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51.
Tamer M. A. Mohamed Delvac Oceandy Sukhpal Prehar Nasser Alatwi Zeinab Hegab Florence M. Baudoin Adam Pickard Aly O. Zaki Raja Nadif Elizabeth J. Cartwright Ludwig Neyses 《The Journal of biological chemistry》2009,284(18):12091-12098
The cardiac neuronal nitric-oxide synthase (nNOS) has been described as a
modulator of cardiac contractility. We have demonstrated previously that
isoform 4b of the sarcolemmal calcium pump (PMCA4b) binds to nNOS in the heart
and that this complex regulates β-adrenergic signal transmission in
vivo. Here, we investigated whether the nNOS-PMCA4b complex serves as a
specific signaling modulator in the heart. PMCA4b transgenic mice (PMCA4b-TG)
showed a significant reduction in nNOS and total NOS activities as well as in
cGMP levels in the heart compared with their wild type (WT) littermates. In
contrast, PMCA4b-TG hearts showed an elevation in cAMP levels compared with
the WT. Adult cardiomyocytes isolated from PMCA4b-TG mice demonstrated a
3-fold increase in Ser16 phospholamban (PLB) phosphorylation as
well as Ser22 and Ser23 cardiac troponin I (cTnI)
phosphorylation at base line compared with the WT. In addition, the relative
induction of PLB phosphorylation and cTnI phosphorylation following
isoproterenol treatment was severely reduced in PMCA4b-TG myocytes, explaining
the blunted physiological response to the β-adrenergic stimulation. In
keeping with the data from the transgenic animals, neonatal rat cardiomyocytes
overexpressing PMCA4b showed a significant reduction in nitric oxide and cGMP
levels. This was accompanied by an increase in cAMP levels, which led to an
increase in both PLB and cTnI phosphorylation at base line. Elevated cAMP
levels were likely due to the modulation of cardiac phosphodiesterase, which
determined the balance between cGMP and cAMP following PMCA4b overexpression.
In conclusion, these results showed that the nNOS-PMCA4b complex regulates
contractility via cAMP and phosphorylation of both PLB and cTnI.Neuronal nitric-oxide synthase
(nNOS)5 is involved in
a number of key processes in cardiomyocytes including calcium cycling
(1), the β-adrenergic
contractile response (2,
3), post-infarct left
ventricular remodeling (4), and
the regulation of redox equilibrium
(5). Moreover, a polymorphism
in an nNOS-interacting protein, CAPON, has been found to form a quantitative
trait for the determination of the QT interval in humans
(6), whereas a mutation in
α1-syntrophin (SNTA1), another interacting partner of nNOS, has been
associated with long QT syndrome
(7). The signaling events
downstream of the nNOS-CAPON
(8) and nNOS-SNTA1
(7) complexes, which are
responsible for mediating cardiac repolarization and sodium current
respectively, have been elucidated. The nNOS-containing protein complex is
therefore of immediate relevance to human pathology.In recent years, we have shown that the sarcolemmal calcium pump, which
ejects calcium to the extracellular compartment (reviewed in Refs.
9 and
10), is an important molecule
involved in signal regulation and transmission in the heart
(11). We have demonstrated
that isoform 4b of the sarcolemmal calcium pump (also known as PMCA4b for
plasma membrane calcium/calmodulin-dependent
ATPase 4b) modulates signaling through a tight molecular
interaction with nNOS, leading to the modulation of β-adrenergic
responsiveness in the heart
(12). However, the events
following signaling through the PMCA4b-nNOS complex remain unknown.In myocardial cells, nNOS has been localized to the sarcolemma
(13), sarcoplasmic reticulum
(2), and mitochondria
(14), and translocation
between compartments has been demonstrated
(15). It has been speculated
that these various localizations provide specificity to NO signaling, but the
exact mechanisms have yet to be elucidated. In this study, we show a mechanism
by which one fraction of nNOS serves highly specific functions through binding
to PMCA4b. As PMCA4b is confined to the sarcolemma and is a calcium pump, it
is the first identified protein to fulfill these aggregate functions. 1) It
acts as an anchoring protein; 2) it regulates nNOS activity; and 3) it
modulates a process at the plasma membrane, i.e. β-adrenergic
signaling. 相似文献
52.
