全文获取类型
收费全文 | 621篇 |
免费 | 50篇 |
出版年
2021年 | 10篇 |
2020年 | 7篇 |
2019年 | 5篇 |
2018年 | 7篇 |
2017年 | 8篇 |
2016年 | 9篇 |
2015年 | 20篇 |
2014年 | 17篇 |
2013年 | 27篇 |
2012年 | 43篇 |
2011年 | 45篇 |
2010年 | 24篇 |
2009年 | 17篇 |
2008年 | 30篇 |
2007年 | 36篇 |
2006年 | 38篇 |
2005年 | 29篇 |
2004年 | 32篇 |
2003年 | 28篇 |
2002年 | 23篇 |
2001年 | 9篇 |
2000年 | 5篇 |
1999年 | 9篇 |
1998年 | 14篇 |
1997年 | 5篇 |
1996年 | 9篇 |
1995年 | 5篇 |
1994年 | 9篇 |
1993年 | 10篇 |
1992年 | 5篇 |
1991年 | 3篇 |
1989年 | 5篇 |
1985年 | 5篇 |
1984年 | 9篇 |
1983年 | 6篇 |
1982年 | 9篇 |
1981年 | 8篇 |
1980年 | 8篇 |
1979年 | 13篇 |
1978年 | 16篇 |
1977年 | 7篇 |
1976年 | 11篇 |
1975年 | 7篇 |
1974年 | 3篇 |
1973年 | 3篇 |
1971年 | 2篇 |
1970年 | 2篇 |
1969年 | 2篇 |
1968年 | 2篇 |
1966年 | 2篇 |
排序方式: 共有671条查询结果,搜索用时 15 毫秒
601.
Machlenkin A Azriel-Rosenfeld R Volovitz I Vadai E Lev A Paz A Goldberger O Reiter Y Tzehoval E Benhar I Eisenbach L 《Cancer immunology, immunotherapy : CII》2007,56(2):217-226
Conventional treatment of recurrent and metastasized prostate cancer (CaP) remains inadequate; this fact mandates development of alternative therapeutic modalities, such as specific active or passive immunotherapy. Previously, we reported the identification of a novel highly immunogenic HLA-A*0201-restricted Prostatic Acid Phosphatase-derived peptide (PAP-3) by a two-step in vivo screening in an HLA-transgenic (HHD) mouse system. In the present study we aimed at elucidating the efficiency of PAP-3-based vaccine upon active antitumor immunization. To this end we established preventive and therapeutic carcinoma models in HHD mice. The 3LL murine Lewis lung carcinoma clone D122 transduced to express HLA-A*0201 and PAP served as a platform for these models. The HLA-A*0201–PAP-3 complex specific recombinant single chain scFV-PAP-3 antibodies were generated and used to confirm an endogenous PAP processing resulting in PAP-3 presentation by HLA-A*0201. PAP-3 based vaccines significantly decreased tumor incidence in a preventive immunization setting. Therapeutic vaccination of HHD mice with PAP-3 led to rejection of early established tumors and to increase of mouse survival. These results strongly support a therapeutic relevance of the identified CTL epitope upon active antitumor immunization. The newly established carcinoma model presented herein might be a useful tool for cancer vaccine design and optimization. 相似文献
602.
603.
