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21.
Dane A. Crossley II Sonnet S. Jonker James W. Hicks Kent L. Thornburg 《Journal of comparative physiology. B, Biochemical, systemic, and environmental physiology》2010,180(7):1057-1065
Angiotensin II (Ang II) is an important regulator of cardiovascular function in adult vertebrates. Although its role in regulating
the adult system has been extensively investigated, the cardiovascular response to Ang II in embryonic vertebrates is relatively
unknown. We investigated the potential of Ang II as a regulator of cardiovascular function in embryonic chickens, which lack
central nervous system control of cardiovascular function throughout the majority of incubation. The cardiovascular response
to Ang II in embryonic chickens was investigated over the final 50% of their development. Ang II produced a dose-dependent
increase in arterial pressure on each day of development studied, and the response increased in intensity as development progressed.
The Ang II type-1 receptor nonspecific competitive peptide antagonist [Sar1 ile8] Ang II blocked the cardiovascular response to subsequent injections of Ang II on day 21 only. The embryonic pressure response
to Ang II (hypertension only) differed from that of adult chickens, in which initial hypotension is followed by hypertension.
The constant level of gene expression for the Ang II receptor, in conjunction with an increasing pressure response to the
peptide, suggests that two Ang II receptor subtypes are present during chicken development. Collectively, the data indicate
that Ang II plays an important role in the cardiovascular development of chickens; however, its role in maintaining basal
function requires further study. 相似文献
22.
Thomas J. Contreras John F. Jemionek John E. French Virginia M. Hartwig Dane A. Walden 《Cryobiology》1980,17(3):243-251
Highly purified human granulocytes isolated from continuous flow centrifugation leukapheresis concentrates by counterflow centrifugation-elutriation were stored at 4 °C in concentrations of 6 × 106 to 1 × 107 granulocytes per milliliter for up to 14 days. The in vitro physiological function assays of phagocytosis, oxygen consumption associated with phagocytosis, bacterial growth inhibition, chemotaxis, and five enzyme analyses indicated good storage survival for up to 4 days. Stored granulocytes separated from other blood cells have greater storage stability than granulocytes stored as leukapheresis concentrates. After 14 days of storage a small percentage of granulocytes still maintained all physiological functions, with the exception of chemotaxis. Of the five enzymes assayed, only the enzyme activity of leucine aminopeptidase decreased significantly by the 14th day of storage. The storage stability of each physiological function assayed decreased as follows: bacterial growth inhibition (most stable), phagocytosis, oxygen consumption, and chemotaxis (least stable). 相似文献
23.
M. Imex Aguirre-Cardenas Dane H. Geddes-Buehre Karin A. Crowhurst 《Biochemistry and Biophysics Reports》2021
HdeA is an acid-stress chaperone that operates in the periplasm of various strains of pathogenic gram-negative bacteria. Its primary function is to prevent irreversible aggregation of other periplasmic proteins when the bacteria enter the acidic environment of the stomach after contaminated food is ingested; its role is therefore to help the bacteria survive long enough to enter and colonize the intestines. The mechanism of operation of HdeA is unusual in that this helical homodimer is inactive when folded at neutral pH but becomes activated at low pH after the dimer dissociates and partially unfolds. Studies with chemical reducing agents previously suggested that the intramolecular disulfide bond is important for maintaining residual structure in HdeA at low pH and may be responsible for positioning exposed hydrophobic residues together for the purpose of binding unfolded client proteins. In order to explore its role in HdeA structure and chaperone function we performed a conservative cysteine to serine mutation of the disulfide. We found that, although residual structure is greatly diminished at pH 2 without the disulfide, it is not completely lost; conversely, the mutant is almost completely random coil at pH 6. Aggregation assays showed that mutated HdeA, although less successful as a chaperone than wild type, still maintains a surprising level of function. These studies highlight that we still have much to learn about the factors that stabilize residual structure at low pH and the role of disulfide bonds. 相似文献
24.