Masochistic dreams, as defined by Beck (1967), are reportedly more prevalent among women and individuals with past or present depression. However, it is unclear whether these prevalence differences are a function of depressogenic personality traits or fluctuating mood symptoms. In the present study, 30 men and 30 women without histories of major depression slept two consecutive nights in a sleep laboratory and reported their dreams from each REM period on the second night. Dream content from this sample was compared to that of 60 depressed participants who were studied previously under the same protocol. Analyses did not support a heightened prevalence of masochistic dreams among women or depressed individuals. Interestingly, the masochistic dreams of the non-depressed sample were equally distributed across the night, whereas depressed individuals tend to report masochistic dreams closer to morning. This hypothesized pattern suggests that masochistic dreams may be pathognomic of depression in that their occurrence near the end of the night affects morning mood with negative dream residue. 相似文献
53.
Properties of a simian virus 40 mutant T antigen substituted in the hydrophobic region: defective ATPase and oligomerization activities and altered phosphorylation accompany an inability to complex with cellular p53. 总被引:2,自引:10,他引:2
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L C Tack C A Cartwright J H Wright W Eckhart K W Peden A Srinivasan J M Pipas 《Journal of virology》1989,63(8):3362-3367
We have analyzed the biochemical properties of a nonviable simian virus 40 (SV40) mutant encoding a large T antigen (T) bearing an amino acid substitution (Pro-584-Leu) in its hydrophobic region. Mutant 5080 has an altered cell type specificity for transformation (transforming mouse C3H10T1/2 but not rat REF52 cells), is defective for viral DNA replication, and encodes a T that is unable to form a complex with the cellular p53 protein (K. Peden, A. Srinivasan, J. Farber, and J. Pipas, Virology 168:13-21, 1989). In this article, we show that 5080-transformed C3H10T1/2 cell lines express an altered T that is synthesized at a significantly higher rate but with a shorter half-life than normal T from wild-type SV40-transformed cells. 5080 T did not oligomerize beyond 5 to 10S in size compared with normal T, which oligomerized predominantly to 14 to 20S species. In addition, the 5080 T complex had significantly decreased ATPase activity and had a 10-fold-lower level of in vivo phosphorylation compared with that of normal T. Two-dimensional phosphopeptide analysis indicated several changes in the specific 32P labeling pattern, with altered phosphorylation occurring at both termini of the mutant protein compared with the wild-type T. Loss of p53 binding is therefore concomitant with changes in ATPase activity, oligomerization, stability, and in vivo phosphorylation of T and can be correlated with defective replication and restricted transformation functions. That so many biochemical changes are associated with a single substitution in the hydrophobic region of T is consistent with its importance in regulating higher-order structural and functional relationships in SV40 T. 相似文献
54.
R.K. Campbell G.L. Barnes B.O. Cartwright R.D. Eikenbary 《Journal of invertebrate pathology》1983,41(1):117-121
Naturally occurring isolates of two entomopathogenic fungi, Beauveria bassiana and Metarhizium anisopliae, pathogenic to the pecan weevil, Curculio caryae, were cultured in flasks of a liquid synthetic culture medium containing one of 22 individual carbohydrate sources to determine growth and sporulation responses. B. bassiana grew best on d-melizitose but sporulated best on d-sucrose, d-trehalose, and d-glucose. M. anisopliae grew best on d-mannose but sporulated best on i-inositol and glycerol. B. bassiana grew least on l-rhamnose but M. anisopliae grew least on d-arabinose. Both fungi sporulated least on d-sorbose. Both fungi utilized d-trehalose, a major component of insect hemolymph. 相似文献
55.
56.
57.
