全文获取类型
收费全文 | 422篇 |
免费 | 20篇 |
国内免费 | 1篇 |
出版年
2024年 | 1篇 |
2023年 | 6篇 |
2022年 | 16篇 |
2021年 | 16篇 |
2020年 | 8篇 |
2019年 | 13篇 |
2018年 | 14篇 |
2017年 | 14篇 |
2016年 | 20篇 |
2015年 | 23篇 |
2014年 | 23篇 |
2013年 | 38篇 |
2012年 | 39篇 |
2011年 | 31篇 |
2010年 | 12篇 |
2009年 | 12篇 |
2008年 | 12篇 |
2007年 | 15篇 |
2006年 | 19篇 |
2005年 | 6篇 |
2004年 | 6篇 |
2003年 | 9篇 |
2002年 | 8篇 |
2001年 | 8篇 |
2000年 | 4篇 |
1999年 | 1篇 |
1998年 | 1篇 |
1997年 | 2篇 |
1996年 | 1篇 |
1995年 | 4篇 |
1994年 | 2篇 |
1993年 | 5篇 |
1992年 | 4篇 |
1991年 | 7篇 |
1990年 | 8篇 |
1989年 | 5篇 |
1988年 | 6篇 |
1987年 | 2篇 |
1986年 | 2篇 |
1985年 | 2篇 |
1984年 | 3篇 |
1983年 | 6篇 |
1980年 | 1篇 |
1977年 | 1篇 |
1976年 | 3篇 |
1975年 | 2篇 |
1973年 | 1篇 |
1971年 | 1篇 |
排序方式: 共有443条查询结果,搜索用时 718 毫秒
381.
382.
Dracheva S Elhakem SL Marcus SM Siever LJ McGurk SR Haroutunian V 《Journal of neurochemistry》2003,87(6):1402-1412
Serotonin 2C receptor (5-HT2CR) heterogeneity in the brain occurs mostly from two different sources: (i) 5-HT2CR mRNA undergoes adenosine-to-inosine editing events at five positions, which leads to amino acid substitutions that produce receptor variants with different pharmacological properties; (ii) 5-HT2CR mRNA is alternatively spliced, resulting in a truncated mRNA isoform (5-HT2CR-tr) which encodes a non-functional serotonin receptor. 5-HT2CR mRNA editing efficiencies and the expression of the full-length and the truncated 5-HT2CR mRNA splice isoforms were analyzed in the prefrontal cortex of elderly subjects with schizophrenia vs. matched controls (ns = 15). No significant differences were found, indicating that there are no alterations in editing or alternative splicing of 5-HT2CRs that are associated with schizophrenia in persons treated with antipsychotic medications. Quantitation of 5-HT2CR and 5-HT2CR-tr mRNA variants revealed that the expression of 5-HT2CR-tr was approximately 50% of that observed for the full-length isoform. 相似文献
383.
Hellberg MR Conrow RE Sharif NA McLaughlin MA Bishop JE Crider JY Dean WD DeWolf KA Pierce DR Sallee VL Selliah RD Severns BS Sproull SJ Williams GW Zinke PW Klimko PG 《Bioorganic & medicinal chemistry》2002,10(6):2031-2049
A series of prostaglandin DP agonists containing a 3-oxa-15-cyclohexyl motif was synthesized and evaluated in several in vitro and in vivo biological assays. The reference compound ZK 118.182 (9beta-chloro-15-cyclohexyl-3-oxa-omega-pentanor PGF(2alpha)) is a potent full agonist at the prostaglandin DP receptor. Saturation of the 13,14 olefin affords AL-6556, which is less potent but is still a full agonist. Replacement of the 9-chlorine with a hydrogen atom or inversion of the carbon 15 stereochemistry also reduces affinity. In in vivo studies ZK 118.182 lowers intraocular pressure (IOP) upon topical application in the ocular hypertensive monkey. Ester, 1-alcohol, and selected amide prodrugs of the carboxylic acid enhance in vivo potency, presumably by increasing bioavailability. The clinical candidate AL-6598, the isopropyl ester prodrug of AL-6556, produces a maximum 53% drop in monkey IOP with a 1 microg dose (0.003% w/w) using a twice-daily dosing regime. Synthetically, AL-6598 was accessed from known intermediate 1 using a novel key sequence to install the cis allyl ether in the alpha chain, involving a selective Swern oxidative desilylation of a primary silyl ether in the presence of a secondary silyl ether. In this manner, 136 g of AL-6598 was synthesized under GMP conditions for evaluation in phase I clinical trials. 相似文献
384.
