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151.
Heart transplantation in baboons using alpha1,3-galactosyltransferase gene-knockout pigs as donors: initial experience 总被引:1,自引:0,他引:1
Kuwaki K Tseng YL Dor FJ Shimizu A Houser SL Sanderson TM Lancos CJ Prabharasuth DD Cheng J Moran K Hisashi Y Mueller N Yamada K Greenstein JL Hawley RJ Patience C Awwad M Fishman JA Robson SC Schuurman HJ Sachs DH Cooper DK 《Nature medicine》2005,11(1):29-31
Hearts from alpha1,3-galactosyltransferase knockout pigs (GalT-KO, n = 8) were transplanted heterotopically into baboons using an anti-CD154 monoclonal antibody-based regimen. The elimination of the galactose-alpha1,3-galactose epitope prevented hyperacute rejection and extended survival of pig hearts in baboons for 2-6 months (median, 78 d); the predominant lesion associated with graft failure was a thrombotic microangiopathy, with resulting ischemic injury. There were no infectious complications directly related to the immunosuppressive regimen. The transplantation of hearts from GalT-KO pigs increased graft survival over previous studies. 相似文献
152.
The dual influences of dissolved organic carbon on hypolimnetic metabolism: organic substrate and photosynthetic reduction 总被引:1,自引:1,他引:0
Jeffrey N. Houser Darren L. Bade Jonathan J. Cole Michael L. Pace 《Biogeochemistry》2003,64(2):247-269
We investigated the effect of dissolved organic carbon (DOC) on hypolimnetic metabolism (accumulation of dissolved inorganic carbon (DIC) and methane (CH4)) in 21 lakes across a gradient of DOC concentrations (308 to 1540 mol C L–1). The highly colored nature of the DOC in these lakes suggests it is mostly of terrestrial origin. Hypolimnetic methane accumulation was positively correlated with epilimnetic DOC concentration (Spearman rank correlation = 0.67; p < 0.01), an indicator of allochthonous DOC inputs, but not with photic zone chlorophyll a concentration (Spearman rank correlation = 0.30; p = 0.22). Hypolimnetic DOC concentrations declined in 19 of 21 lakes during the stratified period at rates that ranged from 0.06 to 53.9 mmol m–2 d–1. The hypolimnetic accumulation of DIC + CH4 was positively correlated with, and, in most cases of comparable magnitude to, this DOC decline suggesting that DOC was an important substrate for hypolimnetic metabolism. The percentage of surface irradiance reaching the thermocline was lower in high DOC lakes (0.3%) than in low DOC lakes (6%), reducing hypolimnetic photosynthesis (as measured by the depth and magnitude of the deep dissolved oxygen maxima) in the high DOC lakes. In June, the hypolimnia of lakes with < 400 mol L–1 DOC had high concentrations of dissolved oxygen and no CH4, while the hypolimnia of lakes with DOC > 800 mol L–1 were completely anoxic and often had high CH4 concentrations. Thus, DOC affects hypolimnetic metabolism via multiple pathways: DOC was significant in supporting hypolimnetic metabolism; and at high concentrations depressed photosynthesis (and therefore oxygen production and DIC consumption) in the hypolimnion. 相似文献
153.
Joseph R Libonati Zebulon V Kendrick Steven R Houser 《Journal of applied physiology》2005,99(6):2121-2127
We examined the effects of sprint training on left ventricular diastolic stiffness during normoxia and after ischemia-reperfusion (I/R). Thirty-seven, male Sprague-Dawley rats, weighing 150-175 g at the initiation of the experiment, were randomly assigned to a sedentary, control group (n = 20) or to a high-intensity, sprint-trained group (n = 17). Animals were trained 5 days/wk on a motor-driven treadmill for 6 wk. High-intensity sprint training consisted of running five 1-min sprints at 75 m/min, 15% grade, interspersed with 1-min active recovery runs at a speed of 20 m/min, 15% grade. Langendorff-derived isolated heart performance was measured before and after 20 min of no-flow ischemia followed by 30 min of reperfusion. Isolated myocytes were harvested from a subset of postischemic hearts. Sprint training reduced Langendorff-derived LV chamber stiffness (P < 0.05) and induced a rightward shift in the LV pressure-volume relationship during both normoxic perfusion and after I/R. LV developed pressure after I/R was also better preserved in hearts obtained from sprint-trained animals (P < 0.05), a result that is in part related to a lower postischemic LV chamber stiffness in sprint-trained hearts. The putative impact of sprint training on postischemic LV chamber stiffness was masked by glycolytic inhibition with iodoacetate, suggesting that glycolysis was involved in the better postischemic recovery observed in sprint-trained hearts. There was a tendency for enhanced postischemic cardiomyocyte shortening in sprint-trained cardiomyocytes compared with control. The rate of myocyte relaxation, i.e., time for 50% relaxation of the Ca(2+) transient amplitude, was similar between groups. These data suggest that additional mechanisms unrelated to Ca(2+) were involved in sprint-induced protection from ischemia-reperfusion-induced LV diastolic dysfunction. 相似文献
154.
