全文获取类型
收费全文 | 905篇 |
免费 | 151篇 |
专业分类
1056篇 |
出版年
2021年 | 7篇 |
2016年 | 18篇 |
2015年 | 30篇 |
2014年 | 28篇 |
2013年 | 40篇 |
2012年 | 44篇 |
2011年 | 32篇 |
2010年 | 18篇 |
2009年 | 25篇 |
2008年 | 34篇 |
2007年 | 27篇 |
2006年 | 36篇 |
2005年 | 31篇 |
2004年 | 34篇 |
2003年 | 19篇 |
2002年 | 30篇 |
2001年 | 26篇 |
2000年 | 33篇 |
1999年 | 27篇 |
1998年 | 13篇 |
1997年 | 7篇 |
1996年 | 8篇 |
1995年 | 6篇 |
1994年 | 8篇 |
1992年 | 26篇 |
1991年 | 23篇 |
1990年 | 23篇 |
1989年 | 18篇 |
1988年 | 15篇 |
1987年 | 17篇 |
1986年 | 20篇 |
1985年 | 18篇 |
1984年 | 15篇 |
1983年 | 12篇 |
1982年 | 19篇 |
1981年 | 12篇 |
1980年 | 13篇 |
1979年 | 12篇 |
1978年 | 14篇 |
1977年 | 16篇 |
1976年 | 15篇 |
1975年 | 13篇 |
1974年 | 16篇 |
1973年 | 21篇 |
1972年 | 8篇 |
1971年 | 13篇 |
1969年 | 15篇 |
1968年 | 12篇 |
1967年 | 9篇 |
1966年 | 12篇 |
排序方式: 共有1056条查询结果,搜索用时 0 毫秒
101.
Systemic infection with Listeria monocytogenes, a Gram-positive intracellular bacterium, has been used extensively to analyze the innate immune response. Macrophages are central to this response, acting as both the host for and principal defense against this bacterium. During pregnancy L. monocytogenes has a predilection for replication at the maternal-placental interface and consequently is an important cause of fetal morbidity and mortality. However, macrophages are mostly excluded from the murine placenta with neutrophils acting as the main immune effector cell against this bacterium. Colony stimulating factor (CSF)-1, a macrophage growth factor, is synthesized in high concentrations by the uterine epithelium during pregnancy, where it is targeted to trophoblast bearing CSF-1-receptors. To define the involvement of CSF-1 in placental immunity, we infected pregnant mice either homozygous or heterozygous for an inactivating recessive mutation in the gene for CSF-1 (osteopetrotic; Csfmop) with L. monocytogenes. CSF-1 was required to recruit neutrophils to the site of listerial infection in the decidua basalis, and infection by Listeria remained unrestrained in its absence. CSF-1 acted by inducing the trophoblast to synthesize the neutrophil chemoattractants (KC) and macrophage inflammatory protein (MIP)-2. Thus, during pregnancy, trophoblast responsive to CSF-1 acts to organize the maternal immune response to bacterial infection at the utero-placental interface. This previously unknown function indicates that the trophoblast acts as a pregnancy-specific component of the innate immune system. 相似文献
102.
The cDNA sequence for the human d-bifunctional protein (D-BP: 17β-hydroxysteroid dehydrogenase IV) was investigated in patients with peroxisomal disorders
belonging to the BP complementation group (CG). In three cases, analysis of polymerase chain reaction products generated from
the patients' cDNA indicated the presence of a deletion within the region corresponding to nucleotides 209–537 of the normal
cDNA sequence. Subsequent sequencing revealed that, in two of the patients, 47 base pairs were missing, with the deletion
corresponding to nucleotides 302/3–349/50 of the normal sequence. In the third patient, a smaller deletion of 22 bp (nucleotides
280/1–302/3) was characterized. Only the mutant sequence was detected in each of these cases, consistent with parental consanguinity.
Both deletions cause a frameshift, and would lead to premature termination of the BP. Available family members were also investigated,
and the findings conformed with expectations for an autosomal recessive disorder. In addition to the deletions, a number of
other base changes have been identified in this series of patients. In particular, one patient, whose parents were also consanguineous,
was homozygous for a base change, which results in a nonconservative substitution of serine 177 with a phenylalanine residue.
The functional significance of this amino acid substitution, as well as the other identified changes, is still to be determined.
Nevertheless, our data provide strong support for the hypothesis that defects in the gene for the D-BP are responsible for
the β-oxidation defect in patients belonging to the BP CG. 相似文献
103.