The genetic factors that contribute to the development of coronary artery disease (CAD) are poorly understood. It is likely that multiple genes that act independently or synergistically contribute to the development of CAD and the outcome. Recently, an insertion/deletion (I/D) polymorphism of the human angiotensin I-converting enzyme (ACE) gene, a major component of the reninangiotensin system (RAS), was identified. The association of the ACE gene D allele with essential hypertension and CAD has been reported in the African-American, Chinese, and Japanese populations. However, other studies have failed to detect such an association. It has been suggested that these inconsistencies may be due to the difference in backgrounds of the population characteristics. In the present study, we investigated the I/D polymorphism of the ACE gene in 103 subjects of both sexes, consisting of 59 normal controls and 44 patients with hypertension. The allele and genotype frequency were significantly different between the hypertensive and control groups (p < 0.01). Among the three ACE I/D variants, the DD genotype was associated with the highest value of the mean systolic blood pressure [SBP] and mean diastolic blood pressure [DBP] (p = < 0.05) in men, but not in women. In the overall population, the mean SBP and DBP was highest in DD subjects, intermediate in I/D subjects, and the least in II subjects 相似文献
385.
Oxidative stress induced by hydrogen peroxide (H2O2) may contribute to the pathogenesis of ischemic-reperfusion injury in the heart. For the purpose of investigating directly the injury potential of H2O2 on heart muscle, a cellular model of H2O2-induced myocardial oxidative stress was developed. This model employed primary monolayer cultures of intact, beating neonatal-rat cardiomy-ocytes and discrete concentrations of reagent H2O2 in defined, supplement-free culture medium. Cardiomyocytes challenged with H2O2 readily metabolized it such that the culture content of H2O2 diminished over time, but was not depleted. The consequent H2O2-induced oxidative stress caused lethal sarcolemmal disruption (as measured by lactate dehydrogenase release), and cardiomyocyte integrity could be preserved by catalase. During oxidative stress, a spectrum of cellular derangements developed, including membrane phospholipid peroxidation, thiol oxidation, consumption of the major chain-breaking membrane antiperoxidant (α-tocopherol), and ATP loss. No net change in the protein or phospholipid contents of cardiomyocyte membranes accompanied H2O2-induced oxidative stress, but an increased turnover of these membrane constituents occurred in response to H2O2. Development of lethal cardiomyocyte injury during H2O2-induced oxidative stress did not require the presence of H2O2 itself; a brief “pulse” exposure of the cardiomyocytes to H2O2 was sufficient to incite the pathogenic mechanism leading to cell disruption. Cardiomyocyte disruption was dependent upon an intracellular source of redox-active iron and the iron-dependent transformation of internalized H2O2 into products (e.g., the hydroxyl radical) capable of initiating lipid peroxidation, since iron chelators and hydroxyl-radical scavengers were cytoprotective. The accelerated turnover of cardiomyocyte-membrane protein and phospholipid was inhibited by antiperoxidants, suggesting that the turnover reflected molecular repair of oxidized membrane constituents. Likewise, the consumption of α-tocopherol and the oxidation of cellular thiols appeared to be epiphenomena of peroxidation. Antiperoxidant interventions coordinately abolished both H2O2-induced lipid peroxidation and sarcolemmal disruption, demonstrating that an intimate pathogenic relationship exists between sarcolemmal peroxidation and lethal compromise of cardiomyocyte integrity in response to H2O2-induced oxidative stress. Although sarcolemmal peroxidation was causally related to cardiomyocyte disruption during H2O2-induced oxidative stress, a nonperoxidative route of H2O2 cytotoxicity was also identified, which was expressed in the complete absence of cardiomyocyte-membrane peroxidation. The latter mode of H2O2-induced cardiomyocyte injury involved ATP loss such that membrane peroxidation and cardiomyocyte disruption on the one hand and cellular de-energization on the other could be completely dissociated. The cellular pathophysiology of H2O2 as a vectorial signal for cardiomyocyte necrosis that “triggers” irreversible peroxidative disruption of the sarcolemma has implications regarding potential mechanisms of oxidative injury in the postischemic heart. 相似文献
386.
387.