Adam H. Freedman Ilan Gronau Rena M. Schweizer Diego Ortega-Del Vecchyo Eunjung Han Pedro M. Silva Marco Galaverni Zhenxin Fan Peter Marx Belen Lorente-Galdos Holly Beale Oscar Ramirez Farhad Hormozdiari Can Alkan Carles Vilà Kevin Squire Eli Geffen Josip Kusak Adam R. Boyko Heidi G. Parker Clarence Lee Vasisht Tadigotla Adam Siepel Carlos D. Bustamante Timothy T. Harkins Stanley F. Nelson Elaine A. Ostrander Tomas Marques-Bonet Robert K. Wayne John Novembre 《PLoS genetics》2014,10(1)
To identify genetic changes underlying dog domestication and reconstruct their early evolutionary history, we generated high-quality genome sequences from three gray wolves, one from each of the three putative centers of dog domestication, two basal dog lineages (Basenji and Dingo) and a golden jackal as an outgroup. Analysis of these sequences supports a demographic model in which dogs and wolves diverged through a dynamic process involving population bottlenecks in both lineages and post-divergence gene flow. In dogs, the domestication bottleneck involved at least a 16-fold reduction in population size, a much more severe bottleneck than estimated previously. A sharp bottleneck in wolves occurred soon after their divergence from dogs, implying that the pool of diversity from which dogs arose was substantially larger than represented by modern wolf populations. We narrow the plausible range for the date of initial dog domestication to an interval spanning 11–16 thousand years ago, predating the rise of agriculture. In light of this finding, we expand upon previous work regarding the increase in copy number of the amylase gene (AMY2B) in dogs, which is believed to have aided digestion of starch in agricultural refuse. We find standing variation for amylase copy number variation in wolves and little or no copy number increase in the Dingo and Husky lineages. In conjunction with the estimated timing of dog origins, these results provide additional support to archaeological finds, suggesting the earliest dogs arose alongside hunter-gathers rather than agriculturists. Regarding the geographic origin of dogs, we find that, surprisingly, none of the extant wolf lineages from putative domestication centers is more closely related to dogs, and, instead, the sampled wolves form a sister monophyletic clade. This result, in combination with dog-wolf admixture during the process of domestication, suggests that a re-evaluation of past hypotheses regarding dog origins is necessary. 相似文献
604.
605.
Jaaved Mohammed Diane Bortolamiol-Becet Alex S. Flynt Ilan Gronau Adam Siepel Eric C. Lai 《RNA (New York, N.Y.)》2014,20(8):1195-1209
The propensity of animal miRNAs to regulate targets bearing modest complementarity, most notably via pairing with miRNA positions ∼2–8 (the “seed”), is believed to drive major aspects of miRNA evolution. First, minimal targeting requirements have allowed most conserved miRNAs to acquire large target cohorts, thus imposing strong selection on miRNAs to maintain their seed sequences. Second, the modest pairing needed for repression suggests that evolutionarily nascent miRNAs may generally induce net detrimental, rather than beneficial, regulatory effects. Hence, levels and activities of newly emerged miRNAs are expected to be limited to preserve the status quo of gene expression. In this study, we unexpectedly show that Drosophila testes specifically express a substantial miRNA population that contravenes these tenets. We find that multiple genomic clusters of testis-restricted miRNAs harbor recently evolved miRNAs, whose experimentally verified orthologs exhibit divergent sequences, even within seed regions. Moreover, this class of miRNAs exhibits higher expression and greater phenotypic capacities in transgenic misexpression assays than do non-testis-restricted miRNAs of similar evolutionary age. These observations suggest that these testis-restricted miRNAs may be evolving adaptively, and several methods of evolutionary analysis provide strong support for this notion. Consistent with this, proof-of-principle tests show that orthologous miRNAs with divergent seeds can distinguish target sensors in a species-cognate manner. Finally, we observe that testis-restricted miRNA clusters exhibit extraordinary dynamics of miRNA gene flux in other Drosophila species. Altogether, our findings reveal a surprising tissue-directed influence of miRNA evolution, involving a distinct mode of miRNA function connected to adaptive gene regulation in the testis. 相似文献
606.
Ilan Ben-Zvi Tami Krichely-Vachdi Olga Feld Merav Lidar Shaye Kivity Avi Livneh 《Orphanet journal of rare diseases》2014,9(1):1-6
Background
To demonstrate and clinically, genetically and demographically characterize familial Mediterranean fever (FMF) patients, maintaining remission despite colchicine abstinence.Methods
FMF patients were screened for an endurance of prolonged remission (≥ 3 years), despite refraining from colchicine. Clinical, demographic and genetic parameters were collected. Data were compared with those of consecutive control FMF subjects, coming to the clinic for their periodic follow up examination.Results
Of 1000 patients screened over 5 years, 33 manifested colchicine-free remission. The mean duration of the remission period was 12.6?±?8.1 years. Patients in the remission group had milder severity of FMF, compared to the control group (22 vs. 11 patients with mild disease, respectively, p?=?0.003) and a longer diagnosis delay (21?±?15.7 vs. 13.4?±?13.5 years, respectively, p?=?0.04). Patients experiencing remission suffered mostly of abdominal attacks, low rate of attacks in other sites and low rate of chronic and non-attack manifestations. When the disease resumed activity, it responded well to colchicine, despite using a lower dose, as compared to the control subjects (p?<?0.001). None of the patients in this group was homozygous for the M694V mutation (p?=?0.0008).Conclusions
Prolonged colchicine-free remission defines a rare and milder form of FMF with unique clinical, demographic, and molecular characteristics. 相似文献607.
608.
One of the oldest and most persistent questions in ecology and evolution is whether natural communities tend to evolve toward saturation and maximal diversity. Robert MacArthur’s classical theory of niche packing and the theory of adaptive radiations both imply that populations will diversify and fully partition any available niche space. However, the saturation of natural populations is still very much an open area of debate and investigation. Additionally, recent evolutionary theory suggests the existence of alternative evolutionary stable states (ESSs), which implies that some stable communities may not be fully saturated. Using models with classical Lotka-Volterra ecological dynamics and three formulations of evolutionary dynamics (a model using adaptive dynamics, an individual-based model, and a partial differential equation model), we show that following an adaptive radiation, communities can often get stuck in low diversity states when limited by mutations of small phenotypic effect. These low diversity metastable states can also be maintained by limited resources and finite population sizes. When small mutations and finite populations are considered together, it is clear that despite the presence of higher-diversity stable states, natural populations are likely not fully saturating their environment and leaving potential niche space unfilled. Additionally, within-species variation can further reduce community diversity from levels predicted by models that assume species-level homogeneity. 相似文献
609.
Roy Kahn Izhar Karbat Nitza Ilan Lior Cohen Stanislav Sokolov William A. Catterall Dalia Gordon Michael Gurevitz 《The Journal of biological chemistry》2009,284(31):20684-20691
The scorpion α-toxin Lqh2 (from Leiurus quinquestriatus hebraeus) is active at various mammalian voltage-gated sodium channels (Navs) and is inactive at insect Navs. To resolve the molecular basis of this preference we used the following strategy: 1) Lqh2 was expressed in recombinant form and key residues important for activity at the rat brain channel rNav1.2a were identified by mutagenesis. These residues form a bipartite functional surface made of a conserved “core domain” (residues of the loops connecting the secondary structure elements of the molecule core), and a variable “NC domain” (five-residue turn and the C-tail) as was reported for other scorpion α-toxins. 2) The functional role of the two domains was validated by their stepwise construction on the similar scaffold of the anti-insect toxin LqhαIT. Analysis of the activity of the intermediate constructs highlighted the critical role of Phe15 of the core domain in toxin potency at rNav1.2a, and has suggested that the shape of the NC-domain is important for toxin efficacy. 3) Based on these findings and by comparison with other scorpion α-toxins we were able to eliminate the activity of Lqh2 at rNav1.4 (skeletal muscle), hNav1.5 (cardiac), and rNav1.6 channels, with no hindrance of its activity at Nav1.1–1.3. These results suggest that by employing a similar approach the design of further target-selective sodium channel modifiers is imminent.The pivotal role of voltage-gated sodium channels (Navs)4 in excitability mark them as major targets for a large variety of toxins that bind at distinct receptor sites and modify their gating (1). These channels are large membrane proteins made of a pore-forming α-subunit of ∼260 kDa and auxiliary β-subunits of ∼30 kDa. The α-subunit is composed of four homologous domains (D1–D4), each consisting of six α-helical transmembrane segments (S1–S6) connected by intracellular and extracellular loops. A key feature in Navs function is their ability to rapidly activate and inactivate, leading to transient increase in Na+ conductance through the cell membrane. This mechanism is attributed to the ability of the positively charged S4 voltage sensors to move across the membrane in response to changes in membrane potential (1, 2).In mammals, at least nine genes encode a variety of Nav subtypes (1, 3), whose expression varies greatly in different tissues (Nav1.1–1.3 mainly in the central nervous system; Nav1.6 in both central and peripheral neurons; Nav1.7 in the peripheral nervous system; Nav1.8 and Nav1.9 in sensory neurons; Nav1.4 and Nav1.5 in skeletal and cardiac muscles, respectively). Nav subtypes are distributed heterogeneously in the human brain and their expression is regulated under developmental and pathological conditions (1, 3–5). In addition, many disorders in humans result from abnormal function due to mutations in various Nav genes (6–8). Thus, ligands that show specificity for Nav subtypes may be used for their identification at various tissues and as leads for design of