Xiangjie Sun Akila Jayaraman Pavithra Maniprasad Rahul Raman Katherine V. Houser Claudia Pappas Hui Zeng Ram Sasisekharan Jacqueline M. Katz Terrence M. Tumpey 《Journal of virology》2013,87(15):8756-8766
The hemagglutinin (HA) protein is a major virulence determinant for the 1918 pandemic influenza virus; however, it encodes no known virulence-associated determinants. In comparison to seasonal influenza viruses of lesser virulence, the 1918 H1N1 virus has fewer glycosylation sequons on the HA globular head region. Using site-directed mutagenesis, we found that a 1918 HA recombinant virus, of high virulence, could be significantly attenuated in mice by adding two additional glycosylation sites (asparagine [Asn] 71 and Asn 286) on the side of the HA head. The 1918 HA recombinant virus was further attenuated by introducing two additional glycosylation sites on the top of the HA head at Asn 142 and Asn 172. In a reciprocal experimental approach, deletion of HA glycosylation sites (Asn 142 and Asn 177, but not Asn 71 and Asn 104) from a seasonal influenza H1N1 virus, A/Solomon Islands/2006 (SI/06), led to increased virulence in mice. The addition of glycosylation sites to 1918 HA and removal of glycosylation sites from SI/06 HA imposed constraints on the theoretical structure surrounding the glycan receptor binding sites, which in turn led to distinct glycan receptor binding properties. The modification of glycosylation sites for the 1918 and SI/06 viruses also caused changes in viral antigenicity based on cross-reactive hemagglutinin inhibition antibody titers with antisera from mice infected with wild-type or glycan mutant viruses. These results demonstrate that glycosylation patterns of the 1918 and seasonal H1N1 viruses directly contribute to differences in virulence and are partially responsible for their distinct antigenicity. 相似文献
155.
James J. Finneran Hollis R. London Dorian S. Houser 《Journal of comparative physiology. A, Neuroethology, sensory, neural, and behavioral physiology》2007,193(8):835-843
Envelope following responses were measured in two bottlenose dolphins in response to sinusoidal amplitude modulated tones
with carrier frequencies from 20 to 60 kHz and modulation rates from 100 to 5,000 Hz. One subject had elevated hearing thresholds
at higher frequencies, with threshold differences between subjects varying from ±4 dB at 20 and 30 kHz to +40 dB at 50 and
60 kHz. At each carrier frequency, evoked response amplitudes and phase angles were plotted with respect to modulation frequency
to construct modulation rate transfer functions. Results showed that both subjects could follow the stimulus envelope components
up to at least 2,000 Hz, regardless of carrier frequency. There were no substantial differences in modulation rate transfer
functions for the two subjects suggesting that reductions in hearing sensitivity did not result in reduced temporal processing
ability. In contrast to earlier studies, phase data showed group delays of approximately 3.5 ms across the tested frequency
range, implying generation site(s) within the brainstem rather than the periphery at modulation rates from 100 to 1,600 Hz.
This discrepancy is believed to be the result of undersampling of the modulation rate during previous phase measurements. 相似文献
156.