The pharmacological basis of glutamate-induced [3H]D-aspartate release was investigated in isolated human, bovine and rabbit retinas. Isolated mammalian retinas were preloaded with [3H]D-aspartate and then prepared for studies of neurotransmitter release using the superfusion method. Release of [3H]D-aspartate was elicited by K+ (50 mM) or by L-glutamate. In bovine retinas, L-glutamate, but not D-glutamate induced an overflow of [3H]D-aspartate that was partially inhibited by low external calcium, -conotoxin (10 nM) or nitrendipine (1 M). Metabotropic glutamate receptor (GLUR) agonists also evoked [3H]D-aspartate release in both bovine and human retinas whereas polyamines only enhanced the excitatory effects of L-glutamate on [3H]D-aspartate release. Antagonists of GLURs and the polyamine site inhibited L-glutamate evoked [3H]D-aspartate overflow with the following rank order of potency: MCPG >ifenprodil > AP-5 > arcaine> MK-801. In conclusion, L-glutamate-induces a stereoselective, calcium-dependent release of [3H]D-aspartate from isolated mammalian retinas that can be mimicked by GLUR agonists (and blocked by both receptor and polyamine site antagonists). 相似文献
388.
Mohammad S Qureshi David J Midmore Shamsa S Syeda Christina L Playford 《Australian Journal of Entomology》2007,46(4):313-319
Abstract In zucchini, the use of row covers until flowering and the insect growth regulator (IGR) pyriproxyfen are effective methods of reducing the number of insects, especially silverleaf whitefly ( Bemisia tabaci (Gennadius) Biotype B), on plants. We compared floating row covers (FRCs) up until flowering with silverleaf whitefly (SLW) introduced (FRC + SLW), or not introduced (FRC-only), or with introduction of SLW in open plots (SLW-only), or with introduction of SLW in open plots with IGR (SLW + IGR). FRC increased temperature and humidity compared with the uncovered treatments. Average fruit weight was less ( P < 0.01) for the FRC + SLW treatment compared with the other treatments and the percentage of marketable fruit was less for the FRC + SLW than for the other three treatments. This result indicates that the use of either row covers or IGR controls whiteflies, reduces fruit damage and increases the size, weight, and quality of fruit, and may also control other sap-sucking insects. However, if SLW are already present on plants, the use of FRC may reduce predation and favour build up of SLW. Thus, FRC and IGR, if used judiciously, may provide an effective alternative to broad-spectrum pesticides in small-scale cucurbit production. 相似文献
389.
Kamaldeen A. Muili Dong Wang Abrahim I. Orabi Sheharyar Sarwar Yuhuan Luo Tanveer A. Javed John F. Eisses Syeda M. Mahmood Shunqian Jin Vijay P. Singh Meena Ananthanaravanan George Perides John A. Williams Jeffery D. Molkentin Sohail Z. Husain 《The Journal of biological chemistry》2013,288(1):570-580
Biliary pancreatitis is the leading cause of acute pancreatitis in both children and adults. A proposed mechanism is the reflux of bile into the pancreatic duct. Bile acid exposure causes pancreatic acinar cell injury through a sustained rise in cytosolic Ca2+. Thus, it would be clinically relevant to know the targets of this aberrant Ca2+ signal. We hypothesized that the Ca2+-activated phosphatase calcineurin is such a Ca2+ target. To examine calcineurin activation, we infected primary acinar cells from mice with an adenovirus expressing the promoter for a downstream calcineurin effector, nuclear factor of activated T-cells (NFAT). The bile acid taurolithocholic acid-3-sulfate (TLCS) was primarily used to examine bile acid responses. TLCS caused calcineurin activation only at concentrations that cause acinar cell injury. The activation of calcineurin by TLCS was abolished by chelating intracellular Ca2+. Pretreatment with 1,2-bis(o-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid (acetoxymethyl ester) (BAPTA-AM) or the three specific calcineurin inhibitors FK506, cyclosporine A, or calcineurin inhibitory peptide prevented bile acid-induced acinar cell injury as measured by lactate dehydrogenase leakage and propidium iodide uptake. The calcineurin inhibitors reduced the intra-acinar activation of chymotrypsinogen within 30 min of TLCS administration, and they also prevented NF-κB activation. In vivo, mice that received FK506 or were deficient in the calcineurin isoform Aβ (CnAβ) subunit had reduced pancreatitis severity after infusion of TLCS or taurocholic acid into the pancreatic duct. In summary, we demonstrate that acinar cell calcineurin is activated in response to Ca2+ generated by bile acid exposure, bile acid-induced pancreatic injury is dependent on calcineurin activation, and calcineurin inhibitors may provide an adjunctive therapy for biliary pancreatitis. 相似文献
390.