-containing receptors in susceptibility to autism, schizophrenia, childhood epilepsy and neurodevelopmental disorders such as Rett Syndrome. However, GluN2A-selective pharmacological probes to explore the therapeutic potential of targeting these receptors have been lacking. Here we disclose a novel series of pyrazine-containing GluN2A antagonists exemplified by MPX-004 (5-(((3-chloro-4-fluorophenyl)sulfonamido)methyl)-N-((2-methylthiazol-5-yl)methyl)pyrazine-2-carboxamide) and MPX-007 (5-(((3-fluoro-4-fluorophenyl)sulfonamido)methyl)-N-((2-methylthiazol-5-yl)methyl)methylpyrazine-2-carboxamide). MPX-004 and MPX-007 inhibit GluN2A-containing NMDA receptors expressed in HEK cells with IC50s of 79 nM and 27 nM, respectively. In contrast, at concentrations that completely inhibited GluN2A activity these compounds have no inhibitory effect on GluN2B or GluN2D receptor-mediated responses in similar HEK cell-based assays. Potency and selectivity were confirmed in electrophysiology assays in Xenopus oocytes expressing GluN2A-D receptor subtypes. Maximal concentrations of MPX-004 and MPX-007 inhibited ~30% of the whole-cell current in rat pyramidal neurons in primary culture and MPX-004 inhibited ~60% of the total NMDA receptor-mediated EPSP in rat hippocampal slices. GluN2A-selectivity at native receptors was confirmed by the finding that MPX-004 had no inhibitory effect on NMDA receptor mediated synaptic currents in cortical slices from GRIN2A knock out mice. Thus, MPX-004 and MPX-007 offer highly selective pharmacological tools to probe GluN2A physiology and involvement in neuropsychiatric and developmental disorders. 相似文献
50.
Ilaria Cova Francesca Clerici Annalia Rossi Valentina Cucumo Roberta Ghiretti Laura Maggiore Simone Pomati Daniela Galimberti Elio Scarpini Claudio Mariani Barbara Caracciolo 《PloS one》2016,11(3)