Zechun Peng Nianhui Zhang Dave Chandra Gregg E. Homanics Richard W. Olsen Carolyn R. Houser 《Neurochemical research》2014,39(6):1104-1117
The α4 subunit of the GABAA receptor (GABAAR) is highly expressed in the thalamus where receptors containing the α4 and δ subunits are major mediators of tonic inhibition. The α4 subunit also exhibits considerable plasticity in a number of physiological and pathological conditions, raising questions about the expression of remaining GABAAR subunits when the α4 subunit is absent. Immunohistochemical studies of an α4 subunit knockout (KO) mouse revealed a substantial decrease in δ subunit expression in the ventrobasal nucleus of the thalamus as well as other forebrain regions where the α4 subunit is normally expressed. In contrast, several subunits associated primarily with phasic inhibition, including the α1 and γ2 subunits, were moderately increased. Intracellular localization of the δ subunit was also altered. While δ subunit labeling was decreased within the neuropil, some labeling remained in the cell bodies of many neurons in the ventrobasal nucleus. Confocal microscopy demonstrated co-localization of this labeling with an endoplasmic reticulum marker, and electron microscopy demonstrated increased immunogold labeling near the endoplasmic reticulum in the α4 KO mouse. These results emphasize the strong partnership of the δ and α4 subunit in the thalamus and suggest that the α4 subunit of the GABAAR plays a critical role in trafficking of the δ subunit to the neuronal surface. The findings also suggest that previously observed reductions in tonic inhibition in the α4 subunit KO mouse are likely to be related to alterations in δ subunit expression, in addition to loss of the α4 subunit. 相似文献
157.
Jeffrey W. Corbett Kevin D. Freeman-Cook Richard Elliott Felix Vajdos Francis Rajamohan Darcy Kohls Eric Marr Hailong Zhang Liang Tong Meihua Tu Sharad Murdande Shawn D. Doran Janet A. Houser Wei Song Christopher J. Jones Steven B. Coffey Leanne Buzon Martha L. Minich Kenneth J. Dirico Susan Tapley William Esler 《Bioorganic & medicinal chemistry letters》2010,20(7):2383-2388
Screening Pfizer’s compound library resulted in the identification of weak acetyl-CoA carboxylase inhibitors, from which were obtained rACC1 CT-domain co-crystal structures. Utilizing HTS hits and structure-based drug discovery, a more rigid inhibitor was designed and led to the discovery of sub-micromolar, spirochromanone non-specific ACC inhibitors. Low nanomolar, non-specific ACC-isozyme inhibitors that exhibited good rat pharmacokinetics were obtained from this chemotype. 相似文献
158.
Vidar Beisvag Frode KR Jünge Hallgeir Bergum Lars Jølsum Stian Lydersen Clara-Cecilie Günther Heri Ramampiaro Mette Langaas Arne K Sandvik Astrid Lægreid 《BMC bioinformatics》2006,7(1):470-13
Background
Modern biology has shifted from "one gene" approaches to methods for genomic-scale analysis like microarray technology, which allow simultaneous measurement of thousands of genes. This has created a need for tools facilitating interpretation of biological data in "batch" mode. However, such tools often leave the investigator with large volumes of apparently unorganized information. To meet this interpretation challenge, gene-set, or cluster testing has become a popular analytical tool. Many gene-set testing methods and software packages are now available, most of which use a variety of statistical tests to assess the genes in a set for biological information. However, the field is still evolving, and there is a great need for "integrated" solutions. 相似文献159.
Irrinki KM Mallilankaraman K Thapa RJ Chandramoorthy HC Smith FJ Jog NR Gandhirajan RK Kelsen SG Houser SR May MJ Balachandran S Madesh M 《Molecular and cellular biology》2011,31(18):3745-3758
Necroptosis represents a form of alternative programmed cell death that is dependent on the kinase RIP1. RIP1-dependent necroptotic death manifests as increased reactive oxygen species (ROS) production in mitochondria and is accompanied by loss of ATP biogenesis and eventual dissipation of mitochondrial membrane potential. Here, we show that tumor necrosis factor alpha (TNF-α)-induced necroptosis requires the adaptor proteins FADD and NEMO. FADD was found to mediate formation of the TNF-α-induced pronecrotic RIP1-RIP3 kinase complex, whereas the IκB Kinase (IKK) subunit NEMO appears to function downstream of RIP1-RIP3. Interestingly, loss of RelA potentiated TNF-α-dependent necroptosis, indicating that NEMO regulates necroptosis independently of NF-κB. Using both pharmacologic and genetic approaches, we demonstrate that the overexpression of antioxidants alleviates ROS elevation and necroptosis. Finally, elimination of BAX and BAK or overexpression of Bcl-x(L) protects cells from necroptosis at a later step. These findings provide evidence that mitochondria play an amplifying role in inflammation-induced necroptosis. 相似文献
160.