Lipovsek D Lippow SM Hackel BJ Gregson MW Cheng P Kapila A Wittrup KD 《Journal of molecular biology》2007,368(4):1024-1041
The 10th human fibronectin type III domain ((10)Fn3) is one of several protein scaffolds used to design and select families of proteins that bind with high affinity and specificity to macromolecular targets. To date, the highest affinity (10)Fn3 variants have been selected by mRNA display of libraries generated by randomizing all three complementarity-determining region -like loops of the (10)Fn3 scaffold. The sub-nanomolar affinities of such antibody mimics have been attributed to the extremely large size of the library accessible by mRNA display (10(12) unique sequences). Here we describe the selection and affinity maturation of (10)Fn3-based antibody mimics with dissociation constants as low as 350 pM selected from significantly smaller libraries (10(7)-10(9) different sequences), which were constructed by randomizing only 14 (10)Fn3 residues. The finding that two adjacent loops in human (10)Fn3 provide a large enough variable surface area to select high-affinity antibody mimics is significant because a smaller deviation from wild-type (10)Fn3 sequence is associated with a higher stability of selected antibody mimics. Our results also demonstrate the utility of an affinity-maturation strategy that led to a 340-fold improvement in affinity by maximizing sampling of sequence space close to the original selected antibody mimic. A striking feature of the highest affinity antibody mimics selected against lysozyme is a pair of cysteines on adjacent loops, in positions 28 and 77, which are critical for the affinity of the (10)Fn3 variant for its target and are close enough to form a disulfide bond. The selection of this cysteine pair is structurally analogous to the natural evolution of disulfide bonds found in new antigen receptors of cartilaginous fish and in camelid heavy-chain variable domains. We propose that future library designs incorporating such an interloop disulfide will further facilitate the selection of high-affinity, highly stable antibody mimics from libraries accessible to phage and yeast surface display methods. 相似文献
25.
MicroRNA (miRNA) transcriptome of mouse retina and identification of a sensory organ-specific miRNA cluster 总被引:6,自引:0,他引:6
26.
27.
Antibodies are used extensively in diagnostics and as therapeutic agents. Achieving high-affinity binding is important for expanding detection limits, extending dissociation half-times, decreasing drug dosages and increasing drug efficacy. However, antibody-affinity maturation in vivo often fails to produce antibody drugs of the targeted potency, making further affinity maturation in vitro by directed evolution or computational design necessary. Here we present an iterative computational design procedure that focuses on electrostatic binding contributions and single mutants. By combining multiple designed mutations, a tenfold affinity improvement to 52 pM was engineered into the anti-epidermal growth factor receptor drug cetuximab (Erbitux), and a 140-fold improvement in affinity to 30 pM was obtained for the anti-lysozyme model antibody D44.1. The generality of the methods was further demonstrated through identification of known affinity-enhancing mutations in the therapeutic antibody bevacizumab (Avastin) and the model anti-fluorescein antibody 4-4-20. These results demonstrate computational capabilities for enhancing and accelerating the development of protein reagents and therapeutics. 相似文献
28.
Newman DM Jones PL Ingram BA 《Comparative biochemistry and physiology. Part A, Molecular & integrative physiology》2007,148(4):876-887
The temporal dynamics of oocyte growth, plasma sex steroids and somatic energy stores were examined during a 12 month ovarian maturation cycle in captive Murray cod Maccullochella peelii peelii under simulated natural photothermal conditions. Ovarian function was found to be relatively uninhibited in captivity, with the exception that post-vitellogenic follicles failed to undergo final maturation, resulting in widespread pre-ovulatory atresia. Seasonal patterns of oocyte growth were characterised by cortical alveoli accumulation in March, deposition of lipids in April, and vitellogenesis between May and September. Two distinct batches of vitellogenic oocytes were found in Murray cod ovaries, indicating a capacity for multiple spawns. Plasma profiles of 17β-oestradiol and testosterone were both highly variable during the maturation period suggesting that multiple roles exist for these steroids during different stages of oocyte growth. Condition factor, liver size and visceral fat stores were all found to increase prior to, or during the peak phase of vitellogenic growth. Murray cod appear to strategically utilise episodes of high feeding activity to accrue energy reserves early in the reproductive cycle prior to its deployment during periods of rapid ovarian growth. 相似文献
29.
Kevin M. Ringelman Christopher K. Williams Patrick K. Devers John M. Coluccy Paul M. Castelli Kurt A. Anderson Jacob L. Bowman Gary R. Costanzo Dane M. Cramer Matt T. Dibona Michael W. Eichholz Min Huang Benjamin Lewis Jr. Dawn M. Plattner Tina Yerkes 《The Journal of wildlife management》2015,79(8):1298-1307
30.
Gilbert AM Bursavich MG Lombardi S Adedoyin A Dwyer JM Hughes Z Kern JC Khawaja X Rosenzweig-Lipson S Moore WJ Neal SJ Olsen M Rizzo SJ Springer D 《Bioorganic & medicinal chemistry letters》2011,21(1):195-199
A series of 3-(pyridin-2-yl-ethynyl)benzamide negative allosteric modulators of the metabotropic glutamate receptor 5 (mGluR5 NAMs) have been prepared. Starting from HTS hit 1 (IC50: 926 nM), potent mGluR5 NAMs showing excellent potencies (IC50s <50 nM) and good physicochemical profiles were prepared by monitoring LipE values. One compound 26 showed excellent mGluR5 binding (Ki: 21 nM) and antagonism (IC50: 8 nM), an excellent rat PK profile (CL: 12 mL/min/kg, %F: 85) and showed oral activity in a mouse 4-Plate Behavioral model of anxiety (MED: 30 mpk) and a mouse Stress Induced Hyperthermia model of anxiety (MED 17.8 mpk). 相似文献