Distribution of Elements in Rat Peripheral Axons and Nerve Cell Bodies Determined by X-Ray Microprobe Analysis 总被引:2,自引:2,他引:0
Richard M. LoPachin Jr. Joan Lowery Joseph Eichberg Joel B. Kirkpatrick† Joiner Cartwright Jr. † Albert J. Saubermann† 《Journal of neurochemistry》1988,51(3):764-775
X-ray microprobe analysis was used to determine concentrations (millimoles of element per kilogram dry weight) of Na, P, Cl, K, and Ca in cellular compartments of frozen, unfixed sections of rat sciatic and tibial nerves and dorsal root ganglion (DRG). Five compartments were examined in peripheral nerve (axoplasm, mitochondria, myelin, extraaxonal space, and Schwann cell cytoplasm), and four were analyzed in DRG nerve cell bodies (cytoplasm, mitochondria, nucleus, and nucleolus). Each morphological compartment exhibited characteristic concentrations of elements. The extraaxonal space contained high concentrations of Na, Cl, and Ca, whereas intraaxonal compartments exhibited lower concentrations of these elements but relatively high K contents. Nerve axoplasm and axonal mitochondria had similar elemental profiles, and both compartments displayed proximodistal gradients of decreasing levels of K, Cl, and, to some extent, Na. Myelin had a selectively high P concentration with low levels of other elements. The elemental concentrations of Schwann cell cytoplasm and DRG were similar, but both were different from that of axoplasm, in that K and Cl were markedly lower whereas P was higher. DRG cell nuclei contained substantially higher K levels than cytoplasm. The subcellular distribution of elements was clearly shown by color-coded images generated by computer-directed digital x-ray imaging. The results of this study demonstrate characteristic elemental distributions for each anatomical compartment, which doubtless reflect nerve cell structure and function. 相似文献
58.
59.
Acute inhibition of PMCA4, but not global ablation,reduces blood pressure and arterial contractility via a nNOS‐dependent mechanism
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Sophronia Lewis Robert Little Florence Baudoin Sukhpal Prehar Ludwig Neyses Elizabeth J. Cartwright Clare Austin 《Journal of cellular and molecular medicine》2018,22(2):861-872
Cardiovascular disease is the world's leading cause of morbidity and mortality, with high blood pressure (BP) contributing to increased severity and number of adverse outcomes. Plasma membrane calcium ATPase 4 (PMCA4) has been previously shown to modulate systemic BP. However, published data are conflicting, with both overexpression and inhibition of PMCA4 in vivo shown to increase arterial contractility. Hence, our objective was to determine the role of PMCA4 in the regulation of BP and to further understand how PMCA4 functionally regulates BP using a novel specific inhibitor to PMCA4, aurintricarboxylic acid (ATA). Our approach assessed conscious BP and contractility of resistance arteries from PMCA4 global knockout (PMCA4KO) mice compared to wild‐type animals. Global ablation of PMCA4 had no significant effect on BP, arterial structure or isolated arterial contractility. ATA treatment significantly reduced BP and arterial contractility in wild‐type mice but had no significant effect in PMCA4KO mice. The effect of ATAin vivo and ex vivo was abolished by the neuronal nitric oxide synthase (nNOS) inhibitor Vinyl‐l ‐NIO. Thus, this highlights differences in the effects of PMCA4 ablation and acute inhibition on the vasculature. Importantly, for doses here used, we show the vascular effects of ATA to be specific for PMCA4 and that ATA may be a further experimental tool for elucidating the role of PMCA4. 相似文献
60.
Malcolm Parker Lindy Willmott Ben White Gail Williams Colleen Cartwright 《Journal of bioethical inquiry》2018,15(1):101-109
Over several decades, ethics and law have been applied to medical education and practice in a way that reflects the continuation during the twentieth century of the strong distinction between facts and values. We explain the development of applied ethics and applied medical law and report selected results that reflect this applied model from an empirical project examining doctors’ decisions on withdrawing/withholding treatment from patients who lack decision-making capacity. The model is critiqued, and an alternative “constitutive” model is supported on the basis that medicine, medical law, and medical ethics exemplify the inevitable entanglement of facts and values. The model requires that ethics and law be taught across the medical education curriculum and integrated with the basic and clinical sciences and that they be perceived as an integral component of medical evidence and practice. Law, in particular, would rank as equal in normative authority to the relevant clinical scientific “facts” of the case, with graduating doctors having as strong a basic command of each category as the other. The normalization of legal knowledge as part of the clinician’s evidence base to be utilized in practice may provide adequate consolation for clinicians who may initially resent further perceived incursions on their traditional independence and discretion. 相似文献