specific drugs. This requires that the bioactive surfaces of these ligands be resolved along with molecular details that determine their specificity.Among the wide range of Nav modifiers, those derived from scorpion venoms play an important role in studying channel activation (β-toxins) and inactivation (α-toxins) (9–11). The channel site of interaction with scorpion α-toxins, named neurotoxin receptor site-3 (12), is shared also by structurally unrelated toxins from sea anemone and spider venoms (13, 14), which raises questions as to its architecture and boundaries. Based on the findings that site-3 toxins eliminate a gating charge component associated with the movement of D4/S4 (15, 16), and that this segment plays a critical role in coupling channel inactivation to activation (17), scorpion α-toxins were postulated to inhibit channel inactivation by hindering the outward movement of this segment during depolarization (9).Scorpion α-toxins constitute a class of structurally and functionally related 61–67-residue long polypeptides reticulated by four conserved disulfide bridges. Despite a common βαββ core (10, 18, 19) these toxins are highly diverse in sequence and preference for insect and mammalian Navs. Indeed, the α-toxin class is divided to pharmacological groups according to their toxicity in insects and mice brain and ability to compete on binding at insect and mammalian Navs (10) (supplemental Fig. S1): (i) classical anti-mammalian toxins, such as Aah2 (from Androctonus australis hector) and Lqh2 (from Leiurus quinquestriatus hebraeus), which bind with high affinity to Navs at rat brain synaptosomes and are practically non-toxic to insects; (ii) α-toxins, such as LqhαIT, which strongly affect insect Navs and are weak in mammalian brain; and (iii) α-like toxins, such as Lqh3 and BmKM1 (from Buthus martensii Karsch), which are active in both mammalian brain and insects.Efforts to identify α-toxin residues involved in the interaction with the Nav receptor site-3 revealed a generally common bioactive surface divided to two topologically distinct domains: a conserved “core domain” formed by residues of the loops connecting the secondary structure elements of the molecule core, and a variable “NC domain” formed by the five-residue turn (residues 8–12) and the C-tail (20–23). These analyses raised the hypothesis that a protruding conformation of the NC domain correlates with high activity at insect Navs, whereas a flat conformation of this domain appears in α-toxins active at the brain channel rNav1.2a (21). The correlation of this structural difference with toxin preference for Nav subtypes was corroborated by constructing the bioactive surface of LqhαIT on the scaffold of the anti-mammalian α-toxin Aah2 ending up with a chimera (Aah2LqhαIT(face)) active on insects, whose NC domain is in the protruding conformation (21). Despite this result, the molecular requirements that enable high affinity binding of classical α-toxins to mammalian Navs have not been clarified, and only initial data about the channel region that constitutes receptor site-3 is available (Refs. 24–26; also see Ref. 10 for review).Lqh2 is a 64-residue long toxin from L. quinquestriatus hebraeus (Israeli yellow scorpion) (27) that is almost identical in sequence (96% identity) to the most active anti-mammalian toxin, Aah2, whose structure and action are documented (18, 28, 29). By functional expression and mutagenesis we uncovered residues on the Lqh2 exterior that are putatively involved in bioactivity. By construction of these residues on the scaffold of the anti-insect toxin LqhαIT we confirmed their bioactive role and differentiated those that determine toxin potency from those contributing to toxin efficacy. Comparison to other α-toxins was then instrumental for the design of an Lqh2 mutant that exhibits high specificity for the neuronal channels hNav1.1, rNav1.2a, and rNav1.3. 相似文献
610.
Hadany L Beker T Eshel I Feldman MW 《Proceedings. Biological sciences / The Royal Society》2006,273(1588):881-885
The reaction of the body to prolonged stress has many harmful effects. Classical theory assumes that stress responses have evolved due to their short-term selective advantages ('flight or fight'), and despite their adverse long-term effects. In contrast, we demonstrate that the adverse effects of stress responses may have a selective advantage. Using an analytical model we show that a gene that causes the early death of a relatively unfit individual can increase in frequency in a structured population even if it has no positive effect on that individual. This result offers a new perspective on the relations between stress factors, stress responses and stress-related diseases. 相似文献