Mechanical properties of actin filament networks depend on preparation, polymerization conditions, and storage of actin monomers. 总被引:3,自引:0,他引:3 下载免费PDF全文
J Xu W H Schwarz J A Ks T P Stossel P A Janmey T D Pollard 《Biophysical journal》1998,74(5):2731-2740
This study investigates possible sources for the variance of more than two orders of magnitude in the published values for the shear moduli of purified actin filaments. Two types of forced oscillatory rheometers used in some of our previous work agree within a factor of three for identical samples. Polymers assembled in EGTA and Mg2+ from fresh, gel-filtered ATP-actin at 1 mg/ml typically have an elastic storage modulus (G') of approximately 1 Pa at a deformation frequency of 0.1-1 Hz. G' is slightly higher when actin is polymerized in KCl with Ca2+ and Mg2+. Gel filtration removes minor contaminants from actin but has little effect on G' for most preparations of actin from acetone powder. Storage of actin monomers without frequent changes of buffer containing fresh ATP and dithiothreitol can result in changes that increase the G' of filaments by more than a factor of 10. Frozen storage can preserve the properties of monomeric actin, but care is necessary to prevent protein denaturation or aggregation due to freezing or thawing. 相似文献
104.
Steve Horvath Abu NM Nazmul-Hossain Rodney PE Pollard Frans GM Kroese Arjan Vissink Cees GM Kallenberg Fred KL Spijkervet Hendrika Bootsma Sara A Michie Sven U Gorr Ammon B Peck Chaochao Cai Hui Zhou David TW Wong 《Arthritis research & therapy》2012,14(6):1-13
Bone tissue has an exceptional quality to regenerate to native tissue in response to injury. However, the fracture repair process requires mechanical stability or a viable biological microenvironment or both to ensure successful healing to native tissue. An improved understanding of the molecular and cellular events that occur during bone repair and remodeling has led to the development of biologic agents that can augment the biological microenvironment and enhance bone repair. Orthobiologics, including stem cells, osteoinductive growth factors, osteoconductive matrices, and anabolic agents, are available clinically for accelerating fracture repair and treatment of compromised bone repair situations like delayed unions and nonunions. Preclinical and clinical studies using biologic agents like recombinant bone morphogenetic proteins have demonstrated an efficacy similar or better than that of autologous bone graft in acute fracture healing. A lack of standardized outcome measures for comparison of biologic agents in clinical fracture repair trials, frequent off-label use, and a limited understanding of the biological activity of these agents at the bone repair site have limited their efficacy in clinical applications. 相似文献
105.
Jonathan Nambiar Adam W Clarke Doris Shim David Mabon Chen Tian Karolina Windloch Chris Buhmann Beau Corazon Matilda Lindgren Matthew Pollard Teresa Domagala Lynn Poulton Anthony G Doyle 《MABS-AUSTIN》2015,7(3):638-650
CD1d is a receptor on antigen-presenting cells involved in triggering cell populations, particularly natural killer T (NKT) cells, to release high levels of cytokines. NKT cells are implicated in asthma pathology and blockade of the CD1d/NKT cell pathway may have therapeutic potential. We developed a potent anti-human CD1d antibody (NIB.2) that possesses high affinity for human and cynomolgus macaque CD1d (KD ∼100 pM) and strong neutralizing activity in human primary cell-based assays (IC50 typically <100 pM). By epitope mapping experiments, we showed that NIB.2 binds to CD1d in close proximity to the interface of CD1d and the Type 1 NKT cell receptor β-chain. Together with data showing that NIB.2 inhibited stimulation via CD1d loaded with different glycolipids, this supports a mechanism whereby NIB.2 inhibits NKT cell activation by inhibiting Type 1 NKT cell receptor β-chain interactions with CD1d, independent of the lipid antigen in the CD1d antigen-binding cleft. The strong in vitro potency of NIB.2 was reflected in vivo in an Ascaris suum cynomolgus macaque asthma model. Compared with vehicle control, NIB.2 treatment significantly reduced bronchoalveolar lavage (BAL) levels of Ascaris-induced cytokines IL-5, IL-8 and IL-1 receptor antagonist, and significantly reduced baseline levels of GM-CSF, IL-6, IL-15, IL-12/23p40, MIP-1α, MIP-1β, and VEGF. At a cellular population level NIB.2 also reduced numbers of BAL lymphocytes and macrophages, and blood eosinophils and basophils. We demonstrate that anti-CD1d antibody blockade of the CD1d/NKT pathway modulates inflammatory parameters in vivo in a primate inflammation model, with therapeutic potential for diseases where the local cytokine milieu is critical. 相似文献
106.
107.
108.
Direct demonstration of actin filament annealing in vitro 总被引:1,自引:5,他引:1
Direct electron microscopic examination confirms that short actin filaments rapidly anneal end-to-end in vitro, leading over time to an increase in filament length at steady state. During annealing of mixtures of native unlabeled filaments and glutaraldehyde-fixed filaments labeled with myosin subfragment-1, the structural polarity within heteropolymers is conserved absolutely. Annealing does not appear to require either ATP hydrolysis or the presence of exogenous actin monomers, suggesting that joining occurs through the direct association of filament ends. During recovery from sonication the initial rate of annealing is consistent with a second-order reaction involving the collision of two filament ends with an apparent annealing rate constant of 10(7) M-1s-1. This rapid phase lasts less than 10 s and is followed by a slow phase lasting minutes to hours. Annealing is calculated to contribute minimally to filament elongation during the initial stages of self-assembly. However, the rapid rate of annealing of sonicated fixed filaments observed in vitro suggests that it may be an efficient mechanism for repairing breaks in filaments and that annealing together with polymer-severing mechanisms may contribute significantly to the dynamics and function of actin filaments in vivo. 相似文献
109.
Manion M Rodriguez B Medvik K Hardy G Harding CV Schooley RT Pollard R Asmuth D Murphy R Barker E Brady KE Landay A Funderburg N Sieg SF Lederman MM 《PloS one》2012,7(1):e30306
Background
Type I interferons play important roles in innate immune defense. In HIV infection, type I interferons may delay disease progression by inhibiting viral replication while at the same time accelerating disease progression by contributing to chronic immune activation.Methods
To investigate the effects of type I interferons in HIV-infection, we obtained cryopreserved peripheral blood mononuclear cell samples from 10 subjects who participated in AIDS Clinical Trials Group Study 5192, a trial investigating the activity of systemic administration of IFNα for twelve weeks to patients with untreated HIV infection. Using flow cytometry, we examined changes in cell cycle status and expression of activation antigens by circulating T cells and their maturation subsets before, during and after IFNα treatment.Results
The proportion of CD38+HLA-DR+CD8+ T cells increased from a mean of 11.7% at baseline to 24.1% after twelve weeks of interferon treatment (p = 0.006). These frequencies dropped to an average of 20.1% six weeks after the end of treatment. In contrast to CD8+ T cells, the frequencies of activated CD4+ T cells did not change with administration of type I interferon (mean percentage of CD38+DR+ cells = 2.62% at baseline and 2.17% after 12 weeks of interferon therapy). As plasma HIV levels fell with interferon therapy, this was correlated with a “paradoxical” increase in CD8+ T cell activation (p<0.001).Conclusion
Administration of type I interferon increased expression of the activation markers CD38 and HLA DR on CD8+ T cells but not on CD4+ T cells of HIV+ persons. These observations suggest that type I interferons may contribute to the high levels of CD8+ T cell activation that occur during HIV infection. 相似文献110.
E. Traiffort H. Pollard J. Moreau M. Ruat J. C. Schwartz M. I. Martinez-Mir J. M. Palacios† 《Journal of neurochemistry》1992,59(1):290-299
125I-Aminopotentidine (125I-APT), a reversible probe of high specific radioactivity and high affinity and selectivity for the H2 receptor, was used to characterize and localize this histamine receptor subtype in human brain samples obtained at autopsy. On membranes of human caudate nucleus, specific 125I-APT binding at equilibrium revealed a single component, with a dissociation constant of 0.3 nM and maximal capacity of about 100 fmol/mg of protein. At 0.2 nM, 125I-APT specific binding, as defined with tiotidine, an H2-receptor antagonist chemically unrelated to iodoaminopotentidine, represented 40-50% of the total. Specific 125I-APT binding was inhibited by a series of typical H2-receptor antagonists that displayed apparent dissociation constants closely similar to corresponding values at the reference biological system, i.e., guinea pig atrium. This indicates that the pharmacology of the H2 receptor is the same in the human brain as on this reference system. However, histamine was about 10-fold more potent in inhibiting 125I-APT binding to membranes of human brain than of guinea pig brain. 125I-APT binding was also inhibited by amitriptyline and mianserin, two antidepressant drugs, in micromolar concentrations corresponding to effective plasma concentrations of treated patients. The distribution of H2 receptors was established autoradiographically with 125I-APT on a series of coronal sections of human brain after assessing the pharmacological specificity of the labeling. The highest density of 125I-APT sites was found in the basal ganglia, various parts of the limbic system, e.g., hippocampus or amygdaloid complex, and the cerebral cortex. H2 receptors displayed a laminar distribution in cerebral cortex and hippocampal formation. A low density of sites was found in cerebellum as well as in hypothalamus, the brain area where all the perikarya and the largest number of axons of histaminergic neurons are found. The widespread distribution of H2 receptors in the human brain is consistent with the alleged modulatory role of histamine mediated by this subtype of receptor